Transforming patient care through translational research in hormone receptor positive breast cancer Professor Erik Knudsen University of Arizona Cancer Center Tucson, United States Professor Aleix Prat Hospital Clinic of Barcelona Barcelona, Spain 170271
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Transforming patient care through translational research in hormone receptor positive
breast cancer
Professor Erik Knudsen
University of Arizona Cancer Center
Tucson United States
Professor Aleix Prat
Hospital Clinic of Barcelona
Barcelona Spain
170271
Disclaimer
ldquoThe statements views and opinions contained in this symposium are
those of the authors and are not endorsed by nor do they necessarily
reflect the opinions of Pfizerrdquo
ldquoThis symposium contains information on investigational products in
development from a research perspective The information aims to be
truthful accurate balanced fair and not misleading It is supported by
relevant scientific data and is non-promotionalrdquo
Agenda
The many faces of CDK46 inhibition
Erik Knudsen
10 minute introduction to the keynote presentation
Transforming patient care through translational research for
HR+ breast cancer
Aleix Prat
40 minute keynote presentation with audience questions
Audience questions and discussion
Closing remarks
Question cards are provided or please raise your hand
Remember to complete your evaluation form
The many faces of CDK46 inhibition
Professor Erik Knudsen
University of Arizona Cancer Center
Tucson United States
170271
Disclosures
Applicability Company
(1) Advisory role Yes Pfizer Eli Lilly
HTG Diagnostics Novartis
(2) Stock ownershipprofit None
(3) Patent royaltieslicensing fees None
(4) Lecturespeaker engagement fees Yes Pfizer Eli Lilly
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
to fulvestrant alone [41] Future follow-up with these
patients may ultimately determine if this combination
increases overall survival in patients with ER mutations
In support of this hypothesis we demonstrate that our ER
Figure 7 Effica cy of palbociclib or everolimus with fulvestrant in a MCF7-Y537SKO background A-B Combination
therapies of fulvestrant (Ful) with either palbociclib (Palbo) or everolimus (Eve) were performed in nude mice All treatments were dosed
in the same experiment and separated for clarity N = 11 Bars represent SEM Relative to vehicle fulvestrant TGI = 52 p = 00118
palbociclib TGI = 62 p = 00032 Palbo+Ful = 5 regression p lt 00001 everolimus TGI = 50 p = 00177 Eve+Ful TGI = 76 p
= 00002
Combination with
Fulvestrant
Combination with
SERD (Bazedoxifine)
Contr
ol
CDT
01micro
M P
D
CDT+0
1microM
PD
1 microM
PD
CDT+1
0microM
PD
0
10
20
30
40
B
rdU
Po
sitiv
e
Cooperation with
Estrogen withdrawal
Positive interactions between endocrine therapy and CDK46 inhibition
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Modified from Johnstone RW et al Nat Rev Drug Discov 20021(4)287-99
ENCORE301 N=130 exemestane +- entinostat
Randomized Phase II study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic ER+ breast cancer
Yardley DA et al J Clin Oncol 201331(17)2128-35
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
Efficacy of immune checkpoint inhibitors in breast cancer
Study Subtype PDL1 IHC Drug ORR (95 CI)
Keynote-012
(Nanda JCO 2016) TNBC gt1
Pembrolizumab
(PD1) 185 (63-381)
Emens
(AACR 2015) TNBC IHC 2-3
Atezolizumab
(PDL1) 24 (8-47)
Javelin
(Dirix SABCS
2015)
ER+TNBC
HER2+ Any
Avelumab
(PDL1) 54 (25-99)
Keynote -028
(Rugo SABCS
2015)
ER+ gt1 Pembrolizumab
(PD1) 12 (25-312)
N=2009 N=1079 N=297 N=256
Tumour infiltrating lymphocytes (TILs) in breast cancer
Loi S et al J Clin Oncol 201331(7)860-7
Patients with CD8+ T cell infliltration le 10 at the 3 weeks biopsy
Patients treated as per
Investigator
End of participation in
the study
c
ULTIMATE TRIAL DESIGN
NCT02997995 PI Fabrice ANDRE
Take-home messages
bull HR+ is biologically heterogeneous at the DNA RNA and protein level further
subclassifications are needed
bull At the RNA level 4 molecular subtypes (LumA LumB HER2-E and Basal-like) can be
identified within HR+HER2-negative disease
bull Targeting the cell-cycle in luminal disease is a promising strategy
ndash CDK46 inhibition seems to be a maintenance therapy like endocrine therapy
ndash CDK46 inhibition monotherapy might be a strategy to pursue in some settings
ndash CDK46 inhibition might be a promising treatment strategy within HR+HER2+ disease (luminal-type)
ndash Currently no molecular biomarkers have been validated to predict CDK46 inhibition survival benefit
bull At the DNA level at least 3 somatic (PIK3CA ESR1 and ERBB2) mutations are promising
bull Targeting acetylation of histones with HDAC inhibitors is also a promising treatment
strategy in combination with endocrine therapy A Phase III trial is ongoing
bull At the microenvironment level immune infiltration (eg CD8 TILs) is infrequent and anti-
PD1PDL1 monotherapy is showing weak results
Thank you
Discussion
Please raise your hand if you have a question
Remember to complete your evaluation form
Closing remarks
Erik Knudsen
Remember to complete your evaluation form
PALOMA2 PALOMA3 MONALEESA-2
FDA-Approval in HR+HER2-
Breast Cancer
Palbociclib
Ribociclib
Abemaciclib Palbociclib
Preferential sensitivity in HR+ 0
10
20
30
40
5
0 6
0
7
0
Ki6
7
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
PIK3CA Mutant
PIK3CA WT PIK3CA Mutant (n=16) PIK3CA WT (n=26)
Ki6
7
Ki6
7
0
10
20
30
40
5
0 6
0
7
0
0
10
20
30
40
5
0 6
0
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
0
1
0
20 3
0
40 5
0
60
7
0
Ki6
7
Ki6
7
Ki6
7
LumA
LumB
LumA (n=15) LumB (n=11)
C0D1 C1D1 C1D15 C0D1 C1D1 C1D15 C0D1 C1D1 C1D15
Ki6
7
C0D1 C1D1 C1D15 Surgery
0
10
20
3
0
40
5
0
60
70
Cycle 5
No Cycle 5
C0D1 C1D1 C1D15 Surgery 0
10
20
3
0
40
50
60
70
Ki6
7
Ki6
7
0
10
20 3
0 4
0 50
60
70
No Cycle 5 Cycle 5
C0D1 C1D1 C1D15 Surgery
A B C
D E F
G H I
Fig 1
Research on April 20 2017 copy 2017 American Association for Cancerclincancerresaacrjournalsorg Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited Author Manuscript Published OnlineFirst on March 7 2017 DOI 1011581078-0432CCR-16-3206
NeoPalAna
Improved progression-free survival in combination with letrozolefulvestrant
Multiple clinical trials
Finn et al 2016 N Engl J Med
Turner et al 2015 N Engl J Med
Hortobagyi et al 2016 N Engl J Med
DeMichele et al 2015 Clin Can Res
Patnaik 2016 Cancer Discovery
Ma et al 2017 Clin Can Res
Complete Cell Cycle Arrest (Ki67lt27)
Anastrazole C1D1 26
Anstrazole+Palbociclib C1D15 87 plt0001)
Abemaciclib and ribociclib are not approved in EU
Rapid progression
Making response more durable
Next steps for treatment
Key questions related to CDK46 inhibition in breast cancer
Turner et al 2015 N Engl J Med
Pro
ba
bili
ty o
f p
rogre
ssio
n-f
ree s
urv
iva
l (
)
Months
100
90
80
70
60
50
40
20
20
10
0
0 2 4 6 8 10 12
Placebondashfulvestrant (N=174)
Median progression-free survival
38 mo (95 CI 35ndash55)
Palbociclibndashfulvestrant (N=347)
Median progression-free survival
92 mo (95 CI 75ndashNE)
Hazard ratio 042 (95 CI 032ndash056)
Plt0001
Efficacy beyond
HR+HER2-
Biomarkers for use of CDK46 inhibitors
bull Only biomarker routinely used is hormone-receptor positivity
bull There are markers of intrinsic resistance to CDK46 inhibition
ndash Loss of RB and over expression of p16
ndash Very rare in resectedprimary HR+HER2- disease (~1)
Witkiewicz et al 2012 Cell Cycle
Lefebvre C et al 2017 Plos Med
Cohen et al 2016 SABCS Oral Presentation
RB Ki67 +DMSO Ki67 +PD
Sensitive
Resistant
p16ink4a
More common RB loss
in endocrine therapy resistant
metastatic disease
Genetic Events
Acquiredselected Genetic events
Evolution to resistance
RB loss Cyclin E CDK6 amplification
Therapy
Nature of progressive disease with CDK46 inhibition
Herrera-Abreu et al 2016 Cancer Res
Knudsen et al 2017 Trends in Cancer
Jansen et al 2017 Cancer Res
Limited analysis of disease that has progressed on treatment
ndash Insights into next line of treatment
ndash Insights into combination therapy
Adaptive signals
Signaling pathways
Reduce response to CDK46 inhibition
PI3K PDK1 AKT MTOR
CDK4 or CDK6
Cyclin D
Adaptive Responses Acquired Resistance
RB RB
P
CDK46 Inhibitor
PI3K
AKT mTOR
PDK1
CDK2
Cyclin D
CDK2
Cyclin E
Preclinical models support
ndash PI3K inhibitors
ndash MTOR inhibitors
ndash PDK1 inhibitors
Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With
ER+HER2- Breast Cancer
PIPA Combination of PI3 Kinase Inhibitors and PAlbociclib (PIPA)
Phase Ib Trial of LEE011 With Everolimus (RAD001) and Exemestane in the Treatment of
Hormone Receptor Positive HER2 Negative Advanced Breast Cancer
Study of LEE011 BYL719 and Letrozole in Advanced ER+ Breast Cancer
Combinations with CDK46 inhibition (triplet therapy)
Investigational drugs not approved in the EU
Vora et al 2014 Cancer Cell
Herrera-Abreu et al 2016 Cancer Res
Jansen et al 2017 Cancer Res
Other breast cancer indications
Witkiewicz et al 2014 Genes and Cancer
Goel et al 2016 Cancer Cell
Geng et al 2002 Nature
Turner and Rheis-Filo 2013 Clin Can Res
Clinical trialsgov
HER2+ breast cancer
Potent activity in preclinical models
Genetic dependence for cyclin D1
Positive combinatorial interactions
An Open-Label Phase IbII Clinical Trial Of
CDK 46 Inhibitor Ribociclib (Lee011) In
Combination With Trastuzumab Or T-Dm1 For
AdvancedMetastatic Her2-Positive Breast
Cancer
Study of Palbociclib and Trastuzumab With or
Without Letrozole in HER2-positive Metastatic
Breast Cancer (PATRICIA)
Study of Palbociclib and T-DM1 in HER2-
positive Metastatic Breast Cancer Her2
HER2CCND1-
HER2CCND1+
CONTROL PD0
10
20
30
40
Phh3-PD
Legend
Legend
Legend
Legend
Legend
Legend
Legend
Select TNBC subtypes
Generally resistant (clinical experience)
However specific subtypeshellip
Phase III trial of palbociclib in combination with
bicalutamide for the treatment of androgen
receptor (AR)+ metastatic breast cancer
(MBC)
Ribociclib and Bicalutamide in AR+ TNBC
A Phase 2 Study of Abemaciclib for Patients
With Retinoblastoma-Positive Triple Negative
Metastatic Breast Cancer
pH
H3
Investigational drugs not approved in HER2+ disease
Summary
bull Development of CDK46 inhibitors was built upon a strong basis of investigation in
cell cycle control---yeast to man
bull The use of CDK46 inhibitors in HR+HER2- breast cancer followed off preclinical
data indicating ldquoexceptional sensitivityrdquo in this form of disease
bull Clinical activity related to positive interaction between CDK46 inhibition and
endocrine therapy
bull Predictive biomarkers are still in ldquoearly developmentrdquo but interrogation of RB-
pathway could be considered to define non-responders
bull Knowledge of progressed disease will be important to delineate subsequent
treatments and combination approaches to enhance durability of response
bull Multiple ongoing clinical studies are interrogating CDK46 inhibitors beyond
HR+HER2- breast cancer with endocrine therapies
Questions
Keynote presentation and discussion
bull Biological complexity of HR+ breast cancer ndash Discussion (5 minutes)
bull CDK46 inhibitors in the treatment of breast cancer ndash Discussion (5 minutes)
bull Signalling pathways epigenetics and immunotherapy
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
Phase II trial comparing chemotherapy to letrozole + palbociclib in PAM50 luminal breast cancer in postmenopausal women (NeoPAL TRIAL PIs Dr Delaloge and Dr Cottu)
Postmenopausal
Untreated Stage II-III
HR+HER2-
AND
PAM50 LumB
Biopsies PAM50 + RNADNA-seq
Letrozole 25 mg +
Ribociclib 600 mg
TREATMENT
S
U
R
G
E
R
Y
RCB 0-1
6 months
N=94
AC ndashgt Paclitaxel
11
Phase II Trial of chemotherapy or letrozole plus ribociclib in PAM50 Luminal BHER2ndash breast cancer (CORALEEN TRIAL PIs Dr Prat and Dr Gavilaacute)
Ribociclib is not approved for use in early BC httpswwwclinicaltrialsregistereuctr-searchtrial2016-003098-17ES
Can we target HR+HER2+ disease
with CDK46 inhibition
Intrinsic subtype distribution within clinically HER2ndash and HER2+ disease
Prat A et al J Natl Cancer Inst 2014106(8)
Luminal B
HER2-enriched
Basal-like
HER2+ cell lines
CDK46 inhibition in HER2+ breast cancer cell lines
Finn RS et al Breast Cancer Res 200911(5)R77
HR+HER2+
N=1648
HR-HER2+
N=1213
360
318
300
22
751
148
74 27
Intrinsic subtype distribution within clinically HER2+ disease based on HR status
Combined analyses of reported datasets Cejalvo et al unpublished
MonarcHER Phase Ib study of abemaciclib in combination with therapies for patients with mBC
Primary objective
bull Evaluate safety and tolerability
of abemaciclib in combination
with endocrine therapies for
HR+HER2ndash mBC or with
trastuzumab for HER2+ mBC
Secondary objectives
bull Pharmacokinetics
bull Anti-tumour activity
Abemaciclib is not approved for use in mBC
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Part A abemaciclib + letrozole
Part B abemaciclib + anastrozole
Part C abemaciclib + tamoxifen
Part D abemaciclib + exemestane
Part E abemaciclib + exemestane +
everolimus
HR+HER2ndash
mBC
Part F abemaciclib + trastuzumab HER2+
mBC
Key eligibility criteria
bull HR+HER2ndash mBC (parts AndashE) or
HER2+ (both HR+ and HRndash) mBC
(part F)
bull Post-menopausal status (natural
surgical or medical parts AndashE) or
any menopausal status (part F)
bull Parts AndashE no prior systemic
chemotherapy for metastatic disease
bull Part F ge1 chemotherapy regimen for
metastatic disease
bull Patients receiving exemestane-
based therapy must have received
ge1 nonsteroidal aromatase inhibitor
for metastatic disease
Abemaciclib combinations show clinical activity in HR+ mBC including HR+HER2+ tumours
Change in tumour size for patients with measurable disease HER2+ mBC
100
50
0
ndash50
ndash100
Change f
rom
baselin
e (
)
20 increase
30 decrease
-
-
- + + + + + + +
+ +
+
+ =HR+ ndash =HRndash
Abemaciclib
+ letrozole
Part A (n = 8)
Abemaciclib
+ anastrozole
Part B (n = 8)
Abemaciclib
+ tamoxifen
Part C (n = 7)
Abemaciclib
+ exemestane
Part D (n = 8)
Abemaciclib
+ exemestane
+ everolimus
Part E (n = 10)
Abemaciclib
+ trastuzumab
Part F (n = 13)
MonarcHER Anti-tumour activity
Abemaciclib is not approved for use in mBC
Truncated at 100
HER2 human epidermal growth factor receptor-2 HR hormone receptor mBC metastatic breast cancer Beeram M et al Abstract LBA18 Presented at ESMO 2016
Phase II trial of neo-adjuvant treatment with palbociclib (NA-PHER2 trial PI Dr Gianni)
Palbociclib is not approved for use in HER2+ disease
BC breast cancer ER oestrogen receptor HER2 human epidermal growth factor receptor-2
ORR objective response rate pCR pathological complete response defined as absence of invasive
cells in breast and axilla (ypT0-ypTis ypN0) at surgery PR progesterone receptor QD daily
H = Herceptintrastuzumab 8 mgkg on first dose 6 mgkg thereafter x 6
P = Pertuzumab 840 mg on first dose 420 mg thereafter x 6
Palbociclib 125 mg orally QD x 21 q 4 wks x 5
Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with
an additional 500 mg dose given two weeks after the initial dose
The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and
fulvestrant (5 administrations every 4 weeks plus the additional dose given two
weeks after the initial dose) was selected to match as closely as possible the total
duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab
HER-2 ER PR and
Ki67 centrally confirmed
Primary endpoints
bull Ki67 changes from
baseline before
therapy at 2
weeks and at
surgery
bull Change in
apoptosis from
baseline before
therapy and at
surgery
Secondary
endpoints
bull pCR
bull ORR
bull Tolerability
NA-PHER2 Pathological and clinical response rate
ITT population (n = 30) n ()
pCR (no invasive cells in breast and axilla)
pCR in breast only
8 (27)
9 (30)
Overall clinical response
bull Complete clinical response
bull Partial response
bull Stable disease
29 (97)
15 (50)
14 (47)
3 (3)
HER2 human epidermal growth factor receptor-2 ITT intent to treat pCR pathological complete response
defined as absence of invasive cells in breast and axilla (ypT0-ypTis ypN0) at surgery
Gianni L et al SABCS 2016 Poster P4-21-39
NCT02530424 Clinicaltrialsgov
Palbociclib is not approved for use in HER2+ disease
Phase II trial of palbociclib and trastuzumab with or without letrozole in HER2+ ABC (PATRICIA Trial PI Dr Ciruelos)
Palbociclib is not approved for use in HER2+ disease
ECOG PS Eastern Cooperative Oncology Group performance status ERndash oestrogen receptor-negative ER+ oestrogen receptor-positive
HER2+ human epidermal growth factor receptor-positive LVEF left ventricular ejection fraction Q3W every 3 weeks R randomised NCT02448420 Clinicaltrialsgov
Enrolment criteria
bullHER2+
bullProgressive or recurrent
locally advanced or
metastatic breast cancer
bullHormone receptor
statues known
bullAt least 2 (maximum 4)
prior lines of treatment for
metastatic breast cancer
including chemotherapy
and trastuzumab
treatment
bullECOG PS 0ndash1
bullLVEF ge50
bullPostmenopausal
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule) +
letrozole 25 mgday
R
N=138
Primary endpoint
bullProgression-free survival at 6
months
Secondary endpoints
bullClinical benefit rate
bullObjective response rate
bullProgression-free survival
bullOverall survival
bullBiomarkers (expression levels
of 110 genes)
bullSafety and cardiac profile
HER2+
ERndash
Trastuzumab 8 mgkg (first dose) and 6
mgkg Q3W
+ palbociclib 200 mgday (21 schedule)
HER2+
ER+
Aim to identify if palbociclib is efficacious in combination with trastuzumab for postmenopausal patients with previously treated HER2+ mBC
Discussion
CDK46 inhibitors in the
treatment of breast cancer
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70
mRNA microRNA Protein
DNA Copy Number DNA Methylation DNA Mutations
tumour cells features1 disease today
HER2 +3 HER2 ISH+
Ki67-low Ki67-high
tumour
microenvironment
Tumor
Infiltrating
Lymphocytes
(TILs)
Courtesy of Dr Pedro Fernaacutendez
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
AP1 or SP1
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Drug Pharma Source Target(s)
BYL719 Novartis PI3Kα
GDC-0032 Genentech PI3Kα
MLN-1117 Millenium PI3Kα
CAL-101 Calistoga PI3Kd
XL-147 ExelixisSanofi Pan-PI3K
BKM120 Novartis Pan-PI3K
GDC-0941 Genentech Pan-PI3K
PKI-587 Pfizer Pan-PI3K
XL-765 ExelixisSanofi PI3KmTOR
BEZ235 Novartis PI3KmTOR
GDC-0980 Genentech PI3KmTOR
PF-4691502 Pfizer PI3KmTOR
MLN-128 Millenium TORC12
OSI-027 OSI Pharma TORC12
AZD2014 AstraZeneca TORC12
AZD5363 AstraZeneca AKT (catalytic)
MK-2206 Merck AKT (allosteric)
GDC-0068 Genentech AKT (catalytic)
PI3KmTOR inhibitors
in clinical development
Taselisib
Alpelisib
Courtesy of Dr Johnston
BYL719 (alpelisib) monotherapy
PI3K inhibition results in enhanced ER function and dependence in HR+ breast cancer
Bosch A et al Sci Transl Med 20157(283)283
Breast cancer HR+HER2-
locally advanced or metastatic
Postmenopausal
Recurrent or progression
during or after an aromatase
inhibitor
Stratification
1) Visceral disease
2) Endocrine sensitivity
3) Geographic region
480 Patients
with a PIK3CA
mutation
120 Patients
without a
PIK3CA
mutation
Taselisib 4 mg 1
vd + Fulvestrant
Placebo 1 vd +
Fulvestrant
Taselisib 4 mg QD
+ Fulvestrant
Placebo QD +
Fulvestrant
21 randomization
21 randomization
Treatment
until
progression of
disease or
unacceptable
toxicity
No cross-over
Main endpoint PFS in patients
with a PIK3CA mutation
SANDPIPER Phase III clinical trial (NCT02340221)
httpsclinicaltrialsgovct2showNCT02340221
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2
MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Interaction
P=007
ESR1 mutations might predict Fulvestrant vs AI survival benefit in HR+ metastatic breast cancer
Retrospective analyses from SoFEA Phase III trial (n=161723)
Fulvestrant-containing regimen vs Exemestane
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
GDC-0810 a novel non-steroidal orally SERD better inhibits mutant ERα than Fulvestrant
Joseph JD et al Elife 2016 Jul 135 pii e15828
NCT01823835 Phase III GDC-0810 +- palbociclib
NCT02569801 Phase II GDC-0810 vs fulvestrant
Tu
mo
r vo
lum
e (
mm
3)
Days post start of treatment
0 7 14 21 28
0
200
400
600
800
1000
Vehicle (-E2)
Tamoxifen 60mgkg
Fulvestrant 200mgkg
GDC-0810 100mgkg
MCF-7HA-ERY537S
ESR1 mutations do not predict palbociclib survival benefit in HR+ metastatic breast cancer
Retrospective Analyses from PALOMA3 Phase III trial (n=360521)
Fulvestrant +- Palbociclib
Fribbens C et al J Clin Oncol 201634(25)2961-8
ESR1-mut ESR1-WT
Interaction
P=074
The estrogen receptor (ER) signaling pathway
Adapted from Ma CX et al Nat Rev Cancer 201515(5)261-75
Estradiol
ERE
AP1 or SP1
CoA
CoA CoR ERE
Transcription
Transcription Transcription
Proliferation
PI3K
AKT
mTOR
RAS
RAF
MEK
MAPK
GRFs
GRB2
N
O
T
C
H
IGF1R EGFR HER2 MET FGFR
p38 JNK
CoA
Cytokines hypoxia stress
Cytosol
Nucleus
Freq 2-23
Response N
CR 5 143
PR 9 257
ORR 14 400
Preliminary analysis SUMMIT phase II trial
NERATINIB +- fulvestrant (N=35)
Activating HER2 mutations in HR+HER2ndash breast cancer
Bose et al Cancer Discovery 2013 Hyman D et al Presented at SABCS 2016 [PD1-08]
The biological complexity of HR+ breast cancer
1 Cancer Genome Atlas Network Nature 2012490(7418)61-70