Novel Therapies for Triple Negative, HER2+ and ER+ Breast ......HER2+ Breast Cancer Following Adjuvant Trastuzumab: Risk of Locoregional or Distant Recurrence Approximately 20% of

Novel Therapies for Triple Negative, HER2+ and ER+ Breast Cancer

Joyce O’Shaughnessy, MDCelebrating Women Chair in Breast Cancer Research

Baylor University Medical CenterTexas Oncology

US OncologyJoyce O’Shaughnessy, MD

Nature, 2012

Subtypes of TNBC and targeted therapy selection

Basal1Basal2

ImmuneModule

Mesenchymal

MesenchymalStem-like

Luminal Apocrine

Cell cycle, DNA damageGFR, glycolysis, p63

B/TCR, cytokines, JAK/STAT

ECM receptorsTGF-βRhoWnt/β-CatEMT

Stem cell markers

Luminal CK’sARFOXA1XBP1

Lehmann BD et. al. J Clin Invest 2011 121(7): 2750

Summary – Triple Negative Breast Cancer

§ Systemic neo/adjuvant chemotherapy• Adjuvant anthracycline (TaxAC vs 6TC) improves DFS in TNBC• Addition of carboplatin to paclitaxel improves pCR rate with as yet

unknown effects on DFS – reasonable for high risk pts• In patients who do not develop a pCR with preoperative chemotherapy,

adjuvant treatment with capecitabine is a reasonable option

§ Promising Approaches• Nab paclitaxel/carboplatin first-line metTNBC• PARP inhibitors gBRCA pts• AKT inhibitors• AR inhibitors • PD-1/PD-L1 inhibitors

4

ABC Trials SchemaNode+ or High Risk Node-Negative

Stratification Variables Number of + Nodes (0, 1-3, 4-9, 10+); Hormone Receptor (ER or PgR+, Both

Negative)

TAC q 3 wk

AC q 2 wk PTX q 2 wk

A

B AC q 3 wk PTX q 1 wk

AC q 2 wk PTX q 1 wkC

D

ARM 1 (TaxAC Options) ARM 2 (TC)

Arm 1 Options Per Study• USOR 06-090 - 1A only• NSABP B-46I/USOR 07132 - 1A only• NSABP B-49 - investigator choice 1A-

1D

Endocrine therapy for ER+ or PgR+ patients for minimum of 5 years

Presented by: Joanne L. Blum, MD, PhD.

TC q 3 wk

ABC Trials: Invasive Disease Free Survival


Years from Randomization

0 1 2 3 4 5 6 7

1965 1575 1007 847 566 317 132

2005 1599 1014 858 594 358 136

Aliv

e an

d In

v. D

isea

se-fr

ee (

%)

20

40

60

80

100

0

Δ=2.5%TaxAC 2062 179 90.7%TC 2094 220 88.2%

Treatment N Events IDFS

HR=1.23, 95% CI (1.01-1.50) P=0.04

4 yr


ABC Trials: IDFS by Hormone and Nodal StatusExploratory Analysis


Ali

ve a

nd

In

v. D

isea

se-f

ree

(%)

0 1 2 3 4 5 6 7

020

4060

8010

0

N- TaxAC, 459 Pts, 37 EventsN- TC, 488 Pts, 52 Events1-3N+ TaxAC, 153 Pts, 21 Events1-3N+ TC, 119 Pts, 28 Events4+N+ TaxAC, 42 Pts, 11 Events4+N+ TC, 40 Pts, 16 Events


Ali

ve a

nd

In

v. D

isea

se-f

ree

(%)

0 1 2 3 4 5 6 7

020

4060

8010

0

N- TaxAC, 358 Pts, 29 EventsN- TC, 378 Pts, 22 Events1-3N+ TaxAC, 771 Pts, 46 Events1-3N+ TC, 789 Pts, 53 Events4+N+ TaxAC, 279 Pts, 35 Events4+N+ TC, 280 Pts, 49 Events

HR Negative HR Positive

Role of Neoadjuvant Platinum in TNBC: Randomized Trials

Study No Backbone Regimen No Carbo Carboplatin

GeparSixto 315 Weekly paclitaxel + liposomal dox + bev 38% 59%P< 0.05

C406063 433 Sequential weekly paclitaxel – AC +/- bev 41% 54% P=0.0029

Tamura et al 75 Sequential weekly pacl+/- Carb AUC5 - CEF 26% 62%

Alba et al 94 EC – Doc +/- Carbo AUC6 30% 30%

Von Minckwitz et al. Lancet Oncol 2014; Sikov et al. JCO 2014; Alba et al. BRCT 2012; Tamura et al. ASCO 2014, Abstract 1107GeparSixto C40603 8

9

10

NRG-BR003

Node-Positive or High-Risk Node-NegativeTriple Negative Breast Cancer

ACx4ÚPaclitaxel qwk x 12

Randomization

ACx4 Ú Paclitaxel qwk x 12+ Carboplatin

beginning with WP

AC: 60 mg/m2 /600 mg/m2 (Std or DD AC); Paclitaxel: 80 mg/m2 IV weekly;Carboplatin: AUC of 5 IV q3 weeks for 4 cycles

Efficacy of neoadjuvant carboplatin plus docetaxel in triple negative breast cancer:

Combined analysis of two cohorts• PATIENTS AND METHODS:

– 190 patients with stage I-IIITNBC treated uniformly on two independent prospective cohorts (KU, Spain)

– Treatment regimen: Cb (AUC 6) + D (75mg/m2) given every 21 days X 6 cycles – all received pegfilgrastim or filgrastim

• RESULTS: – median tumor size 35mm, 52% node pos,16% BRCA1/2 mutation– Stage: 33% stage III, 56% stage II, 11% stage I. – pCR and RCB 0+1 rates were 55% and 68%, respectively)– Multivariable analysis - stage III disease (OR 0.35, p<0.001), T3-4 lesion (OR

0.39, p=0.003), associated with a lower pCR, but not age, BRCA ½ mutation, clinical nodal status; KU site associated with higher rate (OR 1.93, p=0.046)

– Toxicity 21% 7% of patients, respectively, experienced at least one grade 3 or 4 adverse event.

Sharmaetal.Clin CancerRes2016(PMID:27301700)

Lee et al. SABCS 2015 13

Toi M et al. Proc ASCO, 2016

14

15

16

17

Pt is On Study

Weekly paclitaxel ±

New Agent C, D, or EAC

HER2 (+)

HER2(–)

Randomized

I-SPY 2 Adaptive Trial Schema

Weekly paclitaxel & Trastuzumab

±New Agent A, B, or C

AC

Randomized Surgery

Surgery

StratifyingBiomarkers

Biopsyused for

Biomarkers

Stratifying Biomarkers (Established/Approved/IDE) ER, PR

HER2 (IHC, FISH, RPPA, 44K-microarray)MammaPrint 44K microarray

Preoperative MK-2206 AKT inhibitor

• 93 pts MK-2206 + weekly paclitaxel (then AC)• 59 pts weekly paclitaxel alone (then AC)

• pCR TNBC pts 40% with MK-2206 vs 22% control

• 76% probability success MK-2206 phase 3 TNBC –GRADUATED

• RPPA biomarker analyses ongoing

Tripathy D.ASCO2015

Wulfkuhle JD et al ASCO 2015

Preoperative Neratinib

Veliparib/Carboplatin Graduatesin the Triple Negative Signature

SIGNATURE

Estimated pCR Rate(95% probability interval)

Probability Veliparib +Carbo is

Superior to Control

Predictive Probability of Success in

Phase 3Veliparib/

CarboConcurrent

Control

All HER2- 33% (22-43%)

22%(10-35%)

92% 55%

HR+/HER2- 14%(4-27%)

19% (6-35%)

28% 9%

HR-/HER2- 52%(35-69%)

26%(11-40%) 99% 90%

I-SPY 2 Rugo et al, NEJM 2016

Novels Therapies for Metastatic Disease

Tutt et al. SABCS 2014; S3-01

TNT Trial



Metastatic TNBC Exceptional Responders to First-Line Platinum

Isakoff S et al. J Clin Oncol 2015

4/34 highly durable ORR 11.7 % First-line cisplatin (overall ORR 35%)2/35 highly durable ORR 5.7% First-line carboplatin (overall ORR 23%)

TnAcity: Randomized Phase II Trial of Chemotherapy Doublets for First Line metTNBC

Yardley D et al. SABCS 2016, abst 874

TnAcity: PFS and OS First Line metTNBC

• Breast cancers with BRCA1/2 mutations -- defects in homologous recombination DNA repair mechanisms, are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors

• The PARP inhibitor veliparib effective in early trials in combination with carboplatin and paclitaxel

• BROCADE is a randomised, placebo-controlled Phase II trial of veliparib, carboplatin and paclitaxel in locally recurrent or mBC with a BRCA1/2 mutation

Efficacy and tolerability of veliparib + carboplatin + paclitaxel in patients with BRCA1 or BRCA2

mutations in mBC

HS Han, et al. Oral presentation, Abstract S2-05

LR or mBC with BRCA1/2 mutation

(N = 290)R

Veliparib + carboplatin + paclitaxel (n=97)

Placebo + carboplatin + paclitaxel (n=99)

Veliparib + temozolomide (n=94)

SABCS 2016

Number at riskPlacebo + C/P 98 82 61 35 20 8 4 0 0Veliparib + C/CP

95 80 60 38 22 13 4 2 1

Veliparib + carboplatin + paclitaxel: PFSPrimary analysis

Placebo + C/P Veliparib + C/P

Months since randomisation

Prob

abili

ty o

fpr

ogre

ssio

n-fr

ee s

urvi

val

1.0

0.8

0.6

0.4

0.2

0.0

0 4 12 24

Placebo + C/Pn = 98

Veliparib + C/Pn = 95 HR p value

Median PFS, months 12.3 14.1 0.7890.231

(95% CI) (9.3‒14.5) (11.05‒16.2) (0.536‒1.162)

288 16 20 32

Stage 1 Phase II Trial of Enzalutamide in AR+ metTNBC

71yoTNBC5-yearDFI2prior regimensMBCCR32+weeksonRx

73yoTNBC6-yearDFIFirstLineMBC48+weeksonRX

TrainaT,etal.SABCS,2014

Summary – Triple Negative Breast Cancer

§ Systemic neo/adjuvant chemotherapy• Adjuvant anthracycline (TaxAC vs 6TC) improves DFS in TNBC• Addition of carboplatin to paclitaxel improves pCR rate with as yet

unknown effects on DFS – reasonable for high risk pts• In patients who do not develop a pCR with preoperative chemotherapy,

adjuvant treatment with capecitabine is a reasonable option

§ Promising Approaches• Nab paclitaxel/carboplatin first-line metTNBC and ?neoadjuvant• PARP inhibitors gBRCA pts• AKT, AR and PD-1/PD-L1 inhibitors• ADCs against Trop2 (sacituzumab) and GPNMB (glembatumumab)

32

Optimizing Therapy for HER2+ Breast Cancer

HER2+ Breast Cancer Following Adjuvant Trastuzumab: Risk of Locoregional or Distant Recurrence

� Approximately 20% of patients diagnosed with breast cancer are HER2+a (~35,000 patients annually in the USb)

� Trastuzumab has dramatically improved the outcome of HER2+ breast cancerc

� Despite these advances,

– 16-20+% pts recur with invasive breast cancer within 8 to 10 years after initial diagnosisdd,e

� No proven curative therapy for locally recurrent or metastatic HER2+ breast cancer following adjuvant trastuzumab

a Wolff AC, et al. J Clin Oncol 2013;31:3997-4013; b SEER database, 2015; c Dawood S, et al. J Clin Oncol 2010;28:92-98; d Perez E, et al. J Clin Oncol. 2014;32:3744-3752; e Goldhirsch A, et al. Lancet. 2013;382:1021-1028

Amplified

Not Amplified

Amplified

Not Amplified

Focal HER2 Amplification

CEP17

HER2

Current HER2+ Targeted Treatments

3737

a Yardley DA, et al. ASCO BC 201, Abstract 268; b Osborne CK, et al. Annu Rev Med. 2011;62:233-247; c Yamnik RL, et al. J Biol Chem. 2009;284(10):6361-6369; d den Hollander P, et al. Front Oncol. 2013;3:250; e Kümler I, et al. Cancer Rev Treat. 2014;40:259-270.

ER and PR Negative

AC Ú P

AC Ú P+H

N EventsAC→P 911 175AC→P+H 917 103

21.5%

11.9%

B-31/N9831 Cumulative Incidence of Distant Recurrence as a First Event

ER and/or PR Positive

AC Ú P

AC Ú P+H

Cum

ulat

ive

Inci

denc

e (%

)

N EventsAC→P 1105 216AC→P+H 1110 124

22.3%

12.7%


Δ= 9.6%

San Antonio Breast Cancer Symposium, December 4-8, 2012

Δ=9.6%

Slamon DJ, et al. 2015 San Antonio Breast Cancer Symposium. Abstract S5-04.

Disease Free Survival

Standard Trastuzumab-Based Adjuvant Therapy in HER2+ Breast Cancer (BCIRG 006)

One-quarter of patients remain at risk for DFS event after adjuvant trastuzumab therapy

Pertuzumab andtrastuzumab havecomplementarymechanismsofaction

HER2

Dimerisationdomain

Choetal.Nature2003;421:756–760;Fendlyetal.CancerRes1990;50:1550–1558;Franklinetal.Cancer Cell2004;5:317–328;Nahtaetal.CancerRes2004;64:2343–2346;Scheueretal.CancerRes2009;69:9330–9336

Pertuzumab

Trastuzumab

Subdomain IVTrastuzumab:• Inhibitsligand-independent HER2

signaling• ActivatesADCC• PreventsHER2ECDshedding

Pertuzumab:

• Inhibitsligand-dependent HER2dimerizationandsignaling

• Suppresses multipleHERsignallingpathways

• ActivatesADCC

HER1/3/4

CLEOPATRA study design

41HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; PD, progressive disease

Patients withHER2-positive MBC

centrally confirmed(N=808)

Placebo + trastuzumab

1:1

Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not)

Study dosing q3w:- Pertuzumab/Placebo: 840 mg loading dose, 420 mg maintenance- Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance - Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated

Docetaxel≥6 cycles recommended

n=406

n=402

Pertuzumab + trastuzumab

Docetaxel≥6 cycles recommended

PD

PD

Significant improvement in OS in favour of Pertuzumab armConfirmatory Overall survival analysis(Median follow-up: 30 month)

* Stopping boundary for concluding statistical significance at this second interim analysis was p≤0.0138D, docetaxel; Pla, placebo; Ptz, pertuzumab; T, trastuzumab

0 5 10 15 20 25 30 35 400

10

20

30

40

50

60

70

80

90

100

natrisk

0Ptz+T+D

0Pla+T+D

Time(months)

Overallsurvival(%

)

45 50 55

0

0

9

4

33

22

84

67

143

128

230

198

317

285

342

324

371

350

387

383

402

406

89%

94%

1year,Δ 5%

2years ,Δ 12%

69%

81% 3years, Δ 16%

66%

HR=0.6695%CI0.52−0.84

p=0.0008

No. of events%

Median (months)

Ptz + T + D 113 (28%) NR

Pla + T + D 154 (38%) 37.6

50%

Baselga J, et al. N Engl J Med 2012SABCS 2012 P5-18-26

NeoSphere:AdjuvantComponentStudyDesign

GianniL,etal. LancetOncol 2012;13:25–32

FEC,5-fluorouracil, epirubicin, andcyclophosphamide

S

U

R

G

E

R

Y

Studydosing:q3wx4

Patientswithoperableorlocallyadvanced/inflammatoryHER2-positive BC

Chemo-naive&primarytumors>2cm(N=417)

TD(n=107)trastuzumab (8®6mg/kg)docetaxel (75®100mg/m2)

PTD(n=107)pertuzumab (840®420mg)trastuzumab (8®6mg/kg)docetaxel (75®100mg/m2)

PT(n=107)pertuzumab(840®420mg)trastuzumab(8®6mg/kg)

PD(n=96)pertuzumab(840®420mg)docetaxel (75®100mg/m2)

FECq3wx3trastuzumabq3wcycles5–17


docetaxelq3wx4® FEC q3wx3trastuzumabq3wcycles5–17


44Gianni et al. Lancet Oncol 2012; 13: 25

Gianni et al. Lancet Oncol 2012; 13: 25

Aphinity (IBCSG39-11/BIG4-11)

CU-47WORKING DRAFT

Neratinib is active against metastatic HER2+ BC previously treated with trastuzumaba

aBurstein H et al. J Clin Oncol 28:1301-7, 2010

Trastuzumab Emtansine (T-DM1): Mechanism of Action

Emtansine release

Inhibition of microtubule

polymerization

Internalization

HER2

Adapted from LoRusso PM, et al. Clin Cancer Res 2011.

T-DM1

Lysosome

Nucleus

PP

P

Trastuzumab-specific MOA• Antibody-dependent cellular cytotoxicity (ADCC)

• Inhibition of HER2 signaling• Inhibition of HER2 shedding

Overall Survival:T-DM1 vs capecitabine/lapainib

496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5

Cap + LapT-DM1

No. at risk: Time (months)

78.4% 64.7%

51.8%

85.2%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 360.0

0.2

0.4

0.6

0.8

1.0

Prop

ortio

n su

rviv

ing

Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012).

Median (months) No. of eventsCap + Lap 25.1 182T-DM1 30.9 149Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006

Efficacy stoppingboundary P=0.0037orHR=0.727

Katherine Study – NSABP/German Breast Group

NCT01772472

• HER2+, T1c-T4 / N0-3 / M0• Neoadjuvant therapy o 6 cycles/16 weekso Trastuzumab x 9 weeks

• Residual Invasive disease

Trastuzumab6 mg/kg q 3 weeks x 14

T-DM13.6 mg/kg q 3 weeks x 14

N = 1484

Enrollment: completed

Primary Endpoint: Invasive-Free SurvivalSecondary Endpoints: DFS, OS, DDFS, Safety, QOL

-100-75-50-25

0255075

100125150175200225250275

• A ≥30% reduction in the SLDs of target CNS lesions was observed in 43% of patients

CBR, the proportion of patients whose best response was CR, PR or SD ≥6 months

KAMILLA CNS metastases: Efficacy with T-DM1Response in brain mets according to clinical benefit rate (in all lesions, systemic and CNS)

% C

hang

e in

sum

of d

imen

sion

sbr

ain

targ

et le

sion

s

CBR responderYes (n=54)No (n=72)

Montemurro, et al. Poster presentation, Abstract P1-12-10, SABCS 2016

25PatientswithHER2SomaticMutations

• Eachbluecirclerepresentsapatient.• From8publicationswithatotalof1,499patients.• 20%ofpatientshavemutationsataminoacids309or310.• 68%ofpatientshavemutationsataminoacids755-781.

BoseRetal,CancerDiscovery2012

27% new HER2 Alterations met ILC

Ross J. Clin Cancer Res 19:2668, 2013

ERBB2-mutantbreastcancer(Neratinibmonotherapy):Tumorassessments

Data cutoff 24-JUN-2016

* * *

* Denotes patient that progressed with amplified ERBB2

Breast Cancer Cohort

57

Summary: HER2+ Breast Cancer• Alternate chromosome 17 probes can resolve equivocal FISH cases

• Preoperative TCHP for T2+ or N1+ disease – APHINITY results soon

• Neratinib extended therapy improves PFS in ER+ HER2+ disease

• Taxane + trastuzumab + pertuzumab standard first line MBC Rx

• T-DM1 second line Rx (no data post-THP)

• Capecitabine + lapatinib or trastutumab + lapatinib --- continue HER2-targeted therapy throughout metastatic course

• HER2 mutations/amplicons detected in MBC – HER2-directed Rx may be of benefit

Clinical Markers Predictors of Resistance to Endocrine Therapy

• Disease free interval from adjuvant therapy• Duration of response• Prior treatment• HER2 amplification• Lower ER expression

Need for improved hormone therapy with minimal toxicity

Comparison of First Line AI ± Fulvestrant Trials

FACT1 SWOG 02262

No. Patients 514 707De Novo Metastatic Disease

13% 39%

Prior Adjuvant Chemotherapy

45% 33%

Prior Adjuvant Endocrine Therapy (TAM)

68% 40%

Prior Adjuvant AI 1.5% excludedMedian TTP/PFS Range (mo)

10–11 13–15

PFS Benefit No YesMedian OS Benefit, (mo) No, 37.8 vs. 38.2

mosYes, 41.3 vs 47.7

mos

Fulvestrant 500 mg IM on Day 0 followed by 250 mg IM Day 14 and 28 then 250 mg every 28 days

1. Bergh J, et al. J Clin Oncol. 2012;30:1919-25 2. Mehta RS, et al. N Engl J Med. 2012;367:435-44

FALCON:(Fulvestrant and AnastrozoLe COmpared in hormonal therapy Naïve advanced breast cancer)

Randomised, double-blind, parallel-group, international, multicentre studyFollow-up for disease progression and survivalRandomisation of 450 patients was planned to achieve 306 progression events; if the true PFS HR was 0.69 this would provide 90% power for statistical significance at the 5% two-sided level (log-rank test)Stratification factors: prior chemotherapy for advanced disease (yes / no); measurable vs. non-measurable disease (at baseline); locally advanced vs. metastatic diseaseSubgroup analysis of PFS for pre-defined baseline covariates

aAssessed via RECIST 1.1, surgery / radiotherapy for disease worsening, or death; bInterim analysis at the time of PFS analysisEDoCB, expected duration of clinical benefit; EDoR, expected duration of response; FACT-B, Functional Assessment of Cancer Therapy – Breast; TOI, Trial Outcome Index

• Postmenopausal women• Locally advanced or

metastatic breast cancer• ER+ and / or PgR+• HER2-• Endocrine therapy-naïve

Fulvestrant 500 mg(500 mg IM on Days 0, 14 and 28, then every 28 days)

+ placebo to anastrozole

Anastrozole 1 mg (daily PO)

+ placebo to fulvestrant

Primary endpoint: PFSa

Secondary endpoints1:1 • OSb

• ORR• CBR• DoR, EDoR

• DoCB, EDoCB

• HRQoL (FACT-B total and TOI)

• Safety

FALCON: PRIMARY ENDPOINT, PFS

A circle represents a censored observation

HR 0.797 (95% CI 0.637, 0.999); p=0.0486

Median PFSFulvestrant: 16.6 monthsAnastrozole: 13.8 months

Number of patients at risk:FulvestrantAnastrozole

230232

187194

171162

150139

124120

110102

9684

8160

6345

4431

2422

1110

20

00

Prop

ortio

n of p

atien

ts ali

ve an

d pr

ogre

ssio

n fre

e

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.00 3 6 9 12 15 18 21 24 27 30 3633 39

0.2

Fulvestrant (n=230)

Anastrozole (n=232)

FALCON: PFS IN PATIENTS WITH OR WITHOUT VISCERAL DISEASE

Post hoc interaction test p<0.01A circle represents a censored observation

Without visceral disease With visceral disease

HR 0.59 (95% CI 0.42, 0.84)

Median PFS Fulvestrant: 22.3 monthsAnastrozole: 13.8 months

Prop

ortio

n of

patie

nts a

live a

nd pr

ogre

ssion

-free

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.0

0.2 Prop

ortio

n of

patie

nts a

live a

nd pr

ogre

ssion

-free

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.00 5 10 15 20 25 30 35 40

0.2

0 5 10 15 20 25 30 35 40

HR 0.99 (95% CI 0.74, 1.33)

Median PFS Fulvestrant: 13.8 monthsAnastrozole: 15.9 months

Fulvestrant (n=135) Anastrozole (n=119)

Fulvestrant (n=95) Anastrozole (n=113)

BOLERO-2: Study Design

EVE 10 mg daily+

EXE 25 mg daily (n = 485)

Placebo+

EXE 25 mg daily (n = 239)

Endpoints•Primary: PFS (local assessment)•Secondary: OS, ORR, CBR, QOL, safety, PK•Exploratory: Biomarkers

Stratification: • Sensitivity to prior hormone therapy • Presence of visceral metastases

65

Abbreviations: BC, breast cancer; CBR, clinical benefit rate; ER+, estrogen receptor-positive; EVE, everolimus; EXE, exemestane; HER2–, human epidermal growth factor receptor-2–negative; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PK, pharmacokinetics; QOL, quality of life.

Baselga J, et al. N Engl J Med. 2012;366(6):520-529.

N = 724• Postmenopausal women• ER+, HER2– unresectable

locally advanced or metastatic BC

• Recurrence or progression after letrozole or anastrozole

Randomize2:1

BOLERO-2 (18-mo): Final PFS Analysis Based on Local Assessment—Met Primary Endpoint (4.6-mo Prolongation of PFS)

1.0

0.8

0.6

Prob

abili

ty o

f Pr

ogre

ssio

n-Fr

ee S

urvi

val

0.4

0.2

02826242220181614

Time, months121086420

00

10

40

101

131

232

426

579

9917

14727

19442

23661

318103

394146

485239

EVE+EXEPBO+EXE

No. at risk

HR = 0.45 (95% CI, 0.38-0.54)Log-rank P < .0001

Kaplan-Meier mediansEVE+EXE: 7.8 monthsPBO+EXE: 3.2 months

Censoring timesEVE+EXE (n/N = 310/485)PBO+EXE (n/N = 200/239)

Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival.

Yardley DA, et al. Adv Ther. 2013;30(10):870-884. 66

PrECOG 0102• Evaluated everolimus and fulvestrant vs

fulvestrant + placebo (N=131)• Advanced ER+, HER2-, post menopausal • Previously treated with AI, or relapsing on AI• PFS: 10.4 mos vs 5.1 mos (p=0.02)• Expected toxicities

Kornblum SABCS2016

Reversible Histone Acetylation Regulates Gene Expression

Yoo CB and Jones PA. Nat Rev Drug Discov.2006;5:37

Histoneacetylation

Pol2 mRNA

Activated Chromatin(hyper-acetylated

histones)

Ac-

Ac-

Ac-

Ac-

Ac-Ac-

Ac-

Ac-

HAT

TranscriptionalFactors

Corehistones

(hypo-acetylated histones)

Repressed Chromatin

Repressed Chromatin

Cofactors

HDACsHistone

deacetylation

HDACInhibitor

Entinostat and Exemestane

• Post-menopausal ER+ advanced breast cancer

• Progressed on/or relapsed while taking a NSAI

exemestane +entinostat

exemestane +placebo

N= 130

1:1

NSAI settingBone onlyRegion

Yardley et al 2013

Entinostat and Exemestane

PFS: 2.3 mos to 4.3 mosHR 0.73 95% CI 0.5-1.07

mOS: 19.8 mos to 28.1 mosHR 0.59 95% CI 0.36-0.97

Yardley et al 2013

Entinostat and Exemestane: Toxicity

Yardley et al 2013

Entinostat and Exemestane: Phase III

0

100

200

300

400

500

600

700

800

900

1000

MB-175

ZR75

-30

CAMA-1

MB134

HCC202

UACC-893

EFM19

SUM190

EFM19

2A

MB-361

HCC1500

HCC1419

HCC38

MB-415

MCF-10A

UACC-812

HCC2218

ZR75

-1

MDAMB453

184A

1T4

7DMCF7

BT-20

MDAMB435

BT474

SKBR3KPL-1

HCC1143

MDAMB231

HCC1395

SUM-225

HS578T

184B

5

UACC732

CAL-51

BT549

COLO82

4

DU4475

HCC1187

HCC1569

HCC1806

HCC1937

HCC1954

HCC70

MB-436

MB157

MDAMB468

SubtypeLuminal Non-luminal/post EMTHER2 amplified Non-luminalImmortalized

Palbociclib: CDK 4/6 Inhibitor – Breast Panel

Finn RS, et al. Breast Cancer Res. 2009;11(5):R77.

FinnRSetalNEJM2016

Subgroup Analysis of PFS by Biomarker

HR=hazard ratio; LET=letrozole; PAL=palbociclib; PCB=placebo; PFS=progression-free survival.

n HR (95% CI)

All patients

666

0.58 (0.46–0.72)

ER+ER–

504 62

0.57 (0.44–0.74)

0.41 (0.22–0.75)

Rb+Rb–

512 51

0.53 (0.42–0.68)

0.68 (0.31–1.48)

CyclinD1+

CyclinD1–

54915

0.56 (0.44–0.71)

1.0 (0.29–3.46)

p16+p16–

46684

0.52 (0.40–0.67)

0.73 (0.39–1.36)

Ki-67 ≤20%Ki-67 >20%

318235

0.53 (0.38–0.74)

0.57 (0.41–0.79)

0 1 2 3 4

HR (95% CI)

Favors PAL+LET Favors PCB+LET

Percentile n HR (95% CI)

All patients 666

0.58 (0.46–0.72)

ER status

≤25th

>25th to <75th

≥75th

142282142

0.50 (0.32–0.78)

0.53 (0.37–0.74)

0.65 (0.41–1.05)

Rbstatus

≤25th

>25th to <75th

≥75th

154249160

0.57 (0.36–0.88)

0.46 (0.32–0.67)

0.63 (0.42–0.95)

CyclinD1 status

≤25th

>25th to <75th

≥75th

141247176

0.41 (0.26–0.65)

0.69 (0.48–1.00)

0.52 (0.34–0.78)

p16 status

≤25th

>25th to <75th

≥75th

14025815

0.74 (0.46–1.20)

0.62 (0.44–0.89)

0.33 (0.21–

0 .0 0 .5 1 .0 1 .5HR (95% CI)

Favors PAL+LET Favors PCB+LET

Qualitative Analysis Quantitative Analysis

Placebo (3 wks on/ 1wk off)

+ Fulvestrant†

(500 mg IM q4w)

Palbociclib (125 mg QD;

3 wks on/1 wk off)+

Fulvestrant†

(500 mg IM q4w)

†administered on Days 1 and 15 of Cycle 1.

● Visceral metastases● Sensitivity to prior hormonal

therapy● Pre-/peri- vs Post-menopausal

Clinicaltrials.gov NCT01942135

2:1 Randomization

N=521

Stratification:

• Post-menopausal patients must have progressed on prior aromatase inhibitor therapy.

n=347

n=174

• HR+, HER2– ABC• Pre-/peri-* or post-menopausal • Progressed on prior endocrine

therapy:– On or within 12 mo adjuvant– On therapy for ABC

• ≤1 prior chemotherapy regimen for advanced cancer

*All received goserelin.

Design of Phase III Study in Recurrent MBC (1023)-PALOMA-3

0 2 4 6 8 10 12Time (Month)

0

10

20

30

40

50

60

70

80

90

100

PFS

Prob

abili

ty (%

)

347 279 132 59 16 6PAL+FUL

174 109 42 16 6 1PCB+FUL

Number of patients at risk

PALOMA3: Primary Endpoint: PFS (ITT Population)

CI=confidence interval; HR=hazard ratio; ITT=intent-to-treat; NE=not estimable; PFS=progression-free survival.

Palbociclib + Fulvestrant

n=347

Placebo + Fulvestrant

n=174

Median PFS, months(95% CI)

9.2(7.5, NE)

3.8(3.5, 5.5)

HR (95% CI) 0.422 (0.318, 0.560)2-sided P value <0.000001

Turner N et al NEJM 2015

Regardless of study treatment relationshipNON-HEMATOLOGIC ADVERSE EVENTS

Adverse Event≥15% in Either Arm, %

Ribociclib + Letrozolen=334

Placebo + Letrozolen=330

All Grade 3 Grade 4 All Grade 3 Grade 4Nausea 52 2.4 0 29 0.6 0Infections 50 3.6 0.6 42 2.1 0.3Fatigue 37 2.1 0.3 30 0.9 0Diarrhea 35 1.2 0 22 0.9 0Alopecia 33 – – 16 – –Vomiting 29 3.6 0 16 0.9 0Arthralgia 27 0.6 0.3 29 0.9 0Constipation 25 1.2 0 19 0 0Headache 22 0.3 0 19 0.3 0Hot flush 21 0.3 0 24 0 0Back pain 20 2.1 0 18 0.3 0Cough 20 0 – 18 0 –Decreased appetite 19 1.5 0 15 0.3 0Rash 17 0.6 0 7.9 0 0ALT increased 16 7.5 1.8 3.9 1.2 0AST increased 15 4.8 0.9 3.6 1.2 0

u In the ribociclib arm 10 (3.0%) patients experienced Grade 2 QTcF (481–500 ms) and 1 (0.3%) patient experienced Grade 3 QTcF (>500 ms); no dose reductions were required

MONALEESA-3

NCT02422615

MONALEESA-7

NCT02278120

MONARCH 1: Phase 2 Study Design

Previously-treated

HR+/HER2- MBC

Abemaciclib 200 mg orally

Q12H

Treatment continued until unacceptable toxicity or PD

♦ Primary objective• To evaluate abemaciclib with respect to confirmed objective response rate

based on investigator assessment (per RECIST v1.1)

♦ Secondary objectives• Duration of response, progression-free survival, overall survival, clinical

benefit rate, safety

♦ Statistical design• A sample size of 128 patients provides 82% power, assuming a true response

rate of 25%, to exclude an ORR of ≤15 % on the lower bound of the 95 % CI at 12 months follow-up

♦ Clinical trial ID: NCT02102490

MONARCH 1: Prior Therapies♦ Median number of prior systemic regimens (any setting) was 5 (range 2-11)

♦ 100% of patients received taxanes in any setting

♦ Median number of prior systemic regimens for metastatic disease was 3 (range 1-8) Chemotherapy

for Metastatic Disease

N = 132n (%)

# of Regimens

1 67 (50.8)

2 64 (48.5)

3 1 (0.8)

Taxanes 91 (68.9)

Endocrine Therapy for Metastatic Disease

N = 132n (%)

# of Regimens1 48

(36.4)2 25

(18.9)3 24

(18.2)≥ 4 18

Cha

nge

from

Bas

elin

e (%

)

100

0

-100

-50

-30

50

20

Disease Control Rate (CR + PR + SD) = 67.4%

Progressive disease (n = 34)Stable disease (n = 63)Partial response (n = 26)Not assessed (n = 9) aAssessments based on independent review

were comparable

Investigator Assessed ResponseaAbemaciclib

200 mg (N = 132)

Confirmed Objective Response Rate (ORR = CR + PR)(95 % CI)

19.7% (13.3, 27.5)

CRPR

0%19.7%

Stable Disease ≥ 6 months 22.7%Clinical Benefit Rate (CBR = ORR +SD ≥ 6 mos)

42.4 %

MONARCH 1: Response Summary

Dickler M. et al. J Clin Oncol 34, 2016 (suppl; abstr 510)

MONARCH 1: Kaplan-Meier Plots

A. Progression-free Survival

Patients/Events 132/100

Median, months 5.95

95% CI 4.21, 7.50

89 54132 72 43 38 25 1010 10 7 6Pts at Risk:

2 0

Surv

ival

Pro

babi

lity

Pts = patients, NR = not reached

Months MonthsPts at Risk:

132

128

121

116

111

105

92

85

76

65

39

22

8 2 0

B. Overall Survival

Patients/Events 132/62

Median, months 22.32

95% CI 17.7, NR

Surv

ival

Pro

babi

lity

Abemaciclib 200 mg

1.0

0 2 4 6 8 10 12

14

16

18

20

22

24

26

0.0

0.2

0.4

0.6

0.8

0.1

0.3

0.5

0.7

0.9

IIIIIIIII

III

II

IIII

I I IIII

I I I I I I II

aCTCAEVersion4.03,bN = 130forlababnormalities listed,except plateletcount decreased(N = 128), cAbemaciclibisacompetitive inhibitor ofOCT2,MATE1,andMATE2-K,effluxtransporters ofcreatinine;cystatinCcalculatedGFRwasnotraised,dOnepatient whoreceivedcytotoxic chemotherapywithin the30dayfollowupwindow experienced febrileneutropenia

MONARCH 1: Most Common Adverse Events

Investigator Assessed TEAEsa >20% (N = 132)

Grade 1%

Grade 2%

Grade 3%

Grade 4%

All Grades

%Diarrhea 41.7 28.8 19.7 0 90.2Nausea 39.4 21.2 4.5 0 65.2Fatigue 20.5 30.3 13.6 0 64.4Decreased appetite 28.0 14.4 3.0 0 45.5Abdominal pain 22.0 14.4 2.3 0 38.6Vomiting 23.5 10.6 1.5 0 35.6Headache 13.6 6.8 0 0 20.5Pain 12.1 6.8 1.5 0 20.5Lab abnormalitiesb TEAEsa > 40% Creatinine increasedc (CTCAE v 4.03: over baseline) 46.9 50.8 0.8 0 98.5White blood cell decreased 20.0 44.6 27.7 0 92.3Neutrophil count decreased 16.9 43.8 22.3 4.6 87.7d

Anemia 30.0 39.2 0 0 69.2Lymphocyte count decreased 4.6 23.1 13.8 0.8 42.3Platelet count decreased 28.9 10.2 2.3 0 41.4

Abemaciclib (LY2835219): MONARCH 2

Primary endpoint: Progression-Free Survival (PFS)

Women with HR+, HER2-Locally Advanced or

Metastatic Breast Cancer(N=550)

R

LY2835219 + Fulvestrantuntil PD

Placebo + Fulvestrant until PD

A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant with or without LY2835219, a CDK4/6 Inhibitor, for Women with Hormone Receptor Positive, HER2 Negative

Locally Advanced or Metastatic Breast Cancer

2:1

NCT02107703

MARCH 20, 2017: Met its Primary Endpoint

Evolution of ER+ Breast Cancer

1977 1995 2012 201519991997 20102002

Modifeid from Chemlowski epub 2012

20051970

Tamoxifen(1977)

Anastrazole(1995)

Examestane(1999)

Palbociclib(2015)

Toremifene(1997)

Letrozole(1997)

19901980

Everolimus(2012)

Fulvestrant 250 mg(2002)

Fulvestrant 500 mg(2010)

Novel Therapies for Triple Negative, HER2+ and ER+ Breast ......HER2+ Breast Cancer Following Adjuvant Trastuzumab: Risk of Locoregional or Distant Recurrence Approximately 20% of

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