Advances in the Management of Metastatic Her 2 Positive Breast Cancer Sunil Verma MD, MSEd, FRCPC Medical Oncologist Research Lead, Division of Medical Oncology Chair, Breast Medical Oncology Sunnybrook Odette Cancer Centre Associate Professor, University of Toronto
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Advances in the Management of
Metastatic Her 2 Positive Breast Cancer
Sunil Verma MD, MSEd, FRCPC
Medical Oncologist
Research Lead, Division of Medical Oncology
Chair, Breast Medical Oncology
Sunnybrook Odette Cancer Centre
Associate Professor, University of Toronto
HER2 overexpression
associated with more
aggressive phenotype4
1987
The Her 2 Journey
1. Ullrich A, et al. Nature 1984; 309:418−4253;
Anti-HER2 monoclonal
mouse antibody
humanised: trastuzumab6
1992
HER2 gene is cloned2
HER2 protein found to be
overexpressed in breast tumours3
1985
HER2/neu
gene identified1
1984
Anti-HER2
monoclonal mouse
antibody
developed5
1989
Trastuzumab
clinical trials begin
1993−1995
3. Sainsbury JR, et al. Lancet 1985; 1:364−366;
5. Huzdiak RM, et al. Mol Cell Biol 1989; 9:1165–1172;
4. Di Fiore PP, et al. Science 1987; 237:178–182
6. Carter P, et al. Proc Natl Acad Sci USA 1992; 89:4285–4289
2. Ishii S, et al. Proc Natl Acad Sci USA 1985; 82:4920–4924
Her 2 Story Poor Prognostic Marker
Outline
• First Line Treatment
• Second Line Treatment and Beyond
• Individualized Approach
• An Algorithm and Concluding Remarks
Outline
• First Line Treatment
• Second Line Treatment and Beyond
• Individualized Approach
• An Algorithm and Concluding Remarks
OS was a secondary endpoint in the study Chemotherapy = either doxorubicin or epirubicin + cyclophosphamide or paclitaxelOS, overall survival; RR, relative risk of death Adapted from Slamon DJ, et al. N Engl J Med 2001; 344:783–792.
Trastuzumab prolongs overall survival in
HER2-positive MBC
Chemotherapy (n = 234)
Chemotherapy + trastuzumab (n = 235)
Overa
ll s
urv
iva
l (%
)
Time (months after enrolment)
RR = 0.80 (95% CI = 0.64,1.00)
p = 0.046
Median OS:
20.3 months
Median OS:
25.1 months
0
20
40
60
80
100
5 15 25 35 450
First Line Treatment Approach (2001-
2011)
• A number of effective options with chemo and
anti-her2
– Taxanes and Herceptin
– Vinorelbine and Herceptin
– Capecitabine and Anti-Her2
– Doublet chemo with Her 2 generally not used
• Select group of patients may benefit from an
anti-Her2 and anti-estrogen approach
Recent Achievements in
Her 2 positive MBC
First Line
– MA.31
• Taxane + H vs. Taxane + L
– Bolero -1
• Paclitaxel + H vs. Paclitaxel + H +Everolimus
– CLEOPATRA
• Chemo + H vs. Chemo +H+P
8
Gelmon et. al ASCO 20129
Gelmon et. al ASCO 201210
This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute.
San Antonio Breast Cancer Symposium – December 9-13, 2014
• OS, ORR, CBR, Time to response, Safety, Duration of
response
1Discontinued > 12 mo before randomization; 2Paclitaxel: 80 mg/m2 weekly; 3Trastuzumab: 4 mg/kg loading dose on day 1 at cycle 1 followed by 2 mg/kg weekly doses4Patients could discontinue any study treatment due to AEs; other study treatments continued until disease progression or intolerable toxicity
• Inhibits shedding of the HER2 extracellular domain
T-DM1Retains Activity of Herceptinf
KADCYLA Product Monograph. Hoffmann-La Roche Limited. September 11, 2013.
KADCYLA has the additional MOA of DM1. Upon binding to HER2, KADCYLA undergoes
• Receptor-mediated internalization
• Subsequent lysosomal degradation
• Intracellular release of DM1-containing cytotoxic catabolites
• DM1 binding to tubulin, disrupting microtubule networks in the cell, resulting in cell
cycle arrest and apoptotic cell death
T-DM1Intracellular Delivery of DM1
HER2
Lysosomal
degradation
DM1
release*
Internalization
Inhibition of
tubulin
polymerizatio
n
KADCYLA
*The primary DM1-containing cytotoxic catabolite released is lysine-MCC-DM1.
KADCYLA Product Monograph. Hoffmann-La Roche Limited. September 11, 2013.
LoRousso PM, et al. Clin Cancer Res 2011.
PHASE II STUDY
T-DM1 vs. Docetaxel and Trastuzumab
1:1 HER2-positive,
recurrent locally
advanced breast
cancer or MBC
(N=137)
Trastuzumab 8 mg/kg loading dose; 6 mg/kg q3w IV
+ Docetaxel 75 or 100 mg/m2 q3w
(n=70)
Crossover to
T-DM1
(optional)PDa
T-DM13.6 mg/kg q3w IV
(n=67)
PDa
Hurvitz, et al., JCO, 2013
Objective Response by Investigator Patients With Measurable Disease at Baseline
Trastuzumab +
docetaxel
(n=69)a
T-DM1
(n=67)
Patients with an objective response,b n (%) 40 (58.0) 43 (64.2)
95% CI 45.5–69.2 51.8–74.8
Objective responses, n (%)
Complete response 3 (4.3) 7 (10.4)
Partial response 37 (53.6) 36 (53.7)
Stable disease 23 (33.3) 13 (19.4)
Progressive disease 4 (5.8) 8 (11.9)
Unable to evaluate or missing 2 (2.9) 3 (4.5)
Patients with clinical benefit,c n (%) 56 (81.2) 50 (74.6)
95% CI 70.7–89.1 63.2–84.2 aOne patient was not included in the efficacy analysis due to study site withdrawal.bDefined as complete or partial response based on RECIST 1.0 determined on 2 consecutive tumor assessments at least 4
weeks apart.cDefined as objective response any time during the study or maintained stable disease for at least 6 months
from randomization.
Hurvitz SA, et al. Abstract 5.001. ESMO 2011.
Hurvitz, et al., JCO, 2013
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Time (months)
Progression-Free Survival by InvestigatorRandomized Patients
Pro
po
rtio
n p
rog
ressio
n-f
ree
1.0
0.8
0.6
0.4
0.2
0.00 2 4 6 8 10 12 14 16 18 20
Number of patients at risk
T+D 70 66 63 53 43 27 12 4 2 2 0
T-DM1 67 60 51 46 42 35 22 15 6 3 0
Hazard ratio and log-rank P value were from stratified analysis.
First Line• Can we combine Pertuzumab and Herceptin with other
partners
– Other taxanes (PERUSE)
– Other chemotherapies - Vino/Cape (VELVET/PHREXA)
– Other biologics – T-DM1 (MARIANNE negative)
• Developing effective drugs that can target brain
metastases
• Duration of targeted therapy for those responding
• Duration of chemotherapy when receiving dual targeted
therapy
• Combination of endocrine therapy with dual targeted
anti-Her 2 tx for ER+/Her 2 +ve pts32
Outline
• First Line Treatment
• Second Line Treatment and Beyond
• Individualized Approach
• An Algorithm and Concluding Remarks
Second Line
(2006-2010)
• There is continued benefit of trastuzumab
beyond progression
– Capecitabine and Trastuzumab
• There is benefit of Lapatinib in combination with
Capecitabine upon progression on Trastuzumab
Recent Achievements in
Her 2 positive MBC
Second Line and Beyond
– EGF 104900
• L+ H vs L alone
– EMILIA
• T-DM1 vs Cape + L
– Bolero-3
• Vinorelbine + H + Everolimus vs. Vinorelbine
+ H
35
Trastuzumab and LapatinibOverall Survival
EMILIA Study Design
1:1
HER2-positive LABC
or MBC (N=980)
• Prior taxane and
trastuzumab
• Progression on
metastatic treatment
or within 6 months of
adjuvant treatment
PDT-DM1
3.6 mg/kg q3w IV
Capecitabine
1000 mg/m2 PO bid, days 1–14, q3w
+
Lapatinib
1250 mg/day PO qd
PD
Verma et al NEJM 2012
Verma et al NEJM 2012
EMILIA: Progression Free Survival
Verma et al NEJM 2012
EMILIA: Overall Survival
EMILIA
Adverse Events
Verma et al NEJM 201240
2
T-DM1c
(optional
crossover)
TH3RESA Study Schema
• Stratification factors: World region, number of prior regimens for advanced BC,d
presence of visceral disease
• Co-primary endpoints: PFS by investigator and OS
• Key secondary endpoints: ORR by investigator and safety
PD
PDT-DM1
3.6 mg/kg q3w IV(n=400)
Treatment of
physician’s choice
(TPC)b
(n=200)
HER2-positive (central)
advanced BCa
(N=600)
≥2 prior HER2-directed
therapies for advanced BC
Prior treatment with
trastuzumab, lapatinib,
and a taxane
a Advanced BC includes MBC and unresectable locally advanced/recurrent BC.b TPC could have been single-agent chemotherapy, hormonal therapy, or HER2-directed therapy, or a combination of a HER2-directed therapy with
a chemotherapy, hormonal therapy, or other HER2-directed therapy.c First patient in: Sep 2011. Study amended Sep 2012 (following EMILIA 2nd interim OS results) to allow patients in the TPC arm to receive
T-DM1 after documented PD.d Excluding single-agent hormonal therapy.
BC, breast cancer; IV, intravenous; ORR, objective response rate; PD, progressive disease; q3w, every 3 weeks.
1
Wildiers H, et al. ECC 2013; Abstract 15LBA.
.
PFS by Investigator Assessment
Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months.
Unstratified HR=0.521 (P<0.0001).
198 120 62 28 13 6 1 0
404 334 241 114 66 27 12 0
TPC
T-DM1
No. at risk:Time (months)
1412108642
0.0
0.2
0.4
0.6
0.8
1.0
0
Pro
po
rtio
n p
rog
ress
ion
-fre
e
TPC
(n=198)
T-DM1
(n=404)
Median (months) 3.3 6.2
No. of events 129 219
Stratified HR=0.528 (95% CI, 0.422, 0.661)
P<0.0001
Wildiers H, et al. ECC 2013; Abstract 15LBA.
.
First Interim OS Analysis
198
404
169
381
125
316
80
207
51
127
30
65
9
30
0
0
TPC
T-DM1
No. at risk:
3
7
Time (months)
44 patients in the TPC arm received crossover T-DM1 treatment after documented progression.