Transcript Pertuzumab + Trastuzumab + Docetaxel
Metastatic HER2-Positive Breast Cancer: Treatment Selection and Sequencing in the First Line and Beyond
Moderator:
Joseph Gligorov, MD, PhD Head, Cancer Coordination Center HUEP University Cancer Institute Sorbonne University Paris, France
Panelist:
Carlos H. Barrios, MD Professor of Internal Medicine; Director, Oncology Research Unit Pontifícia Universidade Católica Porto Alegre, Brazil
Panelist:
Javier Cortés, MD, PhD Head, Breast Cancer Program Department of Oncology Vall d'Hebron University Hospital Barcelona, Spain
Panelist:
David W. Miles, MD Consultant Medical Oncologist Mount Vernon Cancer Centre London, United Kingdom
This Program Will Review:
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Recent clinical trial data on the management of HER2+ advanced and MBC
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Challenges of integrating HER2-targeting agents into clinical practice
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Selecting a first-line treatment
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Sequencing treatments in second line and beyond
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Knowing how to proceed when evidence is unclear
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Balancing treatment efficacy with patient quality of life HER2 = human epidermal growth factor 2; MBC = metastatic breast cancer
Historical Context: Targeting HER2
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First demonstration of clinical benefit with HER2 targeting: the addition of trastuzumab to chemotherapy* Median time to disease progression Median TTF Chemotherapy + Trastuzumab (n=236) 7.4 months 6.9 months Median OS 25.1 months Chemotherapy Alone (n=234) 4.6 months 4.5 months 20.3 months P value HR=0.51
P<.001
HR=0.58
P<.001
HR=0.80
P=.046
*Either anthracycline + cyclophosphamide or paclitaxel HR = hazard ratio; OS = overall survival; TTF= time to treatment failure
Slamon DJ, et al. N Engl J Med. 2001;344(11):783-792.
Historical Context: Targeting HER2 (cont)
Median time to disease progression Median TTF Paclitaxel + Trastuzumab (n=92) 6.9 months 5.8 months Median OS 22.1 months Paclitaxel Alone (n=96) 3.0 months 2.9 months 18.4 months P value HR=0.38
P<.001
HR=0.46
P<.001
HR=0.80
P=.17
Slamon DJ, et al. N Engl J Med. 2001;344(11):783-792.
Pertuzumab and Trastuzumab:
Mechanisms of Action Trastuzumab binds to subdomain IV and inhibits downstream signalling HER2 Pertuzumab binds to a specific domain II and inhibits ligand-activated dimerization HER1-4 Cell membrane The combined regimen of pertuzumab and trastuzumab offers the potential for a more comprehensive HER blockade
Franklin MC, et al. Cancer Cell. 2004;5(4):317-328.
Phase 2 Study: Pertuzumab + Trastuzumab in Patients Progressing on Trastuzumab Objective response rate Clinical benefit rate* Pertuzumab + Trastuzumab [a] (n=66) 24.2% 50% Pertuzumab Alone [c] (n=29) 3.4% 10.3% Pertuzumab
Pertuzumab + Trastuzumab [c] (n=17) 17.6% 41.2% *Defined as complete response, partial response, and stable disease ≥ 6 months
a. Baselga J, et al. J Clin Oncol. 2010;28(7):1138-1144.
b. Cortes J, et al. J Clin Oncol. 2012;30(14):1594-1600.
CLEOPATRA: Trastuzumab + Docetaxel + Pertuzumab or Placebo 808 patients with centrally confirmed HER2+ MBC 1:1 R A N D O M I Z E Trastuzumab + pertuzumab until progressive disease ≥ 6 cycles of docetaxel recommended Trastuzumab + placebo until progressive disease ≥ 6 cycles of docetaxel recommended
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Study dosing every 3 weeks Pertuzumab/Placebo: 840 mg loading dose, 420 mg maintenance Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance Docetaxel: 75 mg/m 2 , escalating to 100 mg/m 2 if tolerated
Baselga J, et al. N Engl J Med. 2012;366(2):109-119.
CLEOPATRA: Updated Survival Results
Median PFS Median OS Pertuzumab + Trastuzumab + Docetaxel (n=402) Placebo + Trastuzumab + Docetaxel (n=406) 18.7 months 12.4 months
Improvement: 6.3 months
56.5 months 40.8 months
Improvement: 15.7 months
P value HR=0.68
P<.0001
HR=0.68
P<.0002
PFS = progression-free survival
Swain SJ, et al. ESMO 2014. Abstract 350O_PR.
CLEOPATRA: Adverse Events
Pertuzumab + Trastuzumab + Docetaxel (n=408) Grade 3/4 hematologic AEs Leukopenia Neutropenia Febrile neutropenia Diarrhea (grade 3/4) LVEF decline to < 50% and by ≥ 10% points from baseline 12.3% 49.0% 13.7% 9.3% 6.1% AE = adverse event; LVEF = left ventricular ejection fraction
Swain SJ, et al. ESMO 2014. Abstract 350O_PR.
Placebo + Trastuzumab + Docetaxel (n=396) 14.9% 46.2% 7.6% 5.1% 7.4%
PERUSE: Pertuzumab + Trastuzumab + Investigator’s Choice of Taxane
Select Grade 3/4 AEs (Initial Results) 2 0 6 4 14 12 10 8 All patients (N=704) Docetaxel (n=320) Paclitaxel (n=331) Nab-paclitaxel (n=45) Neutropenia Diarrhea Febrile neutropenia Anemia Mucosal inflammation Fatigue Asthenia
Bachelot T, et al. ASCO 2014. Abstract 548.
VELVET: Pertuzumab + Trastuzumab + Vinorelbine Selected AEs (Interim Analysis) Diarrhea Alopecia Neutropenia (grade 3/4) Febrile neutropenia Leukopenia (grade 3/4)
a. Perez E, et al. SABCS 2013. Abstract P2-16-10.
b. Andersson M, et al. J Clin Oncol. 2011;29(3):264-271.
VELVET [a] 49.1% 23.6% 23.6% 5.7% 8.5% HERNATA [b] 11.6% NR 41.5% 10.8% 21
MARIANNE: T-DM1 + Pertuzumab or Placebo vs Trastuzumab + Taxane 1092 patients with HER2+ MBC 1:1:1 M I Z E R A N D O Arm A Trastuzumab + taxane until progressive disease Arm B T-DM1 + pertuzumab until progressive disease Arm C T-DM1 + placebo until progressive disease Primary endpoint: PFS (independent assessment) T-DM1 = trastuzumab emtansine
Ellis PA, et al. ASCO 2011. Abstract TPS102.
First-Line Treatment: Applying Trial Data to Clinical Practice
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Patients on HER2-blocking regimens have better outcomes than ever before
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Dual blockade with trastuzumab + pertuzumab is the standard of care -- maximal blockade of HER2 is clearly critical
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Choice of chemotherapy may not be as important for treatment outcomes; choice of chemotherapy arm is important to minimize side effects
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More research will help determine whether some populations might do well with dual HER2 blockade only, without chemotherapy
The Benefits of Continued HER2 Blockade Beyond Progression
Median TTP Trastuzumab + Capecitabine vs Capecitabine [a] 8.2 vs 5.6 months HR=0.69; P=.0338
Median OS 25.5 vs 20.4 months HR=0.76; P=.257
TTP = time to progression
a. Von Minckwitz G, et al. J Clin Oncol. 2009;27(12):1999-2006.
b. Cameron D, et al. Breast Cancer Res Treat. 2008;112(3):533-543.
c. Cameron D, et al. Oncologist. 2010;15(9):924-934.
Lapatinib + Capecitabine vs Capecitabine [b,c] 6.2 vs 4.3 months HR=0.57; P<.001
75.0 vs 64.7 weeks HR=0.87; P=.206
T-DM1: Antibody Drug Conjugate
HER2 HER2 Cell membrane Intracellular emtansine release
inhibition of microtubule polymerization
LoRusso PM, et al. Clin Cancer Res. 2011;17(20):6437-6447.
EMILIA: T-DM1 vs Lapatinib + Capecitabine
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991 patients previously treated with trastuzumab and a taxane Median PFS Median OS 12-month survival rate 24-month survival rate T-DM1 9.4 months 30.9 months 85.2% 64.7% Lapatinib + Capecitabine 6.4 month 25.1 months 78.4% 51.8% P value HR=.65
P<.0001
HR=.682
P=.0006
Verma S, et al. N Engl J Med. 2012;367(19):1783-1791.
EGF104900: Trastuzumab + Lapatinib
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296 patients previously treated with trastuzumab and a taxane randomly assigned (1:1) to lapatinib
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trastuzumab Median PFS Median OS 12-month survival rate 24-month survival rate Lapatinib 8.1 weeks 9.5 months 80% 70% Lapatinib + Trastuzumab 11.1 weeks 14.0 months 56% 41% P value HR=0.74
P=.011
HR=0.74
P=.026
Blackwell K, et al. J Clin Oncol. 2012;30(21):2585-9252.
BOLERO-3: Trastuzumab + the mTOR Inhibitor Everolimus
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PI3K/Akt/mTOR pathway is upregulated in trastuzumab resistant HER2+ MBC
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Everolimus is an mTORC1 inhibitor that downregulates activity of the pathway Design Outcomes
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569 patients previously treated with trastuzumab + taxane Treated with trastuzumab + vinorelbine + everolimus or placebo
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PFS: 7.00 vs 5.78 months; HR=0.78; P=.0067
ORR: 41% vs 37%; P=.2108
ORR = overall response rate
Andre F, et al. Lancet Oncol. 2014;15(6):580-591.
TH3RESA: T-DM1 in Heavily Pretreated MBC
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600 patients previously treated with ≥ 2 prior therapies (trastuzumab, lapatinib, taxane) randomly assigned (2:1) to T-DM1 or treatment of physician’s choice* ORR Median PFS Median OS (interim analysis) T-DM1 31.3% 6.2 months NE Physician’s choice 8.6% 3.3 months 14.9 months P value P<.0001
HR=0.528
P<.0001
HR=0.552
P=.0034
*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.
NE = not estimable
Krop IE, et al. Lancet Oncol. 2014 ;15(7):689-699.
Second-Line and Beyond: Applying Trial Data to Clinical Practice
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Continued blockade of HER2 is clearly beneficial
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T-DM1 is the standard of care for second-line treatment; there are no patient populations not likely to benefit
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More research is needed to define the optimal treatment regimen in different patient populations
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Role for pertuzumab if not given in the first line
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Sequence of treatments beyond first line
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Using toxicity to drive treatment selection
Conclusions
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Multiple available treatments significantly prolong OS in patients with HER2+ MBC
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Standard of care at all stages: continued HER2+ blockade
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First-line: trastuzumab + pertuzumab (CLEOPATRA)
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Second-line: T-DM1 (EMILIA)
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Ongoing research will help define the best use of each agent in each line of therapy
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With appropriate use of these drugs, HER2+ MBC is beginning to turn into a chronic disease with very good quality of life
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