Metastatic HER2-Positive Breast Cancer: Treatment Selection and Sequencing in the First Line and Beyond Moderator: Panelist: Joseph Gligorov, MD, PhD Javier Cortés, MD, PhD Head, Cancer Coordination Center HUEP University Cancer Institute Sorbonne University Paris, France Head, Breast Cancer Program Department of Oncology Vall d'Hebron University Hospital Barcelona, Spain Panelist: Panelist: Carlos H. Barrios, MD David W. Miles, MD Professor of Internal Medicine; Director, Oncology Research Unit Pontifícia Universidade Católica Porto Alegre, Brazil Consultant Medical Oncologist Mount Vernon Cancer Centre London, United Kingdom This Program Will Review: • Recent clinical trial data on the management of HER2+ advanced and MBC • Challenges of integrating HER2-targeting agents into clinical practice – – – – Selecting a first-line treatment Sequencing treatments in second line and beyond Knowing how to proceed when evidence is unclear Balancing treatment efficacy with patient quality of life HER2 = human epidermal growth factor 2; MBC = metastatic breast cancer Historical Context: Targeting HER2 • First demonstration of clinical benefit with HER2 targeting: the addition of trastuzumab to chemotherapy* Chemotherapy + Trastuzumab (n=236) Chemotherapy Alone (n=234) P value Median time to disease progression 7.4 months 4.6 months HR=0.51 P<.001 Median TTF 6.9 months 4.5 months HR=0.58 P<.001 Median OS 25.1 months 20.3 months 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) Paclitaxel + Trastuzumab (n=92) Paclitaxel Alone (n=96) P value Median time to disease progression 6.9 months 3.0 months HR=0.38 P<.001 Median TTF 5.8 months 2.9 months HR=0.46 P<.001 Median OS 22.1 months 18.4 months 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 Pertuzumab binds to a specific domain II and inhibits ligand-activated dimerization HER2 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) Pertuzumab Alone[c] (n=29) Pertuzumab Pertuzumab + Trastuzumab[c] (n=17) 24.2% 3.4% 17.6% 50% 10.3% 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 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/m2, escalating to 100 mg/m2 if tolerated Baselga J, et al. N Engl J Med. 2012;366(2):109-119. CLEOPATRA: Updated Survival Results Median PFS Pertuzumab + Trastuzumab + Docetaxel (n=402) Placebo + Trastuzumab + Docetaxel (n=406) 18.7 months 12.4 months Improvement: 6.3 months Median OS 56.5 months 40.8 months Improvement: 15.7 months PFS = progression-free survival Swain SJ, et al. ESMO 2014. Abstract 350O_PR. P value HR=0.68 P<.0001 HR=0.68 P<.0002 CLEOPATRA: Adverse Events Pertuzumab + Trastuzumab + Docetaxel (n=408) Placebo + Trastuzumab + Docetaxel (n=396) Leukopenia 12.3% 14.9% Neutropenia 49.0% 46.2% Febrile neutropenia 13.7% 7.6% Diarrhea (grade 3/4) 9.3% 5.1% LVEF decline to < 50% and by ≥ 10% points from baseline 6.1% 7.4% Grade 3/4 hematologic AEs AE = adverse event; LVEF = left ventricular ejection fraction Swain SJ, et al. ESMO 2014. Abstract 350O_PR. PERUSE: Pertuzumab + Trastuzumab + Investigator’s Choice of Taxane Select Grade 3/4 AEs (Initial Results) All patients (N=704) Docetaxel (n=320) Paclitaxel (n=331) Nab-paclitaxel (n=45) 14 Patients (%) 12 10 8 6 4 2 0 Neutropenia Diarrhea Bachelot T, et al. ASCO 2014. Abstract 548. Febrile neutropenia Anemia Mucosal inflammation Fatigue Asthenia VELVET: Pertuzumab + Trastuzumab + Vinorelbine Selected AEs (Interim Analysis) VELVET[a] HERNATA[b] Diarrhea 49.1% 11.6% Alopecia 23.6% NR Neutropenia (grade 3/4) 23.6% 41.5% Febrile neutropenia 5.7% 10.8% Leukopenia (grade 3/4) 8.5% 21 a. Perez E, et al. SABCS 2013. Abstract P2-16-10. b. Andersson M, et al. J Clin Oncol. 2011;29(3):264-271. MARIANNE: T-DM1 + Pertuzumab or Placebo vs Trastuzumab + Taxane Arm A 1092 patients with HER2+ MBC 1:1:1 R A N D O M I Z E 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 • Patients on HER2-blocking regimens have better outcomes than ever before • Dual blockade with trastuzumab + pertuzumab is the standard of care -- maximal blockade of HER2 is clearly critical • Choice of chemotherapy may not be as important for treatment outcomes; choice of chemotherapy arm is important to minimize side effects • 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 Trastuzumab + Capecitabine vs Capecitabine[a] Lapatinib + Capecitabine vs Capecitabine[b,c] Median TTP 8.2 vs 5.6 months HR=0.69; P=.0338 6.2 vs 4.3 months HR=0.57; P<.001 Median OS 25.5 vs 20.4 months HR=0.76; P=.257 75.0 vs 64.7 weeks HR=0.87; P=.206 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. 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 • 991 patients previously treated with trastuzumab and a taxane T-DM1 Lapatinib + Capecitabine P value Median PFS 9.4 months 6.4 month HR=.65 P<.0001 Median OS 30.9 months 25.1 months HR=.682 P=.0006 12-month survival rate 85.2% 78.4% 24-month survival rate 64.7% 51.8% Verma S, et al. N Engl J Med. 2012;367(19):1783-1791. EGF104900: Trastuzumab + Lapatinib • 296 patients previously treated with trastuzumab and a taxane randomly assigned (1:1) to lapatinib ± trastuzumab Lapatinib Lapatinib + Trastuzumab P value Median PFS 8.1 weeks 11.1 weeks HR=0.74 P=.011 Median OS 9.5 months 14.0 months HR=0.74 P=.026 12-month survival rate 80% 56% 24-month survival rate 70% 41% Blackwell K, et al. J Clin Oncol. 2012;30(21):2585-9252. BOLERO-3: Trastuzumab + the mTOR Inhibitor Everolimus • PI3K/Akt/mTOR pathway is upregulated in trastuzumab resistant HER2+ MBC • Everolimus is an mTORC1 inhibitor that downregulates activity of the pathway Design • 569 patients previously treated with trastuzumab + taxane • Treated with trastuzumab + vinorelbine + everolimus or placebo Outcomes • 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 • 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 Physician’s choice P value 31.3% 8.6% P<.0001 6.2 months 3.3 months HR=0.528 P<.0001 NE 14.9 months 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 • Continued blockade of HER2 is clearly beneficial • T-DM1 is the standard of care for second-line treatment; there are no patient populations not likely to benefit • More research is needed to define the optimal treatment regimen in different patient populations – Role for pertuzumab if not given in the first line – Sequence of treatments beyond first line – Using toxicity to drive treatment selection Conclusions • Multiple available treatments significantly prolong OS in patients with HER2+ MBC • Standard of care at all stages: continued HER2+ blockade – First-line: trastuzumab + pertuzumab (CLEOPATRA) – Second-line: T-DM1 (EMILIA) • Ongoing research will help define the best use of each agent in each line of therapy • With appropriate use of these drugs, HER2+ MBC is beginning to turn into a chronic disease with very good quality of life Thank you for participating in this activity. 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