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

• • •

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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