Presentation is loading. Please wait.

Presentation is loading. Please wait.

Metastatic HER2-Positive Breast Cancer: Treatment Selection and Sequencing in the First Line and Beyond Moderator: Joseph Gligorov, MD, PhD Head, Cancer.

Similar presentations


Presentation on theme: "Metastatic HER2-Positive Breast Cancer: Treatment Selection and Sequencing in the First Line and Beyond Moderator: Joseph Gligorov, MD, PhD Head, Cancer."— Presentation transcript:

1 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

2 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

3 Historical Context: Targeting HER2 First demonstration of clinical benefit with HER2 targeting: the addition of trastuzumab to chemotherapy* Slamon DJ, et al. N Engl J Med. 2001;344(11): Chemotherapy + Trastuzumab (n=236) Chemotherapy Alone (n=234) P value Median time to disease progression 7.4 months4.6 months HR=0.51 P<.001 Median TTF6.9 months4.5 months HR=0.58 P<.001 Median OS25.1 months20.3 months HR=0.80 P=.046 *Either anthracycline + cyclophosphamide or paclitaxel HR = hazard ratio; OS = overall survival; TTF= time to treatment failure

4 Historical Context: Targeting HER2 (cont) Paclitaxel + Trastuzumab (n=92) Paclitaxel Alone (n=96) P value Median time to disease progression 6.9 months3.0 months HR=0.38 P<.001 Median TTF5.8 months2.9 months HR=0.46 P<.001 Median OS22.1 months18.4 months HR=0.80 P=.17 Slamon DJ, et al. N Engl J Med. 2001;344(11):

5 HER2 HER1-4 Pertuzumab binds to a specific domain II and inhibits ligand-activated dimerization Trastuzumab binds to subdomain IV and inhibits downstream signalling Pertuzumab and Trastuzumab: Mechanisms of Action The combined regimen of pertuzumab and trastuzumab offers the potential for a more comprehensive HER blockade Cell membrane Franklin MC, et al. Cancer Cell. 2004;5(4):

6 Phase 2 Study: Pertuzumab + Trastuzumab in Patients Progressing on Trastuzumab a. Baselga J, et al. J Clin Oncol. 2010;28(7): b. Cortes J, et al. J Clin Oncol. 2012;30(14): Pertuzumab + Trastuzumab [a] (n=66) Pertuzumab Alone [c] (n=29) Pertuzumab  Pertuzumab + Trastuzumab [c] (n=17) Objective response rate24.2%3.4%17.6% Clinical benefit rate*50%10.3%41.2% *Defined as complete response, partial response, and stable disease ≥ 6 months

7 CLEOPATRA: Trastuzumab + Docetaxel + Pertuzumab or Placebo Baselga J, et al. N Engl J Med. 2012;366(2): patients with centrally confirmed HER2+ MBC ≥ 6 cycles of docetaxel recommended 1:1 Trastuzumab + pertuzumab until progressive disease 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 ≥ 6 cycles of docetaxel recommended Trastuzumab + placebo until progressive disease

8 CLEOPATRA: Updated Survival Results Swain SJ, et al. ESMO Abstract 350O_PR. Pertuzumab + Trastuzumab + Docetaxel (n=402) Placebo + Trastuzumab + Docetaxel (n=406) P value Median PFS18.7 months12.4 months HR=0.68 P<.0001 Improvement: 6.3 months Median OS56.5 months40.8 months HR=0.68 P<.0002 Improvement: 15.7 months PFS = progression-free survival

9 CLEOPATRA: Adverse Events Swain SJ, et al. ESMO Abstract 350O_PR. Pertuzumab + Trastuzumab + Docetaxel (n=408) Placebo + Trastuzumab + Docetaxel (n=396) Grade 3/4 hematologic AEs Leukopenia12.3%14.9% Neutropenia49.0%46.2% Febrile neutropenia13.7%7.6% Diarrhea (grade 3/4)9.3%5.1% LVEF decline to < 50% and by ≥ 10% points from baseline 6.1%7.4% AE = adverse event; LVEF = left ventricular ejection fraction

10 PERUSE: Pertuzumab + Trastuzumab + Investigator’s Choice of Taxane Bachelot T, et al. ASCO Abstract 548. Select Grade 3/4 AEs (Initial Results)

11 VELVET: Pertuzumab + Trastuzumab + Vinorelbine Selected AEs (Interim Analysis) VELVET [a] HERNATA [b] Diarrhea49.1%11.6% Alopecia23.6%NR Neutropenia (grade 3/4)23.6%41.5% Febrile neutropenia5.7%10.8% Leukopenia (grade 3/4)8.5%21 a. Perez E, et al. SABCS Abstract P b. Andersson M, et al. J Clin Oncol. 2011;29(3):

12 MARIANNE: T-DM1 + Pertuzumab or Placebo vs Trastuzumab + Taxane 1092 patients with HER2+ MBC Arm A 1:1:1 Trastuzumab + taxane until progressive disease Primary endpoint: PFS (independent assessment) Arm B T-DM1 + pertuzumab until progressive disease Arm C T-DM1 + placebo until progressive disease Ellis PA, et al. ASCO Abstract TPS102. T-DM1 = trastuzumab emtansine

13 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

14 The Benefits of Continued HER2 Blockade Beyond Progression a. Von Minckwitz G, et al. J Clin Oncol. 2009;27(12): b. Cameron D, et al. Breast Cancer Res Treat. 2008;112(3): c. Cameron D, et al. Oncologist. 2010;15(9): Trastuzumab + Capecitabine vs Capecitabine [a] Lapatinib + Capecitabine vs Capecitabine [b,c] Median TTP 8.2 vs 5.6 months HR=0.69; P= vs 4.3 months HR=0.57; P<.001 Median OS 25.5 vs 20.4 months HR=0.76; P= vs 64.7 weeks HR=0.87; P=.206 TTP = time to progression

15 Cell membrane T-DM1: Antibody Drug Conjugate Intracellular emtansine release  inhibition of microtubule polymerization LoRusso PM, et al. Clin Cancer Res. 2011;17(20): HER2

16 EMILIA: T-DM1 vs Lapatinib + Capecitabine Verma S, et al. N Engl J Med. 2012;367(19): T-DM1 Lapatinib + Capecitabine P value Median PFS9.4 months6.4 month HR=.65 P<.0001 Median OS30.9 months25.1 months HR=.682 P= month survival rate 85.2%78.4% 24-month survival rate 64.7%51.8% 991 patients previously treated with trastuzumab and a taxane

17 EGF104900: Trastuzumab + Lapatinib Blackwell K, et al. J Clin Oncol. 2012;30(21): Lapatinib Lapatinib + Trastuzumab P value Median PFS8.1 weeks11.1 weeks HR=0.74 P=.011 Median OS9.5 months14.0 months HR=0.74 P= month survival rate 80%56% 24-month survival rate 70%41% 296 patients previously treated with trastuzumab and a taxane randomly assigned (1:1) to lapatinib ± trastuzumab

18 BOLERO-3: Trastuzumab + the mTOR Inhibitor Everolimus Andre F, et al. Lancet Oncol. 2014;15(6): 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 PI3K/Akt/mTOR pathway is upregulated in trastuzumab resistant HER2+ MBC Everolimus is an mTORC1 inhibitor that downregulates activity of the pathway ORR = overall response rate

19 TH3RESA: T-DM1 in Heavily Pretreated MBC Krop IE, et al. Lancet Oncol ;15(7): T-DM1Physician’s choiceP value ORR31.3%8.6%P<.0001 Median PFS6.2 months3.3 months HR=0.528 P<.0001 Median OS (interim analysis) NE14.9 months HR=0.552 P= patients previously treated with ≥ 2 prior therapies (trastuzumab, lapatinib, taxane) randomly assigned (2:1) to T-DM1 or treatment of physician’s choice* *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

20 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

21 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

22 Thank you for participating in this activity. To proceed to the CME Post-Test and Activity Evaluation, click on the Earn CME Credit link on this page.


Download ppt "Metastatic HER2-Positive Breast Cancer: Treatment Selection and Sequencing in the First Line and Beyond Moderator: Joseph Gligorov, MD, PhD Head, Cancer."

Similar presentations


Ads by Google