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 BeyondModerator:Joseph Gligorov, MD, PhDHead, Cancer Coordination Center HUEPUniversity Cancer InstituteSorbonne UniversityParis, FrancePanelist:Carlos H. Barrios, MDProfessor of Internal Medicine;Director, Oncology Research UnitPontifícia Universidade CatólicaPorto Alegre, BrazilPanelist:Javier Cortés, MD, PhDHead, Breast Cancer ProgramDepartment of OncologyVall d'Hebron University Hospital Barcelona, SpainDavid W. Miles, MDConsultant Medical OncologistMount Vernon Cancer CentreLondon, United Kingdom
2 This Program Will Review: Recent clinical trial data on the management of HER2+ advanced and MBCChallenges of integrating HER2-targeting agents into clinical practiceSelecting a first-line treatmentSequencing treatments in second line and beyondKnowing how to proceed when evidence is unclearBalancing treatment efficacy with patient quality of lifeHER2 = 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*Chemotherapy + Trastuzumab(n=236)Chemotherapy Alone (n=234)P valueMedian time to disease progression7.4 months4.6 monthsHR=0.51P<.001Median TTF6.9 months4.5 monthsHR=0.58Median OS25.1 months20.3 monthsHR=0.80P=.046*Either anthracycline + cyclophosphamide or paclitaxelHR = hazard ratio; OS = overall survival; TTF= time to treatment failureSlamon DJ, et al. N Engl J Med. 2001;344(11):
4 Historical Context: Targeting HER2 (cont) Paclitaxel + Trastuzumab(n=92)Paclitaxel Alone (n=96)P valueMedian time to disease progression6.9 months3.0 monthsHR=0.38P<.001Median TTF5.8 months2.9 monthsHR=0.46Median OS22.1 months18.4 monthsHR=0.80P=.17Slamon DJ, et al. N Engl J Med. 2001;344(11):
5 Trastuzumab binds to subdomain IV and inhibits downstream signalling Pertuzumab and Trastuzumab: Mechanisms of ActionPertuzumab binds to a specific domain II and inhibits ligand-activated dimerizationTrastuzumab binds to subdomain IV and inhibits downstream signallingHER2HER1-4Cell membraneThe combined regimen of pertuzumab and trastuzumab offers the potential for a more comprehensive HER blockadeFranklin MC, et al. Cancer Cell. 2004;5(4):5
6 Phase 2 Study: Pertuzumab + Trastuzumab in Patients Progressing on Trastuzumab 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 monthsa. Baselga J, et al. J Clin Oncol. 2010;28(7):b. Cortes J, et al. J Clin Oncol. 2012;30(14):
7 CLEOPATRA: Trastuzumab + Docetaxel + Pertuzumab or Placebo RANDOMIZETrastuzumab + pertuzumab until progressive disease808 patients with centrally confirmed HER2+ MBC≥ 6 cycles of docetaxel recommended1:1Trastuzumab + placebo until progressive disease≥ 6 cycles of docetaxel recommendedStudy dosing every 3 weeksPertuzumab/Placebo: 840 mg loading dose, 420 mg maintenanceTrastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenanceDocetaxel: 75 mg/m2, escalating to 100 mg/m2 if toleratedBaselga J, et al. N Engl J Med. 2012;366(2):
11 VELVET: Pertuzumab + Trastuzumab + Vinorelbine Selected AEs (Interim Analysis) VELVET[a]HERNATA[b]Diarrhea49.1%11.6%Alopecia23.6%NRNeutropenia (grade 3/4)41.5%Febrile neutropenia5.7%10.8%Leukopenia (grade 3/4)8.5%21a. Perez E, et al. SABCS Abstract Pb. Andersson M, et al. J Clin Oncol. 2011;29(3):
12 MARIANNE: T-DM1 + Pertuzumab or Placebo vs Trastuzumab + Taxane Arm ARANDOMIZETrastuzumab + taxane until progressive disease1092 patients with HER2+ MBCArm B1:1:1T-DM1 + pertuzumab until progressive diseaseArm CT-DM1 + placebo until progressive diseasePrimary endpoint: PFS (independent assessment)T-DM1 = trastuzumab emtansineEllis PA, et al. ASCO Abstract TPS102.
13 First-Line Treatment: Applying Trial Data to Clinical Practice Patients on HER2-blocking regimens have better outcomes than ever beforeDual blockade with trastuzumab + pertuzumab is the standard of care -- maximal blockade of HER2 is clearly criticalChoice of chemotherapy may not be as important for treatment outcomes; choice of chemotherapy arm is important to minimize side effectsMore 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 Trastuzumab + Capecitabine vs Capecitabine[a]Lapatinib + Capecitabine vsCapecitabine[b,c]Median TTP8.2 vs 5.6 monthsHR=0.69; P=.03386.2 vs 4.3 monthsHR=0.57; P<.001Median OS25.5 vs 20.4 monthsHR=0.76; P=.25775.0 vs 64.7 weeksHR=0.87; P=.206TTP = time to progressiona. 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):
15 T-DM1: Antibody Drug Conjugate HER2HER2Cell membraneIntracellular emtansine release inhibition of microtubule polymerizationLoRusso PM, et al. Clin Cancer Res. 2011;17(20):15
16 EMILIA: T-DM1 vs Lapatinib + Capecitabine 991 patients previously treated with trastuzumab and a taxaneT-DM1Lapatinib + CapecitabineP valueMedian PFS9.4 months6.4 monthHR=.65P<.0001Median OS30.9 months25.1 monthsHR=.682P=.000612-month survival rate85.2%78.4%24-month survival rate64.7%51.8%Verma S, et al. N Engl J Med. 2012;367(19):
17 EGF104900: Trastuzumab + Lapatinib 296 patients previously treated with trastuzumab and a taxane randomly assigned (1:1) to lapatinib ± trastuzumabLapatinibLapatinib + TrastuzumabP valueMedian PFS8.1 weeks11.1 weeksHR=0.74P=.011Median OS9.5 months14.0 monthsP=.02612-month survival rate80%56%24-month survival rate70%41%Blackwell K, et al. J Clin Oncol. 2012;30(21):
18 BOLERO-3: Trastuzumab + the mTOR Inhibitor Everolimus PI3K/Akt/mTOR pathway is upregulated in trastuzumab resistant HER2+ MBCEverolimus is an mTORC1 inhibitor that downregulates activity of the pathwayDesign569 patients previously treated with trastuzumab + taxaneTreated with trastuzumab + vinorelbine + everolimus or placeboOutcomesPFS: vs 5.78 months; HR=0.78; P=.0067ORR: 41% vs 37%; P=.2108ORR = overall response rateAndre F, et al. Lancet Oncol. 2014;15(6):
19 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*T-DM1Physician’s choiceP valueORR31.3%8.6%P<.0001Median PFS6.2 months3.3 monthsHR=0.528Median OS (interim analysis)NE14.9 monthsHR=0.552P=.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 estimableKrop IE, et al. Lancet Oncol ;15(7):
20 Second-Line and Beyond: Applying Trial Data to Clinical Practice Continued blockade of HER2 is clearly beneficialT-DM1 is the standard of care for second-line treatment; there are no patient populations not likely to benefitMore research is needed to define the optimal treatment regimen in different patient populationsRole for pertuzumab if not given in the first lineSequence of treatments beyond first lineUsing toxicity to drive treatment selection
21 ConclusionsMultiple available treatments significantly prolong OS in patients with HER2+ MBCStandard of care at all stages: continued HER2+ blockadeFirst-line: trastuzumab + pertuzumab (CLEOPATRA)Second-line: T-DM1 (EMILIA)Ongoing research will help define the best use of each agent in each line of therapyWith 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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