Palliative Therapie des Mammakarzinoms

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1 Dr. med. Johannes Ettl Interdisziplinäres Brustzentrum und Frauenklinik rechts der Isar, Technische Universität München, Direktorin: Prof. Dr. M. Kiechle Palliative Therapie des Mammakarzinoms Highlights vom ASCO 2012, München 19. Juli 2012

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7 Fazit CALB Wöchentliches Paclitaxel in Kombination mit Subline bearbeiten Bevacizumab bleibt ein Standard d beim bi Her2neg MBCA Beste Wirksamkeit UND Verträglichkeit dieser Kombination Fußzeile

8 Primary Results From EMILIA, a Phase 3 Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine and Lapatinib in HER2-Positive Locally Advanced or Metastatic Breast Cancer Previously Treated With Trastuzumab and a Taxane K Blackwell, 1 D Miles, 2 L Gianni, 3 IE Krop, 4 M Welslau, 5 J Baselga, 6 M Pegram, 7 D-Y Oh, 8 V Diéras, 9 S Olsen, 10 LF Fang, 10, MW Lu, 10 EG Guardino, 10 SV Verma 11 1 Duke Cancer Institute, Durham, NC, USA; 2 Mount Vernon Cancer Center, Northwood, UK; 3 San Raffaele Hospital, Milan, Italy; 4 Dana-Farber Cancer Institute, Boston, MA, USA; 5 Medical Office Hematology, Aschaffenburg, Germany; 6 Massachusetts General Hospital, Boston, MA, USA; 7 University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA; 8 Seoul National University College of Medicine, Seoul, Korea; 9 Institut Curie, Paris, France; 10 Genentech, Inc, South San Francisco, CA, USA; 11 Sunnybrook Odette Cancer Center, Toronto, Canada 8

9 T-DM1: Wirkungsmechanismus HER2 T-DM1 Emtansine release Inhibition of microtubule polymerization Lysosome P P P Internalization Nucleus Clin Cancer Res

10 EMILIA Study Design HER2+ (central) LABC or MBC (N=980) T-DM1 3.6 mg/kg q3w IV PD Prior taxane and trastuzumab Progression on metastatic tx or within 6 mos of adjuvant a tx 11 1:1 Capecitabine 1000 mg/m 2 orally bid, days 1 14, 14 q3w + Lapatinib 1250 mg/day orally qd PD Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease Primary end points: PFS by independent review, OS, and safety Key secondary end points: PFS by investigator, ORR, duration of response, time to symptom progression 10

11 Prior Systemic Treatment Cap + Lap (n=496) T-DM1 (n=495) Prior treatment type, n (%) Taxanes 494 (100) 493 (100) Anthracyclines Endocrine agents 302 (61) 204 (41) 303 (61) 205 (41) Prior therapy for MBC, n (%) Yes No Prior trastuzumab treatment, n (%) EBC only Duration of trastuzumab t treatment, t t n (%) <1 yr 1 yr 438 (88) 58 (12) 495 (100) 77 (16) 435 (88) 60 (12) 495 (100) 78 (16) 212 (43) 210 (42) 284 (57) 285 (58) Median time since last trastuzumab, mos (range) 1.5 (0 98) 1.5 (0 63) 11

12 Proportio on progr ression- free Progression-Free Survival by Independent Review Median (mos) No. events Cap + Lap T-DM Stratified HR=0.650 (95% CI, 0.55, 0.77) P< Time (mos) No. at risk by independent review: Cap + Lap T-DM Unstratified HR=0.66 (P<0.0001). 12

13 Proport tion surv viving Overall Survival: Interim Analysis 84.7% 77.0% 65.4% 47.5% Median (mos) No. events Cap + Lap T-DM1 NR 94 Stratified HR=0.621 (95% CI, 0.48, 0.81) P= Efficacy stopping boundary P= or HR= Time (mos) No. at risk: Cap + Lap T-DM Unstratified HR=0.63 (P=0.0005). NR=not reached. 13

14 Progression-Free Survival Subgroup Analyses Pre-specified Stratification Factors Baseline characteristic All pts Cap + Lap T-DM1 Total Median, Median, HR n mos mos (95% CI) (0.56, 0.78) T-DM1 Cap + Lap better better World region US Western Europe Other (0.51, 0.98) 056( (0.41, 074) 0.74) 0.73 (0.56, 0.94) Number prior chemo regimens for MBC or unresectable LABC (0.55, 0.85) > ( (0.49, 082) 0.82) Presence of visceral disease Yes No ( (0.45, 067) 0.67) (0.71, 1.30) Hazard ratio HRs from unstratified analysis. 14

15 Progression-Free Survival Subgroup Analyses Cap + Lap T-DM1 Baseline T-DM1 Cap + Lap characteristic better better All pts Total n Median, mos Median, mos HR (95% CI) (0.56, 0.78) Age <65 yrs 65 yrs (0.52, 0.74) (0.68, 1.66) ER and PR status ER+ and/or PR+ ER and PR ( (0.58, 091) 0.91) (0.44, 0.72) Line of therapy a First Second Third (0.30, 0.85) 0.69 (0.53, 0.91) (0.55, 0.86) Hazard ratio HRs were from unstratified analysis. a Defined as any systemic therapy, including endocrine or chemotherapy

16 Patient-Reported Outcomes Time to Symptom Progression The FACT-Breast Trial Outcome Index 1 evaluates Physical Well-Being Functional Well-Being Breast Cancer-Specific Symptoms Symptom progression defined as 5-point p decrease from baseline Cap + Lap T-DM1 Time to symptom progression (n=445) (n=450) Median, mos HR (95% CI) P value 0.80 (0.67, 0.95) Brady MJ, et al. J Clin Oncol

17 Non-Hematologic Adverse Events Grade 3 AEs With Incidence 2% Cap + Lap (n=488) T-DM1 (n=490) Adverse Event All Grades, % Grade 3, % All Grades, % Grade 3, % Diarrhea Hand-foot syndrome Vomiting Hypokalemia Fatigue Nausea Mucosal inflammation Increased AST Increased ALT ALT, alanine aminotransferase; AST, aspartate aminotransferase. 17

18 Hematologic Adverse Events Cap + Lap (n=488) T-DM1 (n=490) All Grade, Grade 3, Grade 4, All Grade, Grade 3, Grade 4, Adverse Event % % % % % % Neutropenia Febrile neutropenia Anemia Thrombocytopenia

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25 Fazit Her2pos MBCA In Subline der Trastuzumab Reisistenz ist bearbeiten der Monotherapie T DM1 der Kombinationstherapie Capecitabine/Lapatinib überlegen durch gesteigerter Effektivität i und bessere Verträglichkeit i Lapatinib in der Kombination mit Taxan ist nicht geeeignet für die 1st line Therapie des Her2pos MBCA Beachte: Studienkollektiv EMILIA und MA.31 entspricht immer weniger unseren aktuellen Patientinnen (adjuvante Vorbehandlung mit Trastuzumab Fußzeile

26 ASCO 2012; Posterdicussion, Abstr #527

27 Welche Her2 Bockade(n) zu welcher Zeit? Antibody: Trastuzumab IV P P HER2 Cytotoxic: DM1 Stable linker: MCC Emtansine P P P Trastuzumab Lapatinib P T-DM1 HER3 Ligandenaktiviert Nucleus Pertuzumab II Spector NL, Blackwell KL. J Clin Oncol 2009; Nelson MH, et al. Ann Pharmacother 2006; Lewis Phillips GD, et al. Cancer Res 2008

28 Study design MO28047 PERUSE Study Trastuzumab + Pertuzumab + Taxan (Docetaxel oder Paclitaxeloder nab Paclitaxel; nach Wahl des Prüfarztes) Patienten/ innen mit HER2 positivem Brustkrebs im fortgeschrittenen Stadium, die zuvor nicht mit einer systemischen nicht hormonellen Krebstherapie in der metastasierten Situation behandelt wurden (n = 1.500) Until disease progression, unacceptable toxicity, withdrawal of consent, or death First 105 patients (Cohort 1) Sequential administration of pertuzumab and trastuzumab in separate infusion bags Second 105 patients (Cohort 2) [once 1st cohort is fully recruited] Pertuzumab and trastuzumab administered together in a single infusion bag from Cycle 2 (Cycle 1 in separate infusion bags) Behan Wider ndlung bis rruf der Ei s PD, nich inverständ t akzeptab dniserklär bler Toxiz rung oder ität, r Tod *210 patients ts to be enrolled ed to give 190 evaluable e patients ts (95 patients ts in each cohort)