II Simpósio Internacional de Câncer de Mama para o Oncologista Clínico PROGNOSTICO DE PACIENTES COM CA DE MAMA METASTATICO HER2+: PODEMOS FAZER MAIS? TDM-1 AND BEYOND! INGRID A. MAYER, MD, MSCI Assistant Professor of Medicine Director, Clinical Core of Breast Cancer SPORE Division of Hematology/Oncology
Major clinical advances in HER2+ breast cancer
HER2 Targeted Therapies Pertuzumab Trastuzumab TDM--1 TDM HER2 - HER2 PTEN Lapatinib PI3K SOS RAS Akt RAF MAPK Cell proliferation Cell survival Cell mobility and invasiveness Transcription MEK
Therapy for HER2+ MBC BEFORE Trastuzumab is active in HER2+ BC (survival advantage) Trastuzumab + chemo >> chemo HER2-targeted therapy + endocrine therapy > endocrine therapy in HER2+/ ER+ MBC Chemo doublet + trastuzumab = chemo + trastuzumab Several chemo partners work with trastuzumab
TDM-1 Novel antibody drugconjugate linked to a potent cytotoxic agent (maytansine derivative; a microtubule inhibitor): selectively delivers DM1 to HER2+ cells
Phase II trial of TDM1 in heavily pre-treated patients with HER2+ MBC All patients were exposed to anthracyclines, taxanes, capecitabine, lapatinib and trastuzumab, and had to have more than 2 lines of therapy in the metastatic setting Median number of agents for MBC treatment: 7! Krop et al. JCO 2012
Phase II trial of TDM1 vs. trastuzumab/ docetaxel in 1 st line treatment of HER2+ MBC Perez et al. JCO 2013
EMILIA: Phase III trial of T-DM1 vs. capecitabine + lapatinib HER2+ (central) LABC or MBC (N=980) Prior taxane and trastuzumab Progression of metastatic tx or within 6 months of adjuvant tx 1:1 T-DM1 3.6 mg/kg q3w IV Capecitabine 1000 mg/m2 orally BID, days 1-14, q3w + Lapatinib 1250 mg/day orally QD Stratification: world region, # prior chemo, visceral disease Primary endpoints: PFS, OS and safety Secondary endpoints: PFS by investigator, ORR, duration of response, time to symptom progression Verma, NEJM 2012
EMILIA: Progression free survival 1.0 IRC Cap + Lap T-DM1 HR=0.650 (95% CI, 0.55, 0.77) P<0.0001 Proportion progression-free 0.8 0.6 0.4 0.2 INV Cap + Lap T-DM1 HR=0.658 (95% CI, 0.56, 0.77) P<0.0001 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (mos) No. at risk by independent review: Cap + Lap 496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0 T-DM1 495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0
EMILIA: Responses and treatment duration
EMILIA: Overall survival Proportion surviving 1.0 0.8 0.6 0.4 0.2 Median (mos) No. events Cap + Lap 23.3 129 T-DM1 NR 94 84.7% Stratified HR=0.621 (95% CI, 0.48, 0.81) P=0.0005 Efficacy stopping boundary P=0.0003 or HR=0.617 77.0% 65.4% 47.5% 0.0 No. at risk: Cap + Lap T-DM1 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (mos) 496 469 438 364 296 242 195 155 129 97 74 52 31 17 7 3 2 1 0 495 484 461 390 331 277 220 182 149 123 96 67 46 29 16 5 2 0 0
TH3RESA: A phase III trial of TDM1 vs. physician s choice in patients with previous exposure to trastuzumab, lapatinib and taxane N = 795 N = 795 2:1 randomization
MARIANNE: Phase III study of TMD1 +/- pertuzumab vs. trastuzumab + taxane combination, in 1 st line treatment for HER2+ MBC
Other ongoing trials with T-DM1 in HER2+ Breast Cancer Trial (NCT Identifier) Phase Setting Treatment Primary Endpoint Secondary Endpoints NCT00951665 I Trastuzumab T-DM1 + pertuzumab + AEs, DLTs, PK ORR, PFS, pretreated paclitaxel CBR, duration of response NCT00679341 II Trastuzumab naive T-DM1 versus trastuzumab + docetaxel PFS OS, ORR, CBR, duration of OR, TTSP NCT01745965 II Neoadjuvant T-DM1 versus T-DM1 + pcr OS, cardiac hormonotherapy safety, toxicity, versus trastuzumab + HRQL hormonotherapy NCT01745965 II Neoadjuvant T-DM1 versus T-DM1 + HT versus trastuzumab + HT NCT01772472 III Adjuvant T-DM1 versus trastuzumab pcr IDFS OS, toxicity, safety, HRQL DFS, OS, DRFI, safety, PRO
PI3K pathway and resistance to trastuzumab
Phase III trials of trastuzumab with mtor inhibitors in HER2+ MBC BOLERO - 3 HER2+ LABC or MBC Resistant to trastuzumab and taxane pretreated (N = 569) 1:1 Vinorelbine, trastuzumab + Everolimus 5 mg/d Vinorelbine, trastuzumab + Placebo O Regan et al. ASCO 2013
BOLERO-3: Progression Free Survival O Regan et al. ASCO 2013
Trial comparison in trastuzumab-pretreated HER2+ MBC Trial BOLERO-3 EMILIA EGF100151 Treatment Everolimus + Trastuzumab / Vinorelbine Trastuzumab / Vinorelbine TDM-1 Lapatinib/ Capecitabine Lapatinib/ Capecitabine Capecitabine Setting Prior taxane and Prior taxane and Prior taxane, anthracycline trastuzumab; trastuzumab; and trastuzumab; 75% 2 nd and 3 rd line 88% 2 nd and 3 rd line unknown prior lines PFS (mos) 7.0 5.8 9.6 6.4 8.4 4.1 HR 0.77 HR 0.65 HR 0.47 OS (mos) NR NR 30.9 25.1 17.2 15.1 NR HR 0.68 HR 0.89
Selected ongoing trials with Targeted Agents in HER2 Breast Cancer Trial (NCT Identifier) EVEROLIMUS Phase Setting Treatment Primary Endpoint Secondary Endpoints NCT01305941 II CNS Mets Everolimus + trastuzumab + vinorelbine BOLERO-1 (NCT00876395) III Trastuzumab naive Everolimus + trastuzumab + paclitaxel versus trastuzumab + paclitaxel CNS RR PFS ORR, toxicity OS, ORR, AEs, TTOR, OS, CBR, PK OTHER PI3K BLOCKING AGENTS NCT01285466 I Trastuzumab pretreated BEZ235 or BKM120 + paclitaxel + trastuzumab DLTs AEs, ORR, PK NCT01042925 I/II Trastuzumab pretreated XL147 + trastuzumab + (paclitaxel) MTD, OTR NCT01132664 I Trastuzumab pretreated BKM120 + trastuzumab AEs, DLT ORR PFS, PK, PD PIKHER2 (NCT01589861) I/II Trastuzumab pretreated (with PI3K activation) BKM120 + lapatinib MTD, ORR Safety, CBR, PFS, PK
Available therapies in HER2+ MBC Line of therapy Efficacy Toxicity added to chemo backbone Comments Taxane + Trastuzumab +Pertuzumab TDM-1 Vinorelbine + Trastuzumab + Everolimus Lapatinib + Capecitabine 1st 2nd > 2nd > 2nd > 3rd Would the residual disease posttreatment still be positive? Possible (but questionable) benefit in CNS mets Lapatinib + Trastuzumab Chemo free, possible (but questionable) benefit in CNS mets
How do we chose? QUALITY OF LIFE TOXICITY EFFICACY
Therapy for HER2+ MBC AFTER CT + Trastuzumab + Pertuzumab T-DM1 HER2+ But, consider biopsy of residual disease: IF HER2- Lapatinib + Capecitabine Lapatinib + Trastuzumab CT + Trastuzumab (+/- Everolimus) CT without anti-her2 therapy??