PROGNOSTICO DE PACIENTES COM CA DE MAMA METASTATICO HER2+: PODEMOS FAZER MAIS? TDM-1 AND BEYOND!

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1 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

2 Major clinical advances in HER2+ breast cancer

3 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

4 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

5 TDM-1 Novel antibody drugconjugate linked to a potent cytotoxic agent (maytansine derivative; a microtubule inhibitor): selectively delivers DM1 to HER2+ cells

6 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

7 Phase II trial of TDM1 vs. trastuzumab/ docetaxel in 1 st line treatment of HER2+ MBC Perez et al. JCO 2013

8 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

9 EMILIA: Progression free survival 1.0 IRC Cap + Lap T-DM1 HR=0.650 (95% CI, 0.55, 0.77) P< Proportion progression-free INV Cap + Lap T-DM1 HR=0.658 (95% CI, 0.56, 0.77) P< Time (mos) No. at risk by independent review: Cap + Lap T-DM

10 EMILIA: Responses and treatment duration

11 EMILIA: Overall survival Proportion surviving Median (mos) No. events Cap + Lap T-DM1 NR % Stratified HR=0.621 (95% CI, 0.48, 0.81) P= Efficacy stopping boundary P= or HR= % 65.4% 47.5% 0.0 No. at risk: Cap + Lap T-DM Time (mos)

12 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

13 MARIANNE: Phase III study of TMD1 +/- pertuzumab vs. trastuzumab + taxane combination, in 1 st line treatment for HER2+ MBC

14 Other ongoing trials with T-DM1 in HER2+ Breast Cancer Trial (NCT Identifier) Phase Setting Treatment Primary Endpoint Secondary Endpoints NCT I Trastuzumab T-DM1 + pertuzumab + AEs, DLTs, PK ORR, PFS, pretreated paclitaxel CBR, duration of response NCT II Trastuzumab naive T-DM1 versus trastuzumab + docetaxel PFS OS, ORR, CBR, duration of OR, TTSP NCT II Neoadjuvant T-DM1 versus T-DM1 + pcr OS, cardiac hormonotherapy safety, toxicity, versus trastuzumab + HRQL hormonotherapy NCT II Neoadjuvant T-DM1 versus T-DM1 + HT versus trastuzumab + HT NCT III Adjuvant T-DM1 versus trastuzumab pcr IDFS OS, toxicity, safety, HRQL DFS, OS, DRFI, safety, PRO

15 PI3K pathway and resistance to trastuzumab

16 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

17 BOLERO-3: Progression Free Survival O Regan et al. ASCO 2013

18 Trial comparison in trastuzumab-pretreated HER2+ MBC Trial BOLERO-3 EMILIA EGF 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) HR 0.77 HR 0.65 HR 0.47 OS (mos) NR NR NR HR 0.68 HR 0.89

19 Selected ongoing trials with Targeted Agents in HER2 Breast Cancer Trial (NCT Identifier) EVEROLIMUS Phase Setting Treatment Primary Endpoint Secondary Endpoints NCT II CNS Mets Everolimus + trastuzumab + vinorelbine BOLERO-1 (NCT ) 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 NCT I Trastuzumab pretreated BEZ235 or BKM120 + paclitaxel + trastuzumab DLTs AEs, ORR, PK NCT I/II Trastuzumab pretreated XL147 + trastuzumab + (paclitaxel) MTD, OTR NCT I Trastuzumab pretreated BKM120 + trastuzumab AEs, DLT ORR PFS, PK, PD PIKHER2 (NCT ) I/II Trastuzumab pretreated (with PI3K activation) BKM120 + lapatinib MTD, ORR Safety, CBR, PFS, PK

20 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

21 How do we chose? QUALITY OF LIFE TOXICITY EFFICACY

22 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??