Advanced HER2+ Breast Cancer: New Options and How to Deploy Them. José Baselga MD, PhD

Transcription

1 Advanced HER2 Breast Cancer: New Options and How to Deploy Them José Baselga MD, PhD

2 HER2 signaling results in a multitude of cellular effects, including increased cellular proliferation HER2 HER3 RAS Sos Grb2 Shc Raf P P P P PI3K P P PDK1 P AKT GSK3ß MEK mtor Cyclin D1 BAD NFκB p27 MAPK Cell cycle control Apoptosis Survival Angiogenesis Proliferation Olayioye et al. EMBO J 2000;19: Rowinsky. Annu Rev Med 2004;55:

3 Homodimers HER dimers have different mitogenic signaling Heterodimers HER1:HER1 HER2:HER2 HER3:HER3 HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4 HER2:HER3 HER2:HER4 HER3:HER4 Signaling activity Tzahar et al. Mol Cell Biol 1996;16:

4 Therapies for HER2-positive breast cancer Trastuzumab Pertuzumab T-DM1 Lapatinib, Neratinib HSP-90 Inhib Baselga. Nat Rev Cancer 2009

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6 Probability of survival Trastuzumab enhances overall survival in HER2 metastatic breast cancer Trastuzumab CT CT alone p< Time (months) 1. Slamon DJ, et al. N Engl J Med 2001;344: ; 2. Smith IE, et al. Anticancer Drugs 2001;12(Suppl. 4):S3 S10

7 Trastuzumab beyond progression GBG-26: Study Design MBC HER2-positive Progression under trastuzumab-based first-line therapy (TFI < 6 weeks) with taxane (n = 114) or monotherapy or nontaxane (n = 42) R Capecitabine 2500 mg/m 2 bid d1-14 q21 days continuation of trastuzumab 6 mg/kg q3 weeks (n = 78) Capecitabine 2500 mg/m 2 bid d1-14 q21 days (n = 78) R, randomization; TFI, treatment-free interval Von Minckwitz G, et al. J Clin Oncol. 2009;27(12):

8 Probability Continuation of Trastuzumab Capecitabine Suggests Improvement of Overall Survival a Time from First Progression, months Trastuzumab capecitabine (n = 78) Capecitabine (n = 78) HR = 0.76 (two-sided P =.26; one-sided P =.13) a Von Minckwitz G, et al. J Clin Oncol. 2009;27(12): a Median survival in months OS, overall survival

9 Therapies for HER2-positive breast cancer Trastuzumab Pertuzumab T-DM1 Lapatinib, Neratinib HSP-90 Inhib Baselga. Nat Rev Cancer 2009

10 Capecitabine Lapatinib Versus Capecitabine in LABC or MBC: Study EGF Progressive, HER2 MBC or LABC Previously treated with anthracycline, taxane and trastuzumab* No prior capecitabine Stratification: Disease sites Stage of disease R A N D O M I Z E Lapatinib 1250 mg po qd continuously capecitabine 2000 mg/m 2 /d po days 1-14 q3 weeks Capecitabine 2500 mg/m 2 /d po days 1-14 q 3 weeks Patients on treatment until progression or unacceptable toxicity, then followed for survival *Trastuzumab must have been administered for metastatic disease!! Geyer C, et al. N Engl J Med. 2006;355(26): Cameron D, et al. Breast Cancer Res Treat. 2008;112(3): LABC = locally advanced breast cancer

11 Capecitabine Lapatinib Median TTP Overall Survival Hazard ratio 0.57 (95 % CI, ) Log-rank P = Cameron D, et al. Breast Cancer Res Treat. 2008;112(3):

12 HKI-272 (Neratinib), An Oral Irreversible Pan Erb Receptor Tyrosine Kinase Inhibitor: Tumor Response in Evaluable Population Prior Trastuzumab (n = 61) No Prior Trastuzumab (n = 66) Objective response rate, % PR, % Daily oral dose: 240 mg; dose reduction -1x: 24% of patients, 2x: 5% 16% of patients had dose reductions due to diarrhea Burstein HL, et al. Cancer Res. 2009;69(Suppl 2): Abstract 37.

13 Therapies for HER2-positive breast cancer Trastuzumab Pertuzumab T-DM1 Lapatinib, Neratinib HSP-90 Inhib Baselga. Nat Rev Cancer 2009

14 Trastuzumab and pertuzumab bind to different regions on HER2 and may have synergistic activity Trastuzumab HER2 Pertuzumab HER3 Subdomain IV of HER2 Trastuzumab does not inhibit HER2 dimerization, thus blocking HER2:HER3 Trastuzumab prevents HER2 receptor shedding Trastuzumab blocks HER2 signaling and flags cells for destruction by the immune system Dimerization domain of HER2 Pertuzumab inhibits HER2 from forming dimer pairs Flags cells for destruction by the immune system Pertuzumab does not prevent HER2 receptor shedding

15 Independently-assessed PFS (%) San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, 2012 CLEOPATRA: Significant improvement in median PFS 1,2 (and OS) 3 with pertuzumab n at risk PtzTD PlaTD PFS time (months) PtzTD PlaTD HR = % CI 0.51, 0.75 p < Baselga J, et al. SABCS 2011 (Abstract S5-5); 2. Baselga J, et al. N Engl J Med 2012; 366: ; D, docetaxel; Ptz, pertuzumab; T, trastuzumab 3. Swain S, et al. SABCS 2012 (Poster P ). Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute. 15

16 Overall survival (%) Confirmatory overall survival analysis Median follow-up: 30 months, n=267 OS events n at risk Ptz T D Pla T D year 94% 89% years 81% 69% Time (months) years % 50% Ptz T D: 113 events; median not reached Pla T D: 154 events; median 37.6 months HR= % CI p= Stopping boundary for concluding statistical significance at this second interim analysis was p D, docetaxel; OS, overall survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab

17 Therapies for HER2-positive breast cancer Trastuzumab Pertuzumab T-DM1 Lapatinib, Neratinib HSP-90 Inhib Baselga. Nat Rev Cancer 2009

18 San Antonio Breast Cancer Symposium Henry B. Gonzalez Convention Center December 4 8, CLEOPATRA: Study design 1,2 n = 406 Placebo trastuzumab PD Patients with HER2-positive MBC Centrally confirmed (N = 808) 1:1 Docetaxel* 6 cycles recommended Pertuzumab trastuzumab PD n = 402 Docetaxel* 6 cycles recommended Primary endpoint: Independently-assessed progression-free survival (PFS) Collection of tumor tissue (archival in >90%) and serum samples was mandatory Study dosing q3w: Pertuzumab/placebo: Trastuzumab: Docetaxel: 840 mg loading dose, 420 mg maintenance 8 mg/kg loading dose, 6 mg/kg maintenance 75 mg/m 2, escalating to 100 mg/m 2 if tolerated * < 6 cycles allowed for unacceptable toxicity or PD; > 6 cycles allowed at investigator discretion 1. Baselga J, et al. SABCS 2011 (Abstract S5-5); HER2, human epidermal growth factor receptor 2; PD, progressive disease 2. Baselga J, et al. N Engl J Med 2012; 366: Copyrights for this presentation are held by the author/presenter. Contact baselgaj@mskcc.org for permission to reprint and/or distribute. 18

19 T-DM1: Mechanism of Action HER2 T-DM1 Emtansine release Inhibition of microtubule polymerization Lysosome P P P Internalization Nucleus Adapted from LoRusso PM, et al. Clin Cancer Res

20 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 tx 1:1 Capecitabine 1000 mg/m 2 orally bid, days 1 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

21 Proportion progression-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).

22 Proportion surviving Overall Survival: Interim Analysis % 77.0% 65.4% 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.

23 TDM4788g / BO22589: Phase III study of T-DM1 pertuzumab vs trastuzumab docetaxel in 1st-line HER2-positive MBC Primary end point PFS (IRF assessment) Safety Secondary end points ORR as assessed by IRF OS rate 1-year survival Investigator assessed PFS and ORR Investigator / IRF assessed CBR TTF Duration of objective response Safety and tolerability T-DM1 placebo HER2-positive MBC No prior chemotherapy for metastatic disease (n=1092) T-DM1 pertuzumab Trastuzumab docetaxel

24 Lapatinib in combination with trastuzumab vs. lapatinib alone. Overall Survival Blackwell K. J Clinic Oncol 2012 Blackwell K L et al. JCO 2012;30:

25 HER2 : Everolimus Weekly Trastuzumab and Paclitaxel Phase I Patients With Measurable Disease Lesions cat. V V V V V V NV V V NV V V V V V V V V V V V NV NV NV V NV SD SD SD SD SD SD SD PR PR SD SD PR SD PR PR PR PR PR CR PR PR CR SD SD SD PD Patient resistant to trastuzumab and taxanes Patient resistant to trastuzumab but NOT to taxanes 1) Patient not resistant to trastuzumab or taxanes. Abbreviations: V, visceral; NV, non-visceral; SD, stable disease; PD, progressive disease; PR, partial response; CR, complete response. Hurvitz et al. ESMO/ECCO, Abstract PD-5021.

26 How to Deploy HER2 therapy First Line Pertuzumab Trastuzumab Taxane PFS 18.5 months and proven survival advantage Safe Well tolerated. Chemotherapy for less than 6 months No TDM1 data yet. When available think concomitant vs. sequential Pay attention to PI3K mutant subtype

27 How to Deploy HER2 therapy Second Line TDM1 PFS 9.6 months and proven survival advantage Safe and well tolerated.

28 How to Deploy HER2 therapy Third Line and Beyond Capecitabine and Lapatinib Trastuzumab and Lapatinib Everolimus and Trastuzumab Trastuzumab and other chemotherapies TDM1 or Trastuzumab-Pertuzumab if not prior

29 How to Deploy HER2 therapy Issues to keep in mind Brain metastasis monitoring and treatment Is dual HER2 blockade better that single agent HER2 beyond progression Pertuzumab beyond progression Role of Pi3K mutations Neratinib versus lapatinib? Role of hormonal therapy with dual blockade

30 How to Deploy HER2 therapy Time for Artificial Intelligence? IBM-Wellpoint-MSKCC Partnership