Targe:ng HER2 in Metasta:c Breast Cancer in 2014

Transcription

1 Targe:ng HER2 in Metasta:c Breast Cancer in 2014 Kimberly L. Blackwell MD Professor Department of Medicine and Radia:on Oncology Duke University Medical Center Director, Breast Cancer Program Duke Cancer Ins:tute Durham, North Carolina

2 Overview 1. HER2+ Metasta:c Breast Cancer Trastuzumab Pertuzumab T- DM1 Lapa:nib

3 Pertuzumab and Trastuzumab: Mechanisms of Ac:on Trastuzumab HER2 Pertuzumab HER1/3/4 Subdomain IV Trastuzumab: Inhibits ligand-independent HER2 signaling Activates ADCC Prevents HER2 ECD shedding Dimerization domain Pertuzumab: Inhibits ligand-dependent HER2 dimerization and signaling Activates ADCC Ferguson KM, et al. Mol Cell. 2003;11: Olayioye MA, et al. EMBO J. 2000;19: Hynes NE, et al. Nat Rev Cancer. 2005;5: Rowinsky EK. Annu Rev Med. 2004;55:

4 Trastuzumab

5 Pivotal Phase III Trastuzumab Studies in Metasta:c Breast Cancer Study Median Survival, Mos Chemotherapy Alone Chemotherapy + Trastuzumab HR (95% CI) P Value Paclitaxel (Slamon) [1] ( ).046 Docetaxel (Marty) [2] Not reported Slamon DJ, et al. N Engl J Med. 2001;344: Marty M, et al. J Clin Oncol. 2005;23:

6 Pertuzumab

7 CLEOPATRA Study Design Centrally confirmed HER2- positive locally recurrent, unresectable or MBC 1 hormonal regimen for MBC Prior (neo)adjuvant systemic Rx, including trastuzumab and/or taxane allowed if followed by DFS 12 mos R N = 406 1:1 Docetaxel ( 6 cycles recommended) Trastuzumab Placebo Docetaxel ( 6 cycles recommended) Baseline LVEF 50%; no CHF or LVEF < 50% during or after previous trastuzumab Primary endpoint: Independently assessed PFS N = 402 Baselga J, et al. N Engl J Med. 2012;366: Trastuzumab Pertuzumab

8 Primary endpoint: Independently assessed PFS n = 433 PFS events Progression- free survival (%) n at risk Ptz + T + D Pla + T + D Time (months) D, docetaxel; PFS, progression- free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Ptz + T + D: median 18.5 months Pla + T + D: median 12.4 months = 6.1 months HR = % CI p< Stra:fied by prior treatment status and region

9 CLEOPATRA data are practice changing Significant improvement in OS Confirmatory Overall survival analysis (Median follow-up: 30 month) Overall survival (%) n at risk Ptz + T + D Pla + T + D % 89% 1 year, Δ 5% No. of events % years, Δ 12% 81% 69% Time (months) Median (months) Ptz + T + D 113 (28%) NR Pla + T + D 154 (38%) years, Δ 16% % 50% HR= % CI p= * Stopping boundary for concluding statistical significance at this second interim analysis was p D, docetaxel; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Baselga J, et al. N Engl J Med 2012 SABCS 2012 P

10 CLEOPATRA: Safety Results Select Adverse Events (Grade 3), % Pertuzumab (n = 407) Placebo (n = 397) Neutropenia Febrile neutropenia Leukopenia Diarrhea Peripheral neuropathy Left ventricular systolic dysfunction Baselga J, et al. N Engl J Med. 2012;366:

11 NCCN: First- line Treatment of HER2+ MBC Preferred regimens Docetaxel + trastuzumab + pertuzumab (category 1) Paclitaxel + trastuzumab + pertuzumab Other regimens Chemotherapy + trastuzumab NCCN. Clinical prac:ce guidelines in oncology: breast cancer. v

12 T- DM1

13 T- DM1: Mechanism of Ac:on HER2 T-DM1 Emtansine release Inhibition of microtubule polymerization Lysosome P P P Internalization Nucleus Adapted from LoRusso PM et al. Clin Cancer Res. 2011;17:

14 EMILIA Study Design HER2-Positive (central) LABC or MBC (N = 980) 1:1 T-DM1 3.6 mg/kg IV q3wk PD Prior taxane and trastuzumab Progression on metastatic tx or within 6 months of adjuvant treatment Capecitabine 1000 mg/m 2 PO bid, Days 1-14, q3wk + Lapatinib 1250 mg/day PO qd PD Stra:fica:on factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease Primary endpoints: PFS by independent review, OS, and safety Key secondary endpoints: PFS by inves:gator, ORR, DOR, :me to symptom progression LABC = locally advanced breast cancer; DOR = duration of response. Verma S et al. N Engl J Med. 2012;367:

15 EMILIA: PFS by Independent Review Commidee PFS (%) Lapatinib/capecitabine Median No. of Months 6.4 No. of Events 304 T-DM Stratified hazard ratio, 0.65 (95% CI, ) P< T-DM1 No. at Risk Lapatinib/ capecitabine T-DM1 0 Lapatinib/capecitabine Months Verma S et al. N Engl J Med. 2012;367: Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

16 EMILIA: OS at Second Interim Analysis OS (%) % (95% CI, ) 78.4% (95% CI, ) Lapatinib/capecitabine T-DM1 64.7% (95% CI, ) T-DM1 51.8% (95% CI, ) Lapatinib/capecitabine Median No. of Months No. of Events Stratified hazard ratio 0.68 (95% CI, ) P<0.001 Efficacy stopping boundary, P = or hazard ratio No. at Risk Lap + Cap 0 T-DM Months Verma S et al. N Engl J Med. 2012;367: Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

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 Verma S et al. N Engl J Med. 2012;367: Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

18 Hematologic Adverse Events Adverse Event All Grade % Cap + Lap (n = 488) Grade 3 % Grade 4 % All Grade % T-DM1 (n = 490) Grade 3 % Grade 4 % Neutropenia Febrile neutropenia Anemia Thrombocytopenia Verma S et al. N Engl J Med. 2012;367: Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

19 Small Molecule Inhibitors

20 Pivotal Trial EGF LapaWnib 1500 mg/day PO PaWent PopulaWon HER2+ MBC Mul:ple lines of trastuzumab Progression on trastuzumab at study entry Primary endpoint: PFS Secondary endpoints: OS, ORR, CBR R Crossover at the time of progressive disease LapaWnib 1000 mg/day PO + trastuzumab 4 mg/kg then 2 mg/kg IV q wk Blackwell KL, et al. J Clin Oncol. 2012;30:

21 EGF104900: Overall Survival L + T (n = 148) L (n = 148) 100 n Survival(%) % 80% 6- mo OS 41% 56% 12- mo OS Median OS, mos HR (95% CI) 0.74 ( ) Stratified log-rank P value % of pa:ents in the L arm crossed over to L + T Pts at risk, n Lap 1000/Tras Lap Mos From Randomization Blackwell KL, et al. J Clin Oncol. 2012;30:

22 Treatment of HER2+ MBC Beyond First Line With Previous Trastuzumab Exposure ConWnued HER2 blockade Preferred: T- DM1 Chemotherapy + trastuzumab Trastuzumab + lapa:nib Capecitabine + lapa:nib Vinorelbine + trastuzumab + everolimus?

23 Conclusions In first line metasta:c breast cancer: survival advantage to adding pertuzumab to standard trastuzumab + chemotherapy combina:ons. Past the first line, T- DM1 offers effec:ve and safe therapy. Aker Pertuzumab and T- DM1 strategies, small molecule inhibitors of HER2 should be considered.

24 Thanks!