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
Overview 1. HER2+ Metasta:c Breast Cancer Trastuzumab Pertuzumab T- DM1 Lapa:nib
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;11:507-517. Olayioye MA, et al. EMBO J. 2000;19:3159-3167. Hynes NE, et al. Nat Rev Cancer. 2005;5:341-354. Rowinsky EK. Annu Rev Med. 2004;55:433-457.
Trastuzumab
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] 20.3 25.1 0.80 (0.64-1.00).046 Docetaxel (Marty) [2] 22.7 31.2 Not reported.0325 1. Slamon DJ, et al. N Engl J Med. 2001;344:783-792. 2. Marty M, et al. J Clin Oncol. 2005;23:4265-4274.
Pertuzumab
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;366:109-119. Trastuzumab Pertuzumab
Primary endpoint: Independently assessed PFS n = 433 PFS events Progression- free survival (%) 100 90 80 70 60 50 40 30 20 10 0 n at risk Ptz + T + D Pla + T + D 0 5 10 15 20 25 30 35 40 Time (months) 402 345 267 139 83 32 10 0 0 406 311 209 93 42 17 7 0 0 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 = 0.62 95% CI 0.51 0.75 p<0.0001 Stra:fied by prior treatment status and region
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 100 90 80 70 60 50 40 30 20 10 0 0 5 10 15 20 25 30 35 40 402 406 387 383 94% 89% 1 year, Δ 5% 371 350 No. of events % 342 324 317 285 2 years, Δ 12% 81% 69% Time (months) 230 198 Median (months) Ptz + T + D 113 (28%) NR Pla + T + D 154 (38%) 37.6 143 128 3 years, Δ 16% 84 67 66% 50% 33 22 45 50 55 9 4 HR=0.66 95% CI 0.52 0.84 p=0.0008 0 0 0 0 * Stopping boundary for concluding statistical significance at this second interim analysis was p 0.0138 D, docetaxel; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Baselga J, et al. N Engl J Med 2012 SABCS 2012 P5-18-26
CLEOPATRA: Safety Results Select Adverse Events (Grade 3), % Pertuzumab (n = 407) Placebo (n = 397) Neutropenia 48.9 45.8 Febrile neutropenia 13.8 7.6 Leukopenia 12.3 14.6 Diarrhea 7.9 5.0 Peripheral neuropathy 2.7 1.8 Left ventricular systolic dysfunction 1.2 2.8 Baselga J, et al. N Engl J Med. 2012;366:109-119.
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.1.2014.
T- DM1
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;17:6437-6447.
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;367:1783-1791. 14
EMILIA: PFS by Independent Review Commidee PFS (%) 100 80 60 40 Lapatinib/capecitabine Median No. of Months 6.4 No. of Events 304 T-DM1 9.6 265 Stratified hazard ratio, 0.65 (95% CI, 0.55-0.77) P<0.001 20 T-DM1 No. at Risk Lapatinib/ capecitabine T-DM1 0 Lapatinib/capecitabine 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Months 496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0 495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0 Verma S et al. N Engl J Med. 2012;367:1783-1791. Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
EMILIA: OS at Second Interim Analysis OS (%) 100 80 60 40 85.2% (95% CI, 82.0-88.5) 78.4% (95% CI, 74.6-82.3) Lapatinib/capecitabine T-DM1 64.7% (95% CI, 59.3-70.2) T-DM1 51.8% (95% CI, 45.9-57.7) Lapatinib/capecitabine Median No. of Months 25.1 30.9 No. of Events 182 149 Stratified hazard ratio 0.68 (95% CI, 0.55-0.85) P<0.001 Efficacy stopping boundary, P = 0.0037 or hazard ratio 0.73 20 No. at Risk Lap + Cap 0 T-DM1 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Months 496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4 495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5 Verma S et al. N Engl J Med. 2012;367:1783-1791. Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
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 79.7 20.7 23.3 1.6 Hand-foot syndrome 58.0 16.4 1.2 0.0 Vomiting 29.3 4.5 19.0 0.8 Hypokalemia 8.6 4.1 8.6 2.2 Fatigue 27.9 3.5 35.1 2.4 Nausea 44.7 2.5 39.2 0.8 Mucosal inflammation 19.1 2.3 6.7 0.2 Increased AST 9.4 0.8 22.4 4.3 Increased ALT 8.8 1.4 16.9 2.9 Verma S et al. N Engl J Med. 2012;367:1783-1791. Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
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 8.6 3.5 0.8 5.9 1.6 0.4 Febrile neutropenia 1.0 0.4 0.6 0.0 0.0 0.0 Anemia 8.0 1.6 0.0 10.4 2.7 0.0 Thrombocytopenia 2.5 0.0 0.2 28.0 10.4 2.4 Verma S et al. N Engl J Med. 2012;367:1783-1791. Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Small Molecule Inhibitors
Pivotal Trial EGF104900 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;30:2585-2592.
EGF104900: Overall Survival L + T (n = 148) L (n = 148) 100 n 146 145 Survival(%) 80 60 40 20 70% 80% 6- mo OS 41% 56% 12- mo OS Median OS, mos 14.0 9.5 HR (95% CI) 0.74 (0.57-0.97) Stratified log-rank P value.026 52% of pa:ents in the L arm crossed over to L + T Pts at risk, n Lap 1000/Tras Lap 1500 0 0 146 145 5 10 15 20 25 30 Mos From Randomization 120 100 87 64 63 46 Blackwell KL, et al. J Clin Oncol. 2012;30:2585-2592. 42 28 25 13 1 35
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?
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.
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