LBA40 - Three-year estimate of overall survival in COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib (D) + trametinib (T) in patients (p...

Date 08 October 2016
Event ESMO 2016 Congress
Session Melanoma and other skin tumours
Topics Melanoma and other Skin Tumours
Presenter Caroline Robert
Citation Annals of Oncology (2016) 27 (6): 1-36. 10.1093/annonc/mdw435
Authors C. Robert1, B. Karaszewska2, J. Schachter3, P. Rutkowski4, A. Mackiewicz5, D. Stroyakovskiy6, R. Dummer7, F. Grange8, L. Mortier9, V. Chiarion-Sileni10, K. Drucis11, I. Krajsová12, A. Hauschild13, B. Mookerjee14, J.J. Legos14, Y. Zhang14, S. Lane14, D. Schadendorf15
  • 1Dermatology, Institut Gustave Roussy, 94805 - Villejuif/FR
  • 2Department Of Oncology - Subunit Hematology, Przychodnia Lekarska KOMED, 62-500 - Konin/PL
  • 3Ella Lemelbaum Institute Of Melanoma, Sheba Medical Center, Ramat Gan/IL
  • 4Department Of Soft Tissue/bone Sarcoma And Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, 02-781 - Warsaw/PL
  • 5Department Of Diagnostics And Immunology Of Neoplasm, Poznan University of Medical Sciences, PL61614 - Poznan/PL
  • 6Chemotherapy Department, Moscow City Oncology Hospital No. 62, Moscow/RU
  • 7Department Of Dermatology, University Hospital Zurich, 8091 - Zurich/CH
  • 8Department Of Dermatology, Centre Hospitalier Universitaire Robert Debré, 51092 - Reims/FR
  • 9Department Of Dermatology, CHRU Lille, University Lille 2, 59037 - Lille/FR
  • 10Melanoma And Skin Cancer Unit, Veneto Oncology Institute, Padova/IT
  • 11Swissmed Centrum Zdrowia Sa, Medical University, Gdansk/PL
  • 12Department Of Dermato-oncology, VFN a 1. LF UK Praha, Prague/CZ
  • 13Department Of Dermatology, University Hospital Schleswig-Holstein, 24105 - Kiel/DE
  • 14Global Oncology, Novartis Pharmaceuticals Corporation, 07936 - East Hanover/US
  • 15Department Of Dermatology, University Hospital Essen, 45147 - Essen/DE

Abstract

Background

Prior comparative analyses of COMBI-v (NCT01597908) at a planned interim cutoff and again after 2 y of follow-up (f/u) showed significantly improved outcomes favoring D + T vs vemurafenib (Vem). Durable benefit and sustained tolerability was also seen in some pts receiving D + T (COMBI-v: 2-y OS, 51%; COMBI-d: 2-y OS, 52%; 3-y OS, 44%). Although these results support use of first-line D + T for BRAF V600–mutant melanoma, continued monitoring of these pts for long-term efficacy (eg, OS) is needed to determine the full impact of this regimen.

Methods

In this phase 3, randomized, double-blind study, pts with histologically confirmed unresectable stage IIIC or IV BRAF V600E/K–mutant melanoma were randomized 1:1 to receive first-line D 150 mg BID + T 2 mg QD or Vem 960 mg BID. Based on the OS benefit with D + T at interim analysis, crossover from Vem to D + T was permitted. The primary endpoint is OS; secondary endpoints are PFS, ORR, DOR, and safety.

Results

From Jun 2012 to Oct 2013, 704 pts were enrolled (D + T, n = 352; Vem, n = 352). This updated analysis (cutoff: Jul 2016) occurred after 411 deaths and 16 mo of additional f/u since the 2-y data cutoff (Robert, et al. ECC 2015). A total of 33 Vem pts (9%) crossed over to D + T. Pts in the D + T arm continued to achieve durable OS (D + T vs Vem: 3-y OS, 45% [95% CI, 39-50] vs 32% [95% CI, 27-37]) and PFS (3-y PFS, 25% [95% CI, 20-30] vs 11% [95% CI, 7-16]), with the greatest OS benefit in pts with baseline LDH ≤ ULN and < 3 organ sites with metastasis (D + T vs Vem: 3-y OS, 70% [95% CI, 62-77] vs 46% [95% CI, 38-54]). For OS, 68 D + T pts (19%) and 47 Vem pts (13%) were censored with f/u ongoing. ORR and DOR remained improved with D + T (D + T vs Vem: ORR, 67% [95% CI, 62-72] vs 53% [95% CI, 48-59]; median DOR, 13.8 mo [95% CI, 11.3-17.6] vs 7.6 mo [95% CI, 7.4-9.3]). D + T safety and tolerability continued to remain acceptable with additional f/u; there were no new toxicities or clinically significant changes in previously reported AEs. Of pts in the D + T arm alive at 3 y, 58% remained on D + T.

Conclusions

This updated 3-y efficacy and safety analysis further supports long-term use of D + T in BRAF V600–mutant melanoma.

Clinical trial identification

NCT01597908; first received by clinicaltrials.gov on May 10, 2012.

Legal entity responsible for the study

Study is/remains sponsored by GlaxoSmithKline, however, as of 2 March 2015, dabrafenib and trametinib became assets of Novartis AG.

Funding

Study is/remains sponsored by GlaxoSmithKline, however, as of 2 March 2015, dabrafenib and trametinib became assets of Novartis AG.

Disclosure

C. Robert: Consultancy: Novartis, Amgen, BMS, Merck, Roche Honoraria: Novartis, Amgen, BMS, Merck, Roche. J. Schachter: Consultancy: BMS, MSD, Novartis Honoraria: BMS, MSD, Novartis Speakers Bureau: BMS, MSD, Novartis. P. Rutkowski: Honoraria: Novartis, GSK, Roche, MSD, BMS, Amgen Speakers Bureau: Novartis, MSD, BMS Membership on Board of Directors or Advisory Committee: Novartis, GSK, Roche, MSD, BMS. R. Dummer: Research Funding: Novartis, Merck Sharp & Dhome (MSD), BMS, Roche, GSK. Consultancy: Novartis, Merck Sharp & Dhome, BMS, Roche, GSK, Amgen Membership on Board of Directors or Advisory Committee: Novartis, Merck Sharp & Dhome, BMS, Roche, GSK, Amgen. L. Mortier: Consultancy: Roche, GSK, BMS, MSD Honoraria: Roche, GSK, BMS, MSD. V. Chiarion-Sileni: Consultancy: Novartis, BMS Speakers Bureau: GSK, Novartis Membership on Board of Directors or Advisory Committee: GSK, Novartis, Roche, BMS, MSD. I. Krajsová: Membership on Board of Directors or Advisory Committee: BMS, Roche, Novartis, MSD A. Hauschild: Consultancy/Honoraria: Amgen, BMS, MedImmune, MSD/Merck, Nektar Therapeutics, Novartis, Oncosec, Philogen, Provectus, Regeneron, Roche Other: Amgen, BMS, Celgene, Eisai, GSK, Merck Serono, MSD/Merck, Novartis, Roche (trial grants). B. Mookerjee: Employment: Novartis Equity Ownership: Novartis, GSK, Incyte, AstraZeneca. J.J. Legos: Employment: Novartis Pharmaceuticals Corporation Other: Own company stock. Y. Zhang, S. Lane: Employment: Novartis. D. Schadendorf: Consultancy/Honoraria/Speakers Bureau: Amgen, Novartis, Roche, BMS, MSD Merck, Pfizer Research Funding: BMS, MSD Merck Membership on Board of Directors or Advisory Committee: Amgen, Novartis, Roche, BMS, MSD Merck, Pfizer, Array. All other authors have declared no conflicts of interest.