LBA5_PR - Phase 3, double-Blind, placebo-controlled study of vemurafenib versus vemurafenib + cobimetinib in previously untreated BRAFV600 mutation-positive...

Date 29 September 2014
Event ESMO 2014
Session Presidential Symposium 2
Topics Anti-Cancer Agents & Biologic Therapy
Melanoma and other Skin Tumours
Personalised Medicine
Presenter Grant McArthur
Citation Annals of Oncology (2014) 25 (5): 1-41. 10.1093/annonc/mdu438
Authors G.A. McArthur1, P.A. Ascierto2, J. Larkin3, A. Ribas4, G. Liszkay5, M. Maio6, M. Mandalà7, L.V. Demidov8, D. Stroyakovsky9, L. Thomas10, L. De La Cruz Merino11, V. Atkinson12, C. Dutriaux13, C. Garbe14, I. Chang15, S.P. Hack16, B. Dréno17
  • 1Cancer Therapeutics, Peter MacCallum Cancer Centre, 3002 - East Melbourne/AU
  • 2Melanoma, Cancer Immunotherapy And Innovative Therapies, Istituto Nazionale Tumori Fondazione “G. Pascale”, 80131 - Napoli/IT
  • 3Department Of Medicine, Royal Marsden Hospital, SW3 6JJ - London/GB
  • 4Department Of Medicine, UCLA, Los Angeles/US
  • 5Oncodermatology, National Institute of Oncology, Budapest, 1122 - Budapest/HU
  • 6Oncology, University Hospital of Siena, Siena/IT
  • 7Oncology And Hematology, Papa Giovanni XXIII Hospital, Bergamo/IT
  • 8Tumor Biotherapy, NN Blokhin Russian Cancer Research Center, 115478 - Moscow/RU
  • 9Chemotherapy, Moscow City Oncology Hospital # 62, Istra/RU
  • 10Dermato-oncology, Centre Hospitalier Lyon Sud, Rhone/FR
  • 11Clinical Oncology, Hospital Universitario Virgen Macarena, 41009 - Sevilla/ES
  • 12Division Of Cancer Services, Princess Alexandra Hospital, Woolloongabba/AU
  • 13Dermato-oncology, Hôpital Saint André, Bordeaux/FR
  • 14Dermatology, University of Tubingen, Tubingen/DE
  • 15Product Development, Roche, South San Francisco/US
  • 16Product Development (oncology), Roche/Genentech, 94080 - South San Francisco/US
  • 17Department Of Dermato Cancerology, CHU Nantes - Nantes Hospital University, Nantes/FR

Abstract

Aim

Combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib.

Methods

Between January 2013 and January 2014, 495 patients (pts) were randomly assigned to receive vemurafenib + cobimetinib or vemurafenib + placebo. In a 28–day treatment cycle, vemurafenib was administered at 960 mg twice daily from Days 1-28 and cobimetinib or placebo was administered at 60 mg daily from Days 1–21. Eligibility included treatment-naive BRAFV600 mutation–positive pts with unresectable locally advanced or metastatic melanoma and adequate performance status and organ function. Primary end point was investigator-assessed progression-free survival (PFS).

Results

Median PFS was 9.9 months with the combination compared with 6.2 months in the control arm (hazard ratio [HR] = 0.51; 95% confidence interval [CI], 0.39–0.68; P <0.0001). The rate of complete and partial response was 68% in the combination arm and 45% in the control arm (P <0.0001), including complete response in 10% of pts treated with the combination and 4% of pts in the control group. Subgroup analyses of PFS based on key demographic and tumor characteristics were consistent with PFS in the intent-to-treat population. PFS assessed by independent review was comparable with investigator-assessed PFS. Interim overall survival (OS) data showed an HR of 0.65 (95% CI, 0.42–1.00) but did not cross the prespecified stopping boundary. Vemurafenib + cobimetinib combination, compared with vemurafenib alone, was associated with a higher incidence of grade ≥ 3 adverse events ([AEs] 65% vs 59%); however, there was no difference in the rate of AEs leading to study drug discontinuation and there was a decrease in the occurrence of secondary cutaneous neoplasms with the combination.

Conclusions

Cobimetinib in combination with vemurafenib significantly improved PFS among pts with BRAFV600-mutant metastatic melanoma.

Disclosure

G.A. McArthur: Provided research support for Novartis, Pfizer, Millenium, and Celgene; P.A. Ascierto: Received honoraria for serving on advisory boards for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Glaxo SmithKline, and Novartis; received honoraria and research funds as a consultant for Bristol Myers Squibb, Roche-Genentech, and Ventana; J. Larkin: Serves as non-remunerated consultant to Pfizer, Novartis, GlaxoSmithKline, Bristol-Myers Squibb, Merck Sharp & Dohme, and Roche; A. Ribas: Holds stock in Kite Pharma and serves as consultant, with honoraria, to Amgen, Compugen, Flexus, GlaxoSmithKline, Genentech, Novartis, Merck, and Pierre Fabre; G. Liszkay: Received honoraria for serving on advisory boards for Roche; M. Maio: Serves on advisory boards and as speaker with honoraria for, and has received research grants and fees/patient from, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, GlaxoSmithKline, and MedImmune; M. Mandalà: Serves on advisory boards and as speaker, with honoraria, for GlaxoSmithKline, Roche, and Bristol-Myers Squibb; L.V. Demidov: Received GMTF for advisory boards for MSD; consultant for MSD and Roche; investigator for Roche, GSK, Pfizer, and BMS; speaker for MSD, Roche, and BMS; L. Thomas: Principal investigator for clinical trials sponsored by Roche; institution received honoraria; L. De La Cruz Merino: Participated in advisory boards by Roche; V. Atkinson: Advisory boards for Roche and Bristol-Myers Squibb; speaker for GlaxoSmithKline dabrafenib launch meeting 2014; C. Dutriaux: Investigator for Roche; C. Garbe: Serves on advisory boards and as speaker, with honoraria, for Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Roche, and Philogen, and received research grants from Bristol-Myers Squibb, GlaxoSmithKline, and Roche; I. Chang: Roche employee with salary and stock options; S.P. Hack: Employee of Genentech with salary and stock options; B. Dréno: Served on advisory board, as consultant, and as speaker for Roche for which honoraria was received; served as investigator for Roche for which a grant was received. All other authors have declared no conflicts of interest.