Phase 3, Double-Blind, Placebo-Controlled Study of Vemurafenib Versus Vemurafenib + Cobimetinib in Previously Untreated Brafv600 Mutation–Positive Patients with Unresectable Locally Advanced or Metastatic Melanoma (Nct01689519)

Abstract

Background: 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.