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Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma

James Larkin, M.D., Ph.D., Paolo A. Ascierto, M.D., Brigitte Dréno, M.D., Ph.D., Victoria Atkinson, M.D., Gabriella Liszkay, M.D., Michele Maio, M.D., Mario Mandalà, M.D., Lev Demidov, M.D., Daniil Stroyakovskiy, M.D., Luc Thomas, M.D., Ph.D., Luis de la

N Engl J Med 2014; 371:1867-1876November 13, 2014DOI: 10.1056/NEJMoa1408868

Editorial comment by Prof. R. Dummer:
This month we have decided to present two papers. Both papers were published in the New England Journal of Medicine and report on two prospective randomized trials investigating the clinical outcome of a monotherapy with a BRAF inhibitor versus a combination therapy using a BRAF inhibitor and a MEK inhibitor in patients with BRAF mutated advanced melanoma. In both studies there is a clear advantage for the combination therapy with an increase in progression free survival resulting in an improvement of approximately 40% with an improved response rate. The phase III clinical trial presented by Long reached its primary endpoint progression free survival and the secondary endpoint overall survival. Taking together these studies clearly support combination therapy with a BRAF and MEK inhibitor as the standard of care for BRAF mutated melanoma.



The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma 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.


We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation–positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival.


The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy.


The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600–mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann–La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.)