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N Engl J Med. 2014 Nov 13;371(20):1867-76. doi: 10.1056/NEJMoa1408868. Epub 2014 Sep 29.

Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.

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From Royal Marsden Hospital, London (J.L.); Istituto Nazionale Tumori Fondazione G. Pascale, Naples (P.A.A.), Azienda Ospedaliera Universitaria Senese, Siena (M. Maio), and Papa Giovanni XXIII Hospital, Bergamo (M. Mandalà) - all in Italy; Hôtel Dieu Place Alexis Ricordeau, Nantes (B.D.), Centre Hospitalier Lyon Sud, Pierre-Bénite (L.T.), and Hôpital Saint André, Bordeaux (C.D.) - all in France; Princess Alexandra Hospital, Woolloongabba, QLD (V.A.), and Peter MacCallum Cancer Centre, Melbourne, VIC (G.A.M.) - both in Australia; National Institute of Oncology, Budapest, Hungary (G.L.); N.N. Blokhin Russian Cancer Research Center, Moscow (L.D.), and Moscow City Oncology Hospital 62, Krasnogorsk (D.S.) - both in Russia; Hospital Universitario Virgen Macarena, Seville, Spain (L.C.-M.); University of Tübingen, Tübingen, Germany (C.G.); Genentech, South San Francisco, CA (M.A.S., I.C., N.C., S.P.H.); and Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, Los Angeles (A.R.).



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 number, NCT01689519.).

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