Larkin, JamesAscierto, Paolo ADréno, BrigitteAtkinson, VictoriaLiszkay, GabriellaMaio, MicheleMandalà, MarioDemidov, LevStroyakovskiy, DaniilThomas, Lucde la Cruz-Merino, LuisDutriaux, CarolineGarbe, ClausSovak, Mika AChang, IlsungChoong, NicholasHack, Stephen PMcArthur, Grant ARibas, Antoni2016-03-092016-03-092014-11-13Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N. Engl. J. Med.. 2014 ; 371(20):1867-760028-4793http://hdl.handle.net/10668/2159Clinical Trial, Phase III; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't;BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.).enIndolesSulfonamidesProto-oncogene proteins B-rafMAP quinasa quinasa 1AzetidinesPiperidinasSulfonamidasAzetidinasMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::AgedMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Clinical Protocols::Antineoplastic Protocols::Antineoplastic Combined Chemotherapy ProtocolsMedical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Azetines::AzetidinesMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis::Disease-Free SurvivalMedical Subject Headings::Check Tags::FemaleMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::IndolesMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Survival Analysis::Kaplan-Meier EstimateMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine Kinases::Mitogen-Activated Protein Kinase Kinases::MAP Kinase Kinase 1Medical Subject Headings::Check Tags::MaleMedical Subject Headings::Diseases::Neoplasms::Neoplasms by Histologic Type::Nevi and Melanomas::MelanomaMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::Middle AgedMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::MutationMedical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::PiperidinesMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Neoplasm Proteins::Oncogene Proteins::Proto-Oncogene Proteins::raf Kinases::Proto-Oncogene Proteins B-rafMedical Subject Headings::Chemicals and Drugs::Organic Chemicals::Sulfur Compounds::Sulfones::SulfonamidesMedical Subject Headings::Information Science::Information Science::Data Collection::Vital Statistics::Mortality::Survival RateMedical Subject Headings::Named Groups::Persons::Age Groups::Adultresearch article25265494open access10.1056/NEJMoa14088681533-4406