title: Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.
abstract: 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.).
authors.affiliation: 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.).
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dréno
authors.forename: Victoria
authors.initials: V
authors.lastname: Atkinson
authors.forename: Gabriella
authors.initials: G
authors.lastname: Liszkay
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
authors.forename: Mario
authors.initials: M
authors.lastname: Mandalà
authors.forename: Lev
authors.initials: L
authors.lastname: Demidov
authors.forename: Daniil
authors.initials: D
authors.lastname: Stroyakovskiy
authors.forename: Luc
authors.initials: L
authors.lastname: Thomas
authors.forename: Luis
authors.initials: L
authors.lastname: de la Cruz-Merino
authors.forename: Caroline
authors.initials: C
authors.lastname: Dutriaux
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.forename: Mika A
authors.initials: MA
authors.lastname: Sovak
authors.forename: Ilsung
authors.initials: I
authors.lastname: Chang
authors.forename: Nicholas
authors.initials: N
authors.lastname: Choong
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hack
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001384:Azetidines / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000556:secondary; D008875:Middle Aged; D009154:Mutation; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D015996:Survival Rate; D000077484:Vemurafenib
chemical_list: D001384:Azetidines; D007211:Indoles; D010880:Piperidines; D013449:Sulfonamides; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C574276:cobimetinib