title: Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial.
abstract: BACKGROUND
  The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF(V600)-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies.
  
  
  METHODS
  In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants.
  
  
  RESULTS
  Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months (IQR 8·5-17·3), the updated investigator-assessed median progression-free survival was 12·3 months (95% CI 9·5-13·4) for cobimetinib and vemurafenib versus 7·2 months (5·6-7·5) for placebo and vemurafenib (HR 0·58 [95% CI 0·46-0·72], p<0·0001). The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22·3 months (95% CI 20·3-not estimable) for cobimetinib and vemurafenib versus 17·4 months (95% CI 15·0-19·8) for placebo and vemurafenib (HR 0·70, 95% CI 0·55-0·90; p=0·005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3-4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase (36 [15%] in the cobimetinib and vemurafenib group vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [<1%]), and alanine transaminase increase (28 [11%] vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group.
  
  
  CONCLUSIONS
  These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAF(V600)-mutant melanoma.
  
  
  BACKGROUND
  F Hoffmann-La Roche-Genentech.
authors.affiliation: Istituto Nazionale Tumori Fondazione G Pascale, Naples, Italy.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; University of Melbourne, Parkville, VIC, Australia. Electronic address: grant.mcarthur@petermac.org.
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.affiliation: Nantes University, Nantes, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dréno
authors.affiliation: Princess Alexandra Hospital, Woolloongabba, QLD, Australia.
authors.forename: Victoria
authors.initials: V
authors.lastname: Atkinson
authors.affiliation: National Institute of Oncology, Budapest, Hungary.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Liszkay
authors.affiliation: Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Di Giacomo
authors.affiliation: Papa Giovanni XXIII Hospital, Bergamo, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Mandalà
authors.affiliation: N N Blokhin Russian Cancer Research Center, Moscow, Russia.
authors.forename: Lev
authors.initials: L
authors.lastname: Demidov
authors.affiliation: Moscow City Oncology Hospital 62, Krasnogorsk, Russia.
authors.forename: Daniil
authors.initials: D
authors.lastname: Stroyakovskiy
authors.affiliation: Centre Hospitalier Lyon Sud, Lyon 1 University, Lyon, France; Lyons Cancer Research Center, Lyon, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Thomas
authors.affiliation: Hospital Universitario Virgen Macarena, Seville, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: de la Cruz-Merino
authors.affiliation: Hôpital Saint André, Bordeaux, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dutriaux
authors.affiliation: University of Tübingen, Tübingen, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.affiliation: Genentech Inc, South San Francisco, CA, USA.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Genentech Inc, South San Francisco, CA, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wongchenko
authors.affiliation: Genentech Inc, South San Francisco, CA, USA.
authors.forename: Ilsung
authors.initials: I
authors.lastname: Chang
authors.affiliation: Genentech Inc, South San Francisco, CA, USA.
authors.forename: Jessie J
authors.initials: JJ
authors.lastname: Hsu
authors.affiliation: Genentech Inc, South San Francisco, CA, USA.
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Koralek
authors.affiliation: Genentech Inc, South San Francisco, CA, USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rooney
authors.affiliation: Jonsson Comprehensive Cancer Center at University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: James
authors.initials: J
authors.lastname: Larkin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001384:Azetidines / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000235:genetics; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010880:Piperidines / Q000008:administration & dosage; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D013449:Sulfonamides / Q000008:administration & dosage; D015996:Survival Rate; D000077484:Vemurafenib; D055815:Young Adult
chemical_list: D001384:Azetidines; D014408:Biomarkers, Tumor; D007211:Indoles; D010880:Piperidines; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C574276:cobimetinib