title: Improved survival with vemurafenib in melanoma with BRAF V600E mutation.
abstract: BACKGROUND
  Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation.
  
  
  METHODS
  We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths.
  
  
  RESULTS
  At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects.
  
  
  CONCLUSIONS
  Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.).
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. chapmanp@mskcc.org
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chapman
authors.forename: Axel
authors.initials: A
authors.lastname: Hauschild
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.forename: John B
authors.initials: JB
authors.lastname: Haanen
authors.forename: Paolo
authors.initials: P
authors.lastname: Ascierto
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.forename: Alessandro
authors.initials: A
authors.lastname: Testori
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
authors.forename: David
authors.initials: D
authors.lastname: Hogg
authors.forename: Paul
authors.initials: P
authors.lastname: Lorigan
authors.forename: Celeste
authors.initials: C
authors.lastname: Lebbe
authors.forename: Thomas
authors.initials: T
authors.lastname: Jouary
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.forename: Steven J
authors.initials: SJ
authors.lastname: O'Day
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dreno
authors.forename: Keith
authors.initials: K
authors.lastname: Nolop
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.forename: Betty
authors.initials: B
authors.lastname: Nelson
authors.forename: Jeannie
authors.initials: J
authors.lastname: Hou
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lee
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003606:Dacarbazine / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D057194:Intention to Treat Analysis; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D016019:Survival Analysis; D000077484:Vemurafenib; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; D003606:Dacarbazine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf