title: Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study.
abstract: BACKGROUND
  In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAF(V600) mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAF(V600E) and BRAF(V600K) mutation subgroups.
  
  
  METHODS
  Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAF(V600) mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m(2) of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980.
  
  
  RESULTS
  675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p<0·0001). For the 598 (91%) patients with BRAF(V600E) disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9-14·9) compared with 10·0 months (8·0-14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60-0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2-7·0) and 1·6 months (1·6-2·1), respectively (HR 0·39 [95% CI 0·33-0·47]; p<0·0001). For the 57 (9%) patients with BRAF(V600K) disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2-not estimable) compared with 7·6 months (6·1-16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21-0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4-9·0) and 1·7 months (1·4-2·9), respectively (HR 0·30 [95% CI 0·16-0·56]; p<0·0001). The most frequent grade 3-4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events.
  
  
  CONCLUSIONS
  Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAF(V600E) mutation and in patients with the less common BRAF(V600K) mutation.
  
  
  BACKGROUND
  F Hoffmann-La Roche-Genentech.
authors: Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia. Electronic address: grant.mcarthur@petermac.org.
authors: Grant A
authors: GA
authors: McArthur
authors: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: Paul B
authors: PB
authors: Chapman
authors: Institut Gustave Roussy, Paris, France.
authors: Caroline
authors: C
authors: Robert
authors: Royal Marsden Hospital, London, UK.
authors: James
authors: J
authors: Larkin
authors: The Netherlands Cancer Institute, Amsterdam, Netherlands.
authors: John B
authors: JB
authors: Haanen
authors: University of Zurich, Zurich, Switzerland.
authors: Reinhard
authors: R
authors: Dummer
authors: Jonsson Comprehensive Cancer Center at University of California, Los Angeles, CA, USA.
authors: Antoni
authors: A
authors: Ribas
authors: Princess Margaret Hospital and University Health Network, Toronto, ON, Canada.
authors: David
authors: D
authors: Hogg
authors: The Angeles Clinic and Research Institute, Los Angeles, CA, USA.
authors: Omid
authors: O
authors: Hamid
authors: Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy.
authors: Paolo A
authors: PA
authors: Ascierto
authors: The University of Tübingen, Tübingen, Germany.
authors: Claus
authors: C
authors: Garbe
authors: Istituto Europeo di Oncologia, Milan, Italy.
authors: Alessandro
authors: A
authors: Testori
authors: University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
authors: Michele
authors: M
authors: Maio
authors: University of Manchester, Manchester, UK.
authors: Paul
authors: P
authors: Lorigan
authors: APHP Oncodermatology, Hôpital Saint Louis University, Paris, France.
authors: Celeste
authors: C
authors: Lebbé
authors: Saint André Hospital, Bordeaux, France.
authors: Thomas
authors: T
authors: Jouary
authors: University Hospital Essen, Essen, Germany.
authors: Dirk
authors: D
authors: Schadendorf
authors: Beverly Hills Cancer Center, Beverly Hills, CA, USA.
authors: Stephen J
authors: SJ
authors: O'Day
authors: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: John M
authors: JM
authors: Kirkwood
authors: Gustave-Roussy Cancer Center and University Paris-Sud, Villejuif/Paris Sud, France.
authors: Alexander M
authors: AM
authors: Eggermont
authors: Nantes University Hospital, Nantes, France.
authors: Brigitte
authors: B
authors: Dréno
authors: Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Jeffrey A
authors: JA
authors: Sosman
authors: Massachusetts General Hospital, Boston, MA, USA.
authors: Keith T
authors: KT
authors: Flaherty
authors: Genentech Inc, San Francisco, CA, USA.
authors: Ming
authors: M
authors: Yin
authors: Genentech Inc, San Francisco, CA, USA.
authors: Ivor
authors: I
authors: Caro
authors: Roche Molecular Systems Inc, Pleasanton, CA, USA.
authors: Suzanne
authors: S
authors: Cheng
authors: F Hoffmann-La Roche, Basel, Switzerland.
authors: Kerstin
authors: K
authors: Trunzer
authors: University of Kiel, Kiel, Germany.
authors: Axel
authors: A
authors: Hauschild
mesh_terms: D000328:Adult; D000368:Aged; D003606:Dacarbazine / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; D003606:Dacarbazine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf