title: Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study.
abstract: Vemurafenib has shown activity in patients with BRAFV600 mutated melanoma with brain metastases (BM). This phase 2 study evaluated vemurafenib in patients with/without prior treatment for BM.
  
  
  
  Patients with BRAFV600 mutated melanoma with BM were enrolled into cohort 1 (previously untreated BM) and cohort 2 (previously treated BM) and received vemurafenib (960 mg BID) until disease progression (PD) or intolerance. Primary endpoint was best overall response rate (BORR) in the brain in cohort 1 that was evaluated using modified RECIST 1.1 criteria using lesions ≥0.5 cm to assess response.
  
  
  
  146 patients were treated (cohort 1 n = 90; cohort 2 n = 56), 62% of whom were male. Median (range) time since diagnosis of BM: 1.0 (0-9) month in cohort 1 and 4.2 (1-68) months in cohort 2. Median duration of treatment was 4.1 months (range 0.3-34.5) in cohort 1 and 4.1 months (range 0.2-27.6) in cohort 2. Intracranial BORR in cohort 1 by an independent review committee (IRC) was 18% (2 CRs, 14 PRs). Extracranial BORR by IRC was 33% in cohort 1 and 23% in cohort 2. Median PFS (brain only, investigator-assessed) was 3.7 months (range 0.03-33.4; IQR 1.9-5.6) in cohort 1 and 4.0 months (range 0.3-27.4; IQR 2.2-7.4) in cohort 2. Median OS was 8.9 months (range 0.6-34.5; IQR 4.9-17.0) in cohort 1 and 9.6 months (range 0.7-34.3; IQR 4.5-18.4) in cohort 2. Adverse events (AEs) were similar in type, grade and frequency to other studies of single-agent vemurafenib. Grade 3/4 AEs occurred in 59 (66%) patients in cohort 1 and 36 (64%) in cohort 2. Overall, 84% of patients died during the study (86% in cohort 1 and 80% in cohort 2), mainly due to disease progression.
  
  
  
  The study demonstrates clinically meaningful response rates of melanoma BM to vemurafenib, which was well tolerated and without significant CNS toxicity.
authors.affiliation: Department of Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne and University of Melbourne, Parkville, Australia.
authors.forename: G A
authors.initials: GA
authors.lastname: McArthur
authors.affiliation: AOU Senese Policlinico Santa Maria Alle Scotte, Siena, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Maio
authors.affiliation: Department of Medical Oncology, Hospital Clínic Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Arance
authors.affiliation: Mount Vernon Hospital, Centre for Cancer Treatment, Northwood, UK.
authors.forename: P
authors.initials: P
authors.lastname: Nathan
authors.affiliation: The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Blank
authors.affiliation: University Paris Descartes, Hospital Cochin, APHP, Paris, France.
authors.forename: M-F
authors.initials: MF
authors.lastname: Avril
authors.affiliation: Department of Dermatology, University Hospital Tuebingen, Tuebingen.
authors.forename: C
authors.initials: C
authors.lastname: Garbe
authors.affiliation: Department of Dermatology, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Kiel.
authors.forename: A
authors.initials: A
authors.lastname: Hauschild
authors.affiliation: Department of Dermatology, Comprehensive Cancer Center, University Hospital Essen, Essen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Angeles Clinic and Research Institute, Los Angeles, USA.
authors.forename: O
authors.initials: O
authors.lastname: Hamid
authors.affiliation: Fachklinik Hornheide, Munster, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Fluck
authors.affiliation: Moffitt Cancer Center, Tampa, USA.
authors.forename: M
authors.initials: M
authors.lastname: Thebeau
authors.affiliation: Chaim Sheba Medical Centre, Oncology Institute, Ramat-Gan, Israel.
authors.forename: J
authors.initials: J
authors.lastname: Schachter
authors.affiliation: Crown Princess Cancer Centre Westmead Hospital and Department of Clinical Medicine, Macquarie University, Sydney NSW, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Kefford
authors.affiliation: Seattle Cancer Care Alliance, Seattle, USA.
authors.forename: M
authors.initials: M
authors.lastname: Chamberlain
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Makrutzki
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Robson
authors.affiliation: University of Colorado Cancer Center, Aurora.
authors.forename: R
authors.initials: R
authors.lastname: Gonzalez
authors.affiliation: City of Hope, Duarte, USA.
authors.forename: K
authors.initials: K
authors.lastname: Margolin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000556:secondary; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAFV600 mutated melanoma; brain metastases; phase 2 study; vemurafenib