title: Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study.
abstract: BACKGROUND
  The orally available BRAF kinase inhibitor vemurafenib, compared with dacarbazine, shows improved response rates, progression-free survival (PFS), and overall survival in patients with metastatic melanoma that has a BRAF(V600) mutation. We assessed vemurafenib in patients with advanced metastatic melanoma with BRAF(V600) mutations who had few treatment options.
  
  
  METHODS
  In an open-label, multicentre study, patients with untreated or previously treated melanoma and a BRAF(V600) mutation received oral vemurafenib 960 mg twice a day. The primary endpoint was safety. All analyses were done on the safety population, which included all patients who received at least one dose of vemurafenib. This report is the third interim analysis of this study. This study is registered with ClinicalTrials.gov, number NCT01307397.
  
  
  RESULTS
  Between March 1, 2011, and Jan 31, 2013, 3226 patients were enrolled in 44 countries. 3222 patients received at least one dose of vemurafenib (safety population). At data cutoff, 868 (27%) patients were on study treatment and 2354 (73%) had withdrawn, mainly because of disease progression. Common adverse events of all grades included rash (1592 [49%]), arthralgia (1259 [39%]), fatigue (1093 [34%]), photosensitivity reaction (994 [31%]), alopecia (826 [26%]), and nausea (628 [19%]). 1480 (46%) patients reported grade 3 or 4 adverse events, including cutaneous squamous cell carcinoma (389 [12%]), rash (155 [5%]), liver function abnormalities (165 [5%]), arthralgia (106 [3%]), and fatigue (93 [3%]). Grade 3 and 4 adverse events were reported more frequently in patients aged 75 years and older (n=257; 152 [59%, 95% CI 53-65] and ten [4%, 2-7], respectively) than in those younger than 75 years (n=2965; 1286 [43%, 42-45] and 82 [3%, 2-3], respectively).
  
  
  CONCLUSIONS
  Vemurafenib safety in this diverse population of patients with BRAF(V600) mutated metastatic melanoma, who are more representative of routine clinical practice, was consistent with the safety profile shown in the pivotal trials of this drug.
  
  
  BACKGROUND
  F Hoffmann-La Roche.
authors.affiliation: Royal Marsden Hospital NHS Foundation Trust, London, UK. Electronic address: james.larkin@rmh.nhs.uk.
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.affiliation: Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Del Vecchio
authors.affiliation: Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
authors.affiliation: Dermatooncology Department, General University Hospital, Prague, Czech Republic.
authors.forename: Ivana
authors.initials: I
authors.lastname: Krajsova
authors.affiliation: Ella Institute for Melanoma, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Jacob
authors.initials: J
authors.lastname: Schachter
authors.affiliation: Universitair Ziekenhuis Brussel, Brussels, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Neyns
authors.affiliation: Service of Oncology-Hospital La Paz, Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Espinosa
authors.affiliation: Universität Tübingen-Hautklinik, Tübingen, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.affiliation: Melanoma Oncology Unit, Veneto Oncology Institute, Gattamelata, Padova, Italy.
authors.forename: Vanna Chiarion
authors.initials: VC
authors.lastname: Sileni
authors.affiliation: Medical Oncology, University of Athens, Greece.
authors.forename: Helen
authors.initials: H
authors.lastname: Gogas
authors.affiliation: Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada.
authors.forename: Wilson H
authors.initials: WH
authors.lastname: Miller
authors.affiliation: Papa Giovanni XXIII Hospital, Bergamo, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Mandalà
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands.
authors.forename: Geke A P
authors.initials: GA
authors.lastname: Hospers
authors.affiliation: Department of Medical Oncology, Hospital Clínic, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Arance
authors.affiliation: IRCCS San Martino Hospital-IST, Genoa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Queirolo
authors.affiliation: University Hospital Schleswig-Holstein, Department of Dermatology, Kiel, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Hauschild
authors.affiliation: Cancer Clinical Trials Unit, Royal Adelaide Hospital, and Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Brown
authors.affiliation: F Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Lada
authors.initials: L
authors.lastname: Mitchell
authors.affiliation: F Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Luisa
authors.initials: L
authors.lastname: Veronese
authors.affiliation: Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands. Electronic address: c.blank@nki.nl.
authors.forename: Christian U
authors.initials: CU
authors.lastname: Blank
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001208:Asia; D001315:Australia; D002170:Canada; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005060:Europe; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000556:secondary*; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D012307:Risk Factors; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D013019:South Africa; D013020:South America; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf