title: The European Medicines Agency review of vemurafenib (Zelboraf®) for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma: summary of the scientific assessment of the Committee for Medicinal Products for Human Use.
abstract: The applicant company Roche Registration Ltd. submitted to the European Medicines Agency (EMA) an application for marketing authorisation for vemurafenib. Vemurafenib is a low molecular weight, orally available, inhibitor of oncogenic V600 BRAF serine-threonine kinase. Mutations in the BRAF gene which substitute the valine at amino acid position 600 constitutively activate BRAF proteins, which will drive cell proliferation in the absence of growth factors. Results from a phase 3 trial (N=675) comparing vemurafenib 960 mg twice daily (taken either with or without food) to standard treatment dacarbazine (DTIC) in patients with BRAF V600E mutation-positive unresectable or metastatic melanoma were submitted. The study met its primary efficacy objective after an interim analysis of overall survival. Patients were allowed to cross-over to the experimental arm following disclosure of the study results after the first interim analysis. In the update of the analysis, the median overall survival (OS) was 9.9 months versus 13.2 months for DTIC and vemurafenib, respectively (HR=0.67; 95% confidence interval (CI): 0.54, 0.84; cut-off 3 October 2011). Based on the updated analysis, the CHMP concluded that a survival benefit over DTIC had been convincingly demonstrated, in the overall population. The follow-up was considered sufficiently mature with close to 50% of the events observed. The most common side effects (affecting more than 30% of patients) in vemurafenib treated patients included arthralgia, fatigue, rash, photosensitivity reaction, nausea, alopecia and pruritus. Some patients treated with vemurafenib developed cutaneous squamous cell carcinoma which was readily treated by local surgery. The objective of this paper is to summarise the scientific review of the application leading to regulatory approval in the European Union (EU). The full scientific assessment report and product information, including the Summary of Product Characteristics (SmPC), are available on the EMA website (www.ema.europa.eu).
authors.affiliation: European Medicines Agency, London, United Kingdom. silvy.darochadias@ema.europa.eu
authors.forename: Silvy
authors.initials: S
authors.lastname: da Rocha Dias
authors.forename: Tomas
authors.initials: T
authors.lastname: Salmonson
authors.forename: Barbara
authors.initials: B
authors.lastname: van Zwieten-Boot
authors.forename: Bertil
authors.initials: B
authors.lastname: Jonsson
authors.forename: Serena
authors.initials: S
authors.lastname: Marchetti
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Rosa
authors.initials: R
authors.lastname: Giuliani
authors.forename: Francesco
authors.initials: F
authors.lastname: Pignatti
mesh_terms: D017326:Clinical Trials, Phase III as Topic; D017277:Drug Approval / Q000458:organization & administration*; D004341:Drug Evaluation; D005062:European Union; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D009362:Neoplasm Metastasis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D013449:Sulfonamides / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf