title: Dabrafenib for Treating Unresectable, Advanced or Metastatic BRAF V600 Mutation-Positive Melanoma: An Evidence Review Group Perspective.
abstract: The National Institute for Health and Care Excellence (NICE) invited GlaxoSmithKline, the manufacturer of dabrafenib, to submit evidence for the clinical and cost effectiveness of dabrafenib for the treatment of unresectable, advanced or metastatic BRAF V600 mutation-positive melanoma in accordance with the Institute's Single Technology Appraisal (STA) process. The Liverpool Reviews and Implementation Group (LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article summarizes the ERG's review of the evidence submitted by the company and provides a summary of the Appraisal Committee's (AC) final decision in October 2014. The clinical evidence for dabrafenib was derived from an ongoing phase III, randomized, double-blind, placebo-controlled, international, multicentre clinical trial (BREAK-3) involving 230 patients randomized 2:1 to receive either dabrafenib or dacarbazine. A significant improvement in median progression-free survival (PFS) but not overall survival (OS) was reported in the dabrafenib arm compared with dacarbazine. Vemurafenib is considered a more appropriate comparator than is dacarbazine. The clinical evidence for vemurafenib was derived from a completed phase III, randomized, double-blind, placebo-controlled, international, multicentre clinical trial (BRIM-3) involving 675 patients randomized 1:1 to receive either vemurafenib or dacarbazine. A significant improvement in median PFS and OS was reported in the vemurafenib arm compared with dacarbazine. As there is no direct evidence comparing dabrafenib versus vemurafenib, the company presented an indirect treatment comparison (ITC) that demonstrated no statistical differences between dabrafenib and vemurafenib for PFS or OS. The ERG expressed concerns with the ITC, mainly in relation to the validity of the assumptions underpinning the methodology; the ERG concluded this resulted in findings that are unlikely to be robust or reliable. Dabrafenib and vemurafenib are both available to patients treated by the National Health Service (NHS) in England via a Patient Access Scheme (PAS) in which the costs of the drugs are discounted. Using these discounted costs, the incremental cost-effectiveness ratios (ICERs) generated by the company were £60,980 per quality-adjusted life-year (QALY) for dabrafenib versus dacarbazine and £11,046 per QALY gained for dabrafenib versus vemurafenib. The ERG considered the economic model structure developed by the company to derive the ICERs to be overly complex and based on unsubstantiated assumptions, most importantly in relation to the projection of OS. Applying the latest OS data from BREAK-3 to a less complex model structure increased the estimated ICER for dabrafenib compared with dacarbazine from £60,980 to £112,727 per QALY gained. Since the results from the ITC were considered by the ERG to be neither reliable nor robust, the ERG also considered a cost-effectiveness comparison to be inappropriate due to a lack of meaningful or reliable data. In spite of limitations in the data, the AC took the view that dabrafenib and vemurafenib were "likely" of similar clinical effectiveness. Since the overall costs of these two drugs were similar, the AC recommended the use of dabrafenib in patients with unresectable, advanced or metastatic BRAF V600 mutation-positive melanoma.
authors.affiliation: Liverpool Reviews and Implementation Group, University of Liverpool, Whelan Building, Liverpool, L69 3GB, UK, Nigel.Fleeman@liverpool.ac.uk.
authors.forename: Nigel
authors.initials: N
authors.lastname: Fleeman
authors.forename: Adrian
authors.initials: A
authors.lastname: Bagust
authors.forename: Sophie
authors.initials: S
authors.lastname: Beale
authors.forename: Angela
authors.initials: A
authors.lastname: Boland
authors.forename: Rumona
authors.initials: R
authors.lastname: Dickson
authors.forename: Kerry
authors.initials: K
authors.lastname: Dwan
authors.forename: Marty
authors.initials: M
authors.lastname: Richardson
authors.forename: Yenal
authors.initials: Y
authors.lastname: Dundar
authors.forename: Helen
authors.initials: H
authors.lastname: Davis
authors.forename: Lindsay
authors.initials: L
authors.lastname: Banks
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000191:economics* / Q000627:therapeutic use; D017326:Clinical Trials, Phase III as Topic; D003362:Cost-Benefit Analysis; D018572:Disease-Free Survival; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000191:economics* / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000556:secondary*; D018803:Models, Economic; D009154:Mutation; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010091:Oximes / Q000008:administration & dosage / Q000191:economics* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016032:Randomized Controlled Trials as Topic
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D010091:Oximes; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib