title: Systemic Therapy for Previously Untreated Advanced BRAF-Mutated Melanoma: A Systematic Review and Network Meta-Analysis of Randomized Clinical Trials.
abstract: OBJECTIVE
  Multiple effective first-line systemic treatment options are available for patients with advanced BRAF-mutated melanoma. A lack of head-to-head randomized clinical trials (RCTs) comparing targeted and immunotherapies leaves uncertainty regarding optimal first-line treatment.
  
  
  OBJECTIVE
  To estimate the relative efficacy and safety of systemic therapies for advanced, treatment-naive, BRAF-mutated melanoma.
  
  
  METHODS
  We searched MEDLINE, Embase, and the Cochrane Central Registry of Controlled Trials for phase 2 or 3 RCTs published up until April 29, 2016.
  
  
  METHODS
  We included RCTs in which at least 1 intervention was a targeted (BRAF or MEK) or an immune checkpoint (cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] or programmed cell death 1 [PD-1]) inhibitor.
  
  
  METHODS
  Two reviewers performed study selection, data abstraction, and risk of bias assessment. We performed a Bayesian network meta-analysis using a fixed-effect model to combine direct comparisons with indirect evidence. We estimated hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and odds ratios (OR) for objective response rate (ORR) and serious adverse events.
  
  
  RESULTS
  Sixteen eligible articles reporting 15 RCTs involving 6662 patients assigned to 1 of 10 treatment strategies were included. Both BRAF/MEK and PD-1 were associated with improved OS benefit compared with all other treatments except CTLA-4/granulocyte macrophage colony-stimulating factor. There was no significant difference in OS between BRAF/MEK and PD-1 (HR, 1.02; 95% credible interval [CrI], 0.72-1.45). The network meta-analysis showed a significant advantage of BRAF/MEK compared with all other treatment strategies for PFS. BRAF/MEK was associated with higher ORR (OR, 2.00; 95% CrI, 1.64-2.45) compared with BRAF alone, with both being superior in achieving ORR compared with other treatments. Chemotherapy and PD-1 were associated with lowest risk of serious adverse events. There was no significant difference in the risk of serious adverse events between chemotherapy and PD-1 (OR, 1.00; 95% CrI, 0.74-1.34).
  
  
  CONCLUSIONS
  Compared with other treatments, BRAF/MEK and PD-1 inhibition significantly improved OS. The favorable safety profile of PD-1 inhibitors supports using this option as first-line therapy in circumstances where rapid response is not a priority.
authors: Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton , Ontario, Canada.
authors: Tahira
authors: T
authors: Devji
authors: Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton , Ontario, Canada2Department of Oncology, McMaster University, Hamilton, Ontario, Canada.
authors: Oren
authors: O
authors: Levine
authors: Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton , Ontario, Canada.
authors: Binod
authors: B
authors: Neupane
authors: Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton , Ontario, Canada.
authors: Joseph
authors: J
authors: Beyene
authors: Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton , Ontario, Canada3Father Sean O'Sullivan Research Centre, St Joseph's Healthcare-Hamilton, Hamilton, Ontario, Canada.
authors: Feng
authors: F
authors: Xie
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D018572:Disease-Free Survival; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D058990:Molecular Targeted Therapy; D009154:Mutation; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D016032:Randomized Controlled Trials as Topic; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases