Systemic Therapy for Previously Untreated Advanced BRAF-Mutated Melanoma: A Systematic Review and Network Meta-Analysis of Randomized Clinical Trials

JAMA Oncol. 2017 Mar 1;3(3):366-373. doi: 10.1001/jamaoncol.2016.4877.

Abstract

Importance: 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.

Data sources: We searched MEDLINE, Embase, and the Cochrane Central Registry of Controlled Trials for phase 2 or 3 RCTs published up until April 29, 2016.

Study selection: 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.

Data extraction and synthesis: 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 and relevance: 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.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • CTLA-4 Antigen / antagonists & inhibitors
  • Disease-Free Survival
  • Humans
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Molecular Targeted Therapy
  • Mutation*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / genetics*
  • Randomized Controlled Trials as Topic
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / genetics
  • Survival Analysis
  • Treatment Outcome

Substances

  • CTLA-4 Antigen
  • CTLA4 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Protein Kinase Inhibitors
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Mitogen-Activated Protein Kinase Kinases