Network Meta-analysis of Progression-Free Survival and Overall Survival in First-Line Treatment of BRAF Mutation-Positive Metastatic Melanoma

INTRODUCTION The present study aimed to inform an economic evaluation of dabrafenib and trametinib combination as first-line treatment of metastatic melanoma in a Canadian setting. A network meta-analysis was conducted to estimate hazard ratios (HRs) for progression-free survival (PFS)and overall survival (OS) of dabrafenib plus trametinib versus other first-line treatments of BRAF mutation-positive metastatic melanoma including dabrafenib, trametinib, vemurafenib, ipilimumab, and dacarbazine (DTIC). METHODS HRs for PFS and OS were from randomized controlled trials identified from systematic literature reviews. HRs for PFS and OS (adjusted for crossover as appropriate) were analyzed using multivariate and univariate Bayesian network meta-analysis. RESULTS In multivariate network-meta analyses (HRs for PFS and OS estimated simultaneously to account for the correlation of treatment effects on PFS and OS), HRs (95% credible interval) for PFS and OS favored dabrafenib plus trametinib [PFS: 0.23 (0.18-0.29) versus DTIC, 0.32 (0.24-0.42) versus ipilimumab plus DTIC, 0.52 (0.32-0.83) versus trametinib, 0.57 (0.48-0.69) versus vemurafenib, and 0.59 (0.50-0.71) versus dabrafenib]; OS [0.41 (0.29-0.56) versus DTIC, 0.52 (0.38-0.71) versus ipilimumab plus DTIC, 0.68 (0.47-0.95) versus trametinib, 0.69 (0.57-0.84) versus vemurafenib, and 0.72 (0.60-0.85) versus dabrafenib]. The beneficial effects on OS of dabrafenib plus trametinib versus ipilimumab plus DTIC and versus trametinib were attenuated when HRs were estimated using univariate network meta-analysis (HRs for PFS and OS estimated separately). CONCLUSION This analysis demonstrates improved PFS and OS with dabrafenib + trametinib versus dabrafenib, trametinib, vemurafenib, ipilimumab plus DTIC, and DTIC as first-line treatment for patients with BRAF mutation-positive metastatic melanoma. FUNDING Novartis Pharmaceuticals.