Comparative efficacy and safety of targeted therapies for BRAF-mutant unresectable or metastatic melanoma: Results from a systematic literature review and a network meta-analysis

Background: The objective of this study was to estimate the relative efficacy and safety of targeted therapies for the treatment of metastatic melanoma using a network meta-analysis (NMA). Methods: A systematic literature review (SLR) identified studies in Medline, Embase and Cochrane published until November 2020. Screening used prespecified eligibility criteria. Following a transitivity assessment across included studies, Bayesian NMA was conducted. Results: A total of 43 publications reporting 15 targeted therapy trials and 42 reporting 18 immunotherapy trials were retained from the SLR and considered for the NMA. Due to substantial between-study heterogeneity with immunotherapy trials, the analysis considered a network restricted to targeted therapies. Among combination therapies, encorafenib + binimetinib was superior to dabrafenib + trametinib for overall response rate (OR = 1.86; 95 % credible interval [CrI] 1.10, 3.17), superior to vemurafenib + cobimetinib with fewer serious adverse events (SAEs) (OR = 0.51; 95 % CrI 0.29, 0.91) and fewer discontinuations due to AEs (OR = 0.45; 95 % CrI 0.21, 0.96), and superior to atezolizumab + vemurafenib + cobimetinib with fewer SAEs (OR = 0.41; 95 % CrI 0.21, 0.82). Atezolizumab + vemurafenib + cobimetinib and encorafenib + binimetinib were generally comparable for efficacy endpoints. Among double combination therapies, encorafenib + binimetinib showed high probabilities of being better for all efficacy and safety endpoints. Conclusions: This NMA confirms that combination therapies are more efficacious than monotherapies. Encorafenib + binimetinib has a favourable efficacy profile compared to other double combination therapies and a favourable safety profile compared to both double and triple combination therapies.