Comparative efficacy and safety of combination therapies for advanced melanoma: A network meta-analysis

Abstract

Background: Currently, the major treatment modalities of advanced melanoma are immune check point and mitogen-activated protein kinase (MAPK) pathway inhibitors. As lacking head-to-head randomizedcontrolled trials (RCTs) comparing immune check point and MAPK pathway inhibitors, we evaluated the efficacy and toxicity with different treatment combinations of immune check point or MAPK pathway inhibitors for advanced melanoma by network meta-analysis. Methods: We searched for RCTs in Pubmed, Embase, Ovid MEDLINE, Web of Science and Cochrane Central Register for Controlled Trials through March 2017. Two reviewers performed a network meta-analysis by assessing the hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), as well as by evaluating serious adverse events (SAEs). Results: Twenty-four eligible RCTs involving 10,951 patients assigned to 11 treatment modalities were included. The combination of BRAF and MEK inhibitors demonstrated an improved OS benefit compared with all the other treatments except programmed death-1/ligand-1 (PD-1/L1) blockade because the difference in OS between the BRAF-MEK inhibitor combination and PD-1 blockade (HR: 0.85; 95% credible interval (CrI): 0.59, 1.21) was not significant. For PFS, the BRAF and MEK inhibitor combination showed a significant advantage compared with other treatments apart from the combination of PD-1/L1 and cytotoxic T lymphocyte-associated antigen-4(CTLA-4) blockade (HR:0.61; 95% CrI: 0.30, 1.25). The MEK inhibitor combined with chemotherapy was associated with the highest risk of SAEs (HR: 1.76 95% CrI: 1.21, 2.48). Conclusions: The combination of BRAF and MEK inhibitors exhibited a survival advantage in OS and PFS and comparable risk of toxicity compared with chemotherapy.