Therapeutic efficacy and safety of combined BRAF and MEK inhibition in patients with malignant melanoma: a meta-analysis

Background: Recent clinical studies have shown that initial therapy with combined BRAF and mitogen-activated extracellular signal-regulated kinase (MEK) inhibition is more effective in metastatic melanoma than single-agent BRAF inhibitors. However, the response rates with single-agent BRAF are low. Thus, the objective of this study was to conduct a meta-analysis of randomized controlled trials to compare the efficacy and adverse events risk between monotherapy and combination therapy. Materials and methods: Searches were made in PubMed and EMBASE electronic databases and conference abstracts published by the American Society of Clinical Oncology from 2000 to 2017. Outcomes included overall response, progression-free survival, and overall survival, as well as the incidence rate of adverse events. Results: Eight trials comprising 2,664 patients were included in the meta-analysis. Patients with combined therapies showed superior results compared to those with BRAF inhibitors alone for the following: overall response rate (combined relative risk [RR] = 1.34, 95% confidence interval [95% CI]: 1.24-1.45, P, 0.00001), progression-free survival (combined hazards ratio [HR] = 0.58, 95% CI: 0.52-0.64, P, 0.00001), and overall survival rate (combined HR = 0.70, 95% CI: 0.62-0.80, P, 0.00001). Patients with combination therapies had higher incidence of adverse events including pyrexia (combined RR = 2.00, 95% CI: 1.40-2.84), nausea (combined RR = 1.41, 95% CI: 1.03-1.94), diarrhea (combined RR = 1.50, 95% CI: 1.08-2.06), and vomiting (combined RR = 1.87, 95% CI: 01.52-2.31) compared to those with BRAF inhibitors alone. Conclusion: These data suggested that the combined BRAF and MEK inhibition was associated with a significant improvement in overall response, progression-free survival, and overall survival, but increased the incidence of adverse events among the patients with BRAF V600mutated metastatic melanoma. Further large-scale, high-quality, placebo-controlled, double-blind trials are needed to confirm this conclusion.