BRAF and MEK Inhibitors and Their Toxicities: A Meta-Analysis

SIMPLE SUMMARY: To date, one of the reference therapies for the treatment of mutated BRAF metastatic melanoma is based on the combination of BRAF and MEK inhibitors. Although many trials have compared BRAF and MEK inhibitor combination therapies, there is no evidence of superiority in the use of one of the three combinations over the others. Furthermore, comparative data on safety are scarce. To help clinicians tailor patients’ treatment using the most appropriate BRAF/MEK inhibitor combinations, we performed a meta-analysis of adverse events associated with each treatment combination. ABSTRACT: Purpose: This meta-analysis summarizes the incidence of treatment-related adverse events (AE) of BRAFi and MEKi. Methods: A systematic search of Medline/PubMed was conducted to identify suitable articles published in English up to 31 December 2021. The primary outcomes were profiles for all-grade and grade 3 or higher treatment-related AEs, and the analysis of single side effects belonging to both categories. Results: The overall incidence of treatment-related all-grade Aes was 99% for Encorafenib (95% CI: 0.97–1.00) and 97% for Trametinib (95% CI: 0.92–0.99; I(2) = 66%) and Binimetinib (95% CI: 0.94–0.99; I(2) = 0%). In combined therapies, the rate was 98% for both Vemurafenib + Cobimetinib (95% CI: 0.96–0.99; I(2) = 77%) and Encorafenib + Binimetinib (95% CI: 0.96–1.00). Grade 3 or higher adverse events were reported in 69% of cases for Binimetinib (95% CI: 0.50–0.84; I(2) = 71%), 68% for Encorafenib (95% CI: 0.61–0.74), and 72% for Vemurafenib + Cobimetinib (95% CI: 0.65–0.79; I(2) = 84%). The most common grade 1–2 AEs were pyrexia (43%) and fatigue (28%) for Dabrafenib + Trametinib and diarrhea for both Vemurafenib + Cobimetinib (52%) and Encorafenib + Binimetinib (34%). The most common AEs of grade 3 or higher were pyrexia, rash, and hypertension for Dabrafenib + Trametinib (6%), rash and hypertension for Encorafenib + Binimetinib (6%), and increased AST and ALT for Vemurafenib + Cobimetinib (10%). Conclusions: Our study provides comprehensive data on treatment-related adverse events of BRAFi and MEKi combination therapies, showing related toxicity profiles to offer a helpful tool for clinicians in the choice of therapy.