Neurologic adverse events associated with BRAF and MEK inhibitor therapy in patients with malignant melanoma: a disproportionality analysis using the Food and Drug Administration Adverse Event Reporting System.

Abstract

BRAF and MEK inhibitor (BRAFi + MEKi) therapy has improved the treatment of solid tumors with BRAF mutation. However, their neurologic adverse events (nAEs) have been largely unexplored. This study aimed to provide clinicians with more updated knowledge on nAEs associated with BRAFi + MEKi therapy in patients with malignant melanoma compared with nonmelanoma cancers. The United States Food and Drug Administration Adverse Event Reporting System was queried from 2011 to 2022 to capture nAEs reported for the BRAFi + MEKi therapies, vemurafenib plus cobimetinib (V + C), dabrafenib plus trametinib (D + T), and encorafenib plus binimetinib (E + B). A disproportionality analysis was performed to calculate their reporting odds ratios (RORs) and 95% confidence intervals (CIs) using a control group of antineoplastic medications. There were 2881 BRAFi + MEKi therapy-associated nAE cases, the majority of which listed malignant melanoma as the reason for use (87.5, 66.7, and 62.0% for V + C, D + T, and E + B, respectively). Several novel associations were identified; including epidural lipomatosis (ROR: 320.07, 95% CI: 123.76-827.77 for V + C), peripheral nerve lesion (ROR: 185.64, 95% CI: 73.95-466.03 for V + C), Guillain-Barre syndrome (RORs: 8.80, 2.94, and 11.79, 95% CIs: 3.65-21.22, 1.40-6.19, and 5.87-23.66 for V + C, D + T, and E + B), demyelinating polyneuropathy (RORs: 24.72 and 78.98, 95% CI: 8.16-74.86 and 24.84-251.13 for D + T and E + B), and multiple sclerosis (ROR: 5.90, 95% CI: 3.06-11.40 for D + T) in melanoma patients. nAEs in the setting of BRAFi + MEKi therapy should be a safety consideration when utilizing these medications.