Trends of adverse event reports associated with BRAF and MEK inhibitors and combinations: a retrospective disproportionality analysis using the FDA adverse event reporting system database from 2012 to 2021

Invasive cases of melanoma have increased by 44% annually in the past decade. B-Raf serine-threonine kinase (BRAF)/Mitogen-activated protein kinase kinase (MEK) inhibitors have become the standard of care for stage III/IV BRAF mutant melanoma. Due to limited adverse event (AE) data based on clinical trials, we aimed to describe and compare the AE and outcomes associated with melanoma therapies. A retrospective disproportionality analysis was conducted to assess and compare the trends of AEs associated with BRAF/MEK inhibitors and combinations. The primary data were extracted from the Food and Drug Administration (FDA) Adverse Event Reporting System database from 2012 to 2021. Study drugs included BRAF/MEK inhibitors (dabrafenib, trametinib, vemurafenib, cobimetinib, encorafenib, and binimetinib). A reporting odds ratio (ROR) was calculated for the most common AEs and outcomes reported. We found 195 640 unique AE reports associated with BRAF and MEK inhibitor usage, representing 52 772 patients. The leading AEs associated with BRAFi and MEKi use were as follows: pyrexia, fatigue, nausea, diarrhea, rash, vomiting, and arthralgia. Encorafenib and binimetinib had significant odds for nausea [ROR, 1.91 (1.73-2.11) and ROR, 1.91 (1.73-2.11), respectively]. The incidence of fatigue was highest in the encorafenib [ROR, 1.71 (1.54-1.90)], binimetinib [ROR, 1.74 (1.57-1.94)], and vemurafenib [ROR, 1.27 (1.14-1.27)] groups. Cobimetinib had significantly increased odds for developing a disability [ROR, 4.95 (4.28-5.74)], having a hospitalization [ROR, 2.08 (1.99-2.17)], and experiencing a life-threatening event [ROR, 1.78 (1.55-2.03)]. AE reports associated with melanoma therapies are sizable and significant. Healthcare professionals should be aware of the AE profiles attributable to the melanoma treatment and management.