Abstract
Aim: The selective BRAF and MEK inhibitors (BRAFi+MEKi) have substantially improved the survival of melanoma patients with BRAF V600 mutations. However, BRAFi+MEKi can also cause severe or fatal outcomes. We aimed to identify and compare serious adverse events (sAEs) that are significantly associated with BRAFi+MEKi. Methods: In this pharmacovigilance study, we reviewed FDA Adverse Event Reporting System (FAERS) data in order to detect sAE reporting in patients treated with the combination therapies vemurafenib+cobimetinib (V+C), dabrafenib+trametinib (D+T) and encorafenib+binimetinib (E+B). We evaluated the disproportionate reporting of BRAFi+MEKi-associated sAEs. Significant associations were further analyzed to identify combination-specific safety signals among BRAFi+MEKi. Results: From January 2018 through June 2019, we identified 11,721 sAE reports in patients receiving BRAFi+MEKi. Comparison of BRAFi+MEKi combinations demonstrates that skin toxicities, including Stevens–Johnson syndrome, were disproportionally reported using V+C, with an age-adjusted reporting odds ratio (adj. ROR) of 3.4 (95%CI, 2.9–4.0), whereas fever was most significantly associated with D+T treatment with an adj. ROR of 1.9 (95%CI, 1.5–2.4). Significant associations using E+B treatment include peripheral neuropathies (adj. ROR 2.7; 95%CI, 1.2–6.1) and renal disorders (adj. ROR 4.1; 95%CI, 1.3–12.5). Notably, we found an increase in the proportion of Guillain–Barré syndrome reports (adj. ROR 8.5; 95%CI, 2.1–35.0) in patients administered E+B. Conclusion: BRAFi+MEKi combinations share a similar safety profile attributed to class effects, yet concomitantly, these combinations display distinctive effects that can dramatically impact patients’ health. Owing to the limitations of pharmacovigilance studies, some findings warrant further validation. However, the possibility of an increased risk for these events should be considered in patient care.
Highlights
Combination therapy with BRAF plus MEK inhibitors (BRAFi+MEKi) has transformed the treatment landscape and improved the clinical outcomes of patients with melanoma harboring BRAFv600 mutations [1,2,3,4,5,6,7]
In order to compare reactions between different BRAFi+MEKi combinations that are differentially elevated compared to other drugs, we first performed a disproportionality analysis compared to the background
The most common serious adverse events (sAEs) reports in patients exposed to V+C were epidermal and dermal conditions with 311 (13.3%) cases (IC = 2.1; false discovery rate (FDR) < 10−130 ), followed by general systems disorders not elsewhere classified (NEC) with 249 (10.6%) cases (IC = 0.42; FDR < 10−6 ) (Supplementary Table S1)
Summary
Combination therapy with BRAF plus MEK inhibitors (BRAFi+MEKi) has transformed the treatment landscape and improved the clinical outcomes of patients with melanoma harboring BRAFv600 mutations [1,2,3,4,5,6,7]. Treatment with BRAFi+MEKi produces response rates of 68% for vemurafenib+. The safety profiles of BRAFi+MEKi monotherapy and combination therapies were evaluated during the confirmatory trials [1,2,3,4,5,6,10,11,12,13,14,15,16,17,18]. The addition of MEKi to BRAFi was associated with higher risk for developing various adverse events (AE); the co-administration of MEKi may mitigate some of the toxicities of BRAFi induced by ‘paradoxical activation’ of the mitogen-activated protein kinase (MAPK)
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