Cutaneous Adverse Drug Reactions Associated With BRAF and MEK Inhibitors: A Real-World Analysis of WHO...

BRAF inhibitors and MEK inhibitors (MEKi) have reshaped the treatment of BRAF^V600-mutant malignancies; however, cutaneous adverse drug reactions (ADRs) remain a frequent and clinically impactful toxicity. Although clinical trials provide insight into their safety profiles, real-world data on dermatologic ADRs are limited. We conducted a retrospective pharmacovigilance analysis of the WHO VigiAccess database, examining individual case safety reports (ICSRs) for seven BRAF and MEKi up to May 2025. Disproportionality analyses (reporting odds ratio (ROR), proportional reporting ratio (PRR), with 95% confidence intervals (CIs)) were performed for high-frequency dermatologic ADRs. Shannon entropy was used to assess the diversity of toxicity profiles across agents. Among 72,720 ICSRs, skin-related ADRs accounted for 39.78% of reports with vemurafenib, 16.49% with dabrafenib, and 14.62% with encorafenib. Among MEKi, the proportion of skin-related ADRs was highest for selumetinib (40.03%) and cobimetinib (34.31%). Rash was the predominant ADR across agents, but selumetinib demonstrated a significant disproportionality for dermatitis acneiform (ROR = 6.46, 95% CI [5.10, 8.18]). Photosensitivity reactions were most frequently reported with vemurafenib (11.31%) and cobimetinib (12.02%). Shannon entropy analysis identified two groups with differing ADR profile diversity: a higher-diversity group (cobimetinib, H = 3.66; dabrafenib, H = 3.60) and a lower-diversity group (trametinib, H = 3.51; binimetinib, H = 3.47); all cross-group comparisons were statistically significant after Holm-Bonferroni correction (p < 0.05). Chi-squared tests confirmed significant differences in skin ADR frequencies among agents (BRAF inhibitors: χ²(2) = 1393.21, p < 0.001, Cramér's V = 0.255; MEKi: χ²(3) = 1129.77, p < 0.001, Cramér's V = 0.175), with effect sizes indicating clinical relevance. Cutaneous ADRs are a defining toxicity of MAPK pathway inhibitors, with substantial interagent variability in frequency and phenotype. Real-world pharmacovigilance data underscore the necessity for agent-specific dermatologic monitoring strategies. Clinical pharmacists play a pivotal role in early ADR detection and management, enhancing adherence and optimizing therapeutic outcomes.