Hand-foot skin reaction associated with vascular endothelial growth factor receptor tyrosine kinase inhibitors: a FAERS-based pharmacovigilance study

Introduction: Hand-foot skin reaction (HFSR) is a prevalent and dose-limiting cutaneous toxicity associated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), often compromising treatment continuity and efficacy. Methods: This pharmacovigilance study analyzed reports from the FDA Adverse Event Reporting System (FAERS) database (Q1 2004-Q2 2025). After standard data cleaning, disproportionality analyses using the ROR, PRR, MGPS, and BCPNN were performed to quantify signals for HFSR associated with 11 VEGFR-TKIs. Patient demographics, time-to-onset, and clinical outcomes were also assessed. Results: A total of 8,668 HFSR reports were analyzed. Eight VEGFR-TKIs generated positive HFSR signals across all four algorithms. Sorafenib and regorafenib showed greater disproportionality. The median time to HFSR onset was 16 days, with most drugs showing an early failure pattern. Subgroup analysis showed that female patients reported stronger signals and had a median onset time (14 days) earlier than male patients (17 days). Hospitalization was the most frequently reported serious outcome. Conclusion: This large-scale analysis confirmed a significant association between VEGFR-TKIs and HFSR, with significant differences in reported signal values between specific drugs. Proactive, individualized monitoring, particularly during the initial weeks of therapy, is crucial for managing this impactful toxicity.