Comparative Safety Profiling of Sorafenib, Regorafenib, and Lenvatinib in Hepatobiliary-Pancreatic Tumors: Signal Mining and Risk Factor Analysis Using the US FDA Adverse Event Reporting System

Objective: To systematically evaluate the potential adverse event (ADE) risk profiles of sorafenib, regorafenib, and lenvatinib in the treatment of hepatobiliary-pancreatic tumors (HBPT) . Methods: Data from the U.S. FDA Adverse Event Reporting System (FAERS) from Q1 2004 to Q4 2024 were extracted. Proportional imbalance analysis (using Reporting Odds Ratio [ROR] and Proportional Reporting Ratio [PRR]) was employed for signal detection, combined with K-means clustering and logistic regression models to analyze risk factors. Results: A total of 10,793 ADE reports were included (sorafenib: 5,195; lenvatinib: 4,878; regorafenib: 720). At the System Organ Class level, the most common ADEs for sorafenib were gastrointestinal disorders (4,088 cases) and skin disorders (2,924 cases). Regorafenib showed tumor progression (316 cases) as its primary signal, while lenvatinib was characterized by metabolism-related abnormalities such as decreased appetite (659 cases). Logistic regression revealed: females had a 2.3-fold higher adjusted risk of alopecia with sorafenib than males (95% CI 1.8–2.9), and for lenvatinib users, every 10 kg increase in body weight elevated the risk of confusion by 18% (OR=1.18, p=0.032). Temporal analysis indicated that 82.6% of ADEs occurred within 30 days of treatment, but sorafenib-related metastatic tumor reports were delayed to a median of 200 days (IQR 150–258). Conclusion: This study is the first to systematically reveal distinct ADE profiles of the three targeted therapies for HBPT. Sorafenib and regorafenib may promote tumor progression through unknown mechanisms, while lenvatinib’s metabolism-related toxicities warrant clinical vigilance. These findings provide evidence-based insights for personalized treatment strategies and early toxicity monitoring.