Gastrointestinal adverse events associated with Lenvatinib versus Lenvatinib plus Pembrolizumab: A pharmacovigilance study in FDA adverse event reporting system

This study aimed to empirically analyze gastrointestinal adverse events associated with Lenvatinib monotherapy and its combination with Pembrolizumab using FDA FAERS data (January 2015-December 2023), focusing on risk profiles, temporal patterns, and influencing factors. Proportional disproportionality analysis (ROR, PRR, BCPNN, EBGM) evaluated drug-AE associations. Kaplan-Meier curves characterized temporal distributions, while Wilcoxon rank-sum test compared median time-to-onset between regimens. Univariate logistic regression identified independent risk factors. A total of 291 severe gastrointestinal AEs reports were included. The gastrointestinal system had the most positive AE signals in both treatment groups. Perforation events showed strong positive signals in both regimens, while haemorrhage and fistula events were unique positive signals in the lenvatinib monotherapy group. In contrast, colitis and pancreatitis positive signals were more common in the combination therapy group. Most gastrointestinal AEs in both groups occurred within the first month of treatment. The monotherapy group had a significantly shorter median onset time than the combination therapy group (27 days vs. 38 days, P = 0.003). Logistic regression indicated that female sex (OR = 0.195, P = 0.022) and low-dose medication (OR = 0.240, P = 0.049) were independent protective factors for gastrointestinal AEs in the monotherapy group. This first comprehensive comparison reveals distinct gastrointestinal toxicity profiles: monotherapy predisposes to acute bleeding/fistulas, while combination therapy increases delayed tumor-related complications. Intensive monitoring during the first treatment month and gender/dosage-adjusted prevention strategies are recommended. These findings provide evidence-based insights for optimizing safety management of targeted-immunotherapy combinations.