Organ perforation and fistula formation as adverse events in patients receiving tyrosine kinase inhibitors: A post-market analysis.

528 Background: Vascular Endothelial Growth Factor (VEGF)-targeted tyrosine kinase inhibitors (TKIs), such as lenvatinib and cabozantinib, offer significant survival benefits in solid tumors, including renal cell carcinoma (RCC), thyroid cancer, hepatocellular carcinoma, and endometrial cancer. However, rare but serious adverse events (AEs), such as organ perforation and fistula formation, have been reported. This study evaluates the incidence and risk of these events in patients treated with VEGF-TKIs using post-marketing data from the FDA Adverse Event Reporting System (FAERS). Methods: We queried the FAERS database for reports of organ perforation and fistula formation associated with cabozantinib, lenvatinib, axitinib, and tivozanib from January 1, 2012, to June 30, 2024. A disproportionality analysis was performed using reporting odds ratios (ROR) to assess the association between VEGF-TKIs and these adverse events. Cases were categorized by organ site, with a focus on gastrointestinal (GI) tract-related events. Results: We identified 65,194 reports, including 917 cases of organ perforation and 482 cases of fistula formation. Among the perforation cases, 245 (27%) were intestinal, followed by gastric (5%). Fistula cases included 11% anal, 9% female genital tract and 6% were GI-related. Regarding TKI distribution, 19% of perforation cases were linked to cabozantinib, 35% to lenvatinib, and 46% to other TKIs (axitinib, tivozanib, or multiple TKIs). For fistula cases, 18% were associated with cabozantinib, 41% with lenvatinib, and 41% with other TKIs. Among these reports, 27% of perforations and 20% of fistulas occurred in patients with RCC. Disproportionality analysis revealed a significantly higher risk of both organ perforation (ROR: 3.41, 95% CI: 2.36–4.93) and fistula formation (ROR: 17.06, 95% CI: 14.46–20.12) in VEGF-TKI treated patients. Conclusions: Patients treated with VEGF-targeted TKIs, particularly lenvatinib, have a significantly increased risk of organ perforation and fistula formation. Lenvatinib was associated with a higher incidence of these adverse events compared to cabozantinib. These findings highlight the need for increased clinical awareness and monitoring, particularly in patients with RCC. Further research is necessary to better understand the mechanisms underlying these complications and to develop preventive strategies.