Disproportionate reporting of ischemic gastrointestinal injury associated with lenvatinib: A FAERS pharmacovigilance analysis.

Abstract

e23416 Background: Vascular endothelial growth factor (VEGF)–targeted tyrosine kinase inhibitors (TKIs) are widely used across solid tumors. While end-stage gastrointestinal (GI) complications such as perforation and fistula formation have been described, ischemic GI injury (e.g., ischemic colitis and mesenteric ischemia) represents a distinct vascular toxicity phenotype that has not been systematically characterized in post-marketing pharmacovigilance data. We assessed disproportionate reporting of ischemic GI injury associated with VEGF-targeted TKIs in the FDA Adverse Event Reporting System (FAERS). Methods: We analyzed quarterly ASCII FAERS data from October–December 2012 through October–December 2024. Reports were deduplicated at the case level by retaining the most recent FDA receipt date per CASEID. Exposure was defined as primary suspect reports for VEGF-targeted TKIs (lenvatinib, cabozantinib, axitinib, tivozanib; generic and brand names). Ischemic GI injury was identified using MedDRA Preferred Terms including ischemic colitis, mesenteric ischemia, and intestinal, bowel, or colonic ischemia. Disproportionality was assessed using reporting odds ratios (RORs) with 95% confidence intervals, applying Haldane–Anscombe correction for sparse events, within a real-world pharmacovigilance framework for post-marketing safety signal detection. Results: Among 15,473,015 deduplicated FAERS cases, 3,540 reports included ischemic GI injury terms, with 71,838 VEGF-targeted TKI primary suspect reports. At the class level, VEGF-targeted TKIs were not associated with significantly increased reporting of ischemic GI injury (ROR 1.37, 95% CI 0.91–2.08; 22 events). In drug-specific analyses, lenvatinib demonstrated a significant disproportionality signal (10/22,143 reports; ROR 2.08, 95% CI 1.13–3.81). No significant signal was observed for cabozantinib (6/33,859; ROR 0.84, 95% CI 0.39–1.81) or axitinib (6/14,639; ROR 1.94, 95% CI 0.90–4.19). Tivozanib analyses were limited by sparse events (0/1,197; ROR 1.82, 95% CI 0.11–29.19). Conclusions: In FAERS data from 2012–2024, ischemic GI injury did not demonstrate a class-wide disproportionality signal among VEGF-targeted TKIs; however, a significant drug-specific signal was observed with lenvatinib. These findings support heightened clinical vigilance for ischemic GI presentations in patients receiving lenvatinib and highlight the need for confirmation in longitudinal real-world datasets. As with all spontaneous reporting systems, causality and incidence cannot be inferred. As a real-world pharmacovigilance study, these findings identify a severe but underrecognized ischemic gastrointestinal injury reporting signal associated with lenvatinib, informing post-marketing safety surveillance, clinical recognition, and timely treatment interruption in routine practice.