Real-world safety of first-line enfortumab vedotin plus pembrolizumab in advanced urothelial carcinoma: evidence from VigiBase and FAERS.

Abstract

Compared with platinum-based chemotherapy, the combination of enfortumab vedotin and pembrolizumab (EV + Pembro) achieves higher durable response rates and improves survival outcomes in patients with locally advanced or metastatic urothelial carcinoma. As the first regimen pairing an immune checkpoint inhibitor with an antibody-drug conjugate, it offers a novel, effective option. Yet evidence has largely been derived from clinical trials, and robust, comprehensive real-world characterization of adverse drug events (ADEs) remains limited. It is therefore essential to examine recent real-world data to delineate the safety profile of EV + Pembro with greater precision. We conducted disproportionality analyses of ADE reports related to EV + Pembro from the FDA Adverse Event Reporting System (FAERS) and the WHO VigiBase. Signal detection algorithms, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Multi-item Gamma Poisson Shrinker (MGPS), and Bayesian Confidence Propagation Neural Network (BCPNN), were used to identify significant safety signals. Additionally, the time to onset of ADEs was assessed. A total of 892 reports from VigiBase and 1,698 reports from FAERS were analyzed across 25 system organ classes. Several previously unlisted ADEs in the product labeling were identified, such as dehydration, cholestasis, ileus, and tumor lysis syndrome. Subgroup analysis revealed that male patients were more prone to dehydration and renal impairment, while female patients were more likely to experience skin discoloration and alopecia. The median onset time for ADEs was 18 days, with males experiencing ADEs significantly earlier than females. Immune system disorders had the shortest median onset time, while surgical and medical procedures had the longest. This real-world analysis confirms known adverse reactions and identifies new safety signals for EV + Pembro. It also highlights differential risk profiles across subgroups, providing valuable insights for clinical practice. Further research is needed to validate these findings and refine patient management strategies.