The real-world safety profile of enfortumab vedotin with or without pembrolizumab: insights from a comparative analysis of FAERS.

INTRODUCTION: The combination of enfortumab vedotin and pembrolizumab (EV+P) has revolutionized advanced urothelial carcinoma treatment, yet their combined real-world safety profile remains insufficiently characterized. This study aimed to quantitatively compare the adverse event (AE) landscapes of EV+P and EV monotherapy using the FAERS data. METHODS: A case/non-case study design was conducted on FAERS data from 2020 Q4 to 2025 Q3. Disproportionality signals were evaluated at the System Organ Class (SOC), High-Level Group Term (HLGT), and Preferred Term (PT) levels. Time-to-onset was analyzed using the Kaplan-Meier method, and narrative review was performed to validate pneumonitis signals. RESULTS: We identified 3, 004 and 2, 265 AE reports for EV and EV+P, respectively. EV+P demonstrated significantly higher risks across nine SOCs, most notably in endocrine (OR: 5.88), immune system (OR: 2.03), and respiratory (OR: 1.71) disorders. At the PT level, EV+P was strongly associated with hepatitis (OR: 14.79), immune-mediated enterocolitis (OR: 11.77), adrenal insufficiency (OR: 9.14), and pneumonitis (OR: 2.75). Potential novel signals like hearing disorders (OR: 10.64) and dental/gingival conditions (OR: 9.31) were noted but lacked statistical robustness post-correction. Literature validation confirmed a higher incidence of any-grade pneumonitis with EV+P (10% vs. 3.5%). Furthermore, EV+P suggested a potentially earlier onset for several toxicities, including eye (FDR P = 0.047) and skin disorders (FDR P = 0.011). CONCLUSION: EV + P demonstrates a broader and more intense AE spectrum than EV monotherapy, driven largely by immune-related toxicities and potential synergistic organ injury. These findings emphasize the need for vigilant clinical monitoring and early intervention when employing this combination therapy.