Real-world incidence of G3-G4 adverse events with enfortumab vedotin in patients with advanced urothelial carcinoma (ARON-2EV study)

Abstract Enfortumab vedotin (EV) is an antibody–drug conjugate targeting Nectin-4 and is approved for patients with advanced urothelial carcinoma (UC) who have progressed after platinum-based chemotherapy and immune checkpoint inhibitors. While clinical trials have demonstrated manageable safety profiles, real-world toxicity data remain limited. We conducted a multi-center retrospective study of consecutive patients with locally advanced or metastatic UC treated with EV between January 2022 and April 2025. Demographic, clinical, and treatment-related data were extracted from electronic medical records. Primary endpoints included incidence of G3-G4 AEs, dose reductions, and discontinuations. A total of 770 patients were included; 195 patients (25%) reported G3-G4 AEs. The most common G3-G4 AEs were dermatologic (10%), neuropathy (9%) and diarrhea (7%). Seventy-four patients (10%) discontinued EV due to G3-G4 AEs. Both the median OS (21.3 months vs 16.1 months, p = 0.010) and PFS (8.2 months vs 6.8 months, p = 0.012) were significantly longer in patients who started EV therapy at standard dose versus at reduced dose. In conclusion, this real-world cohort showed that EV demonstrated a toxicity profile broadly consistent with clinical trial data, though rates of dose modification were substantial. Enhanced monitoring and early toxicity management may optimize treatment continuity in advanced UC patients.