Toxicity, Dose Intensity, and Clinical Outcomes with First-Line Enfortumab Vedotin Plus Pembrolizumab in Advanced Urothelial Carcinoma: A Multicenter Real-World Study

Background: Enfortumab vedotin plus pembrolizumab (EVP) is the standard first-line treatment for locally advanced or metastatic urothelial carcinoma (la/mUC); however, real-world toxicity patterns, timing of onset, and prognostic significance of treatment-related adverse events (AEs) remain incompletely characterized. Methods: We conducted a retrospective, multicenter analysis of 60 la/mUC patients treated with first-line EVP in Alberta, Canada (September 2024–January 2026). Treatment related toxicities, time to AE onset, dose modifications, and treatment discontinuation were assessed. Progression-free survival (PFS) and overall survival (OS) were analyzed. Results: The median age was 69 years, 82% of patients were male, and 80% had metastatic disease at treatment initiation. Histology was pure urothelial in 82% and mixed in 18%. Median follow-up was 10.3 months, and the median number of EV and pembrolizumab cycles was seven and eight, respectively. Rash (63%), fatigue (57%), and peripheral neuropathy (47%) were the most common adverse events, with median onset at 17, 29, and 90 days, respectively. Dose reductions occurred in 62%, dose delays in 43%, and treatment discontinuation in 38%. An initial enfortumab vedotin dose of 1.25 mg/kg was associated with improved PFS (HR 0.30, 95% CI 0.13–0.68; p = 0.004) and OS (HR 0.32, 95% CI 0.10–0.97; p = 0.044) compared with 1.0 mg/kg. Neuropathy was associated with improved PFS (HR 0.32, 95% CI 0.14–0.73; p = 0.007) and OS (HR 0.24, 95% CI 0.07–0.87; p = 0.029), while rash was associated with improved OS (HR 0.31, 95% CI 0.11–0.91; p = 0.032). Conclusions: EVP was associated with frequent treatment-related adverse events requiring dose modifications, and the development of rash and peripheral neuropathy was associated with favorable survival outcomes.