Real-world retrospective analysis of outcomes, treatment duration, dose intensity, and safety of enfortumab vedotin with or without pembrolizumab in urothelial carcinoma.

Abstract

e16580 Background: Enfortumab vedotin (EV) in combination with pembrolizumab (P) has been FDA-approved for patients with locally advanced or metastatic urothelial carcinoma (la/mUC), based on the EV-302 trial, which demonstrated superior survival outcomes compared to traditional chemotherapy. This study aims to evaluate real-world treatment outcomes, duration, dose intensity (DI), and safety profiles of EV with or without P. Methods: We conducted a retrospective, single-center study involving patients with urothelial carcinoma who received EV ± P at the Medical University of South Carolina from January 1, 2019, to August 31, 2025. Treatment duration was defined as the interval from the first dose of EV to 14 days post-last dose or December 31, 2025, whichever occurred first. DI (mg/kg/week) was calculated as the total dose of EV divided by treatment duration. Cox proportional hazards models were used to examine the associations between DI, progression-free survival (PFS), and overall survival (OS). Results: Of 78 patients included, 58% (n = 45) received EV+P concurrently. The concurrent (EV+P) group demonstrated a median OS of 22.4 months (95% CI, 15-NR) and PFS of 9.1 months (95% CI, 5.0-14.7), compared to 12.2 months (95% CI, 9.1-17.0) and 4.4 months (95% CI, 2.8-8.3) in the EV-monotherapy group. Notably, 50% of the total cohort required dose reductions. Discontinuation rates were high in both the concurrent (91%) and monotherapy (97%) groups, but primary drivers differed: in the EV+P group, treatment-related toxicities were the leading cause of discontinuation (59% vs. 27% for disease progression), predominanly neuropathy (24%), whereas disease progression was the primary cause in the monotherapy group (53% vs. 25% for toxicities). Median treatment duration was 4.2 months for both groups. Median DI was lower in the concurrent group (0.63 mg/kg/week) than in the monotherapy group (0.70 mg/kg/week), both of which fell short of the trial-standard DI of 0.83 and 0.94 mg/kg/week. For patients receiving 3 or more doses of EV who discontinued due to toxicities, lower DI was significantly associated with better PFS (p < 0.05) after adjusting for age, gender, performance status, and comorbidities, though it did not significantly impact OS. Conclusions: Real-world EV+P outcomes in this population are more modest than trial results, characterized by prevalent toxicity-related treatment discontinuation. The association between lower DI and longer PFS may be explained by the fact that patients with extended treatment duration naturally require more dose modifications to manage side effects. Because OS was not significantly affected by DI in this study, practitioners may consider judicious dose adjustments to help maintain a balance between clinical efficacy and treatment-limiting toxicity.