Initial Enfortumab Vedotin Dose Reduction and Outcomes in Pretreated Advanced Urothelial Carcinoma

Importance Initial enfortumab vedotin (EV) dose selection is increasingly relevant in advanced urothelial carcinoma (UC). Reduced starting doses may be selected for some patients, but their associations with clinical outcomes and tolerability remain uncertain. Objective To evaluate the association of physician-selected initial EV dose reduction with clinical outcomes among patients with advanced UC. Design, Setting, and Participants This retrospective multicenter cohort study of patients with advanced UC who initiated EV monotherapy after platinum-based chemotherapy and immune checkpoint inhibition was conducted at 18 institutions in Korea from January 1, 2023, to May 31, 2025, with follow-up through May 31, 2026. Data were analyzed in June 2026. Exposures Initial EV dose reduction at first administration, before treatment-related toxicity. The primary comparison was reduced-dose (≥10% reduction) vs full-dose (<10% reduction) EV monotherapy; post hoc analyses used less than 10%, 10% to 20%, and greater than 20% categories. Main Outcomes and Measures Progression-free survival (PFS) and overall survival (OS) were the primary outcomes. Secondary outcomes included objective response and treatment-emergent peripheral neuropathy (PN). Results Among 368 patients (median [IQR] age, 68.0 [62.0-74.0] years; 267 male [72.6%] and 101 female [27.4%]), median (IQR) follow-up was 15.4 (8.4-20.0) months. Median PFS was 5.7 months in the reduced-dose group and 6.3 months in the full-dose group (adjusted hazard ratio [HR], 1.24; 95% CI, 0.95-1.61); median OS was 10.1 and 10.5 months, respectively (adjusted HR, 1.07; 95% CI, 0.81-1.43). Objective response occurred in 65 of 146 response-evaluable patients (44.5%) in the reduced-dose group and 95 of 179 (53.1%) in the full-dose group. Grade 3 or higher PN occurred in 6 of 170 reduced-dose patients (3.5%) and 20 of 198 full-dose patients (10.1%) (adjusted odds ratio, 0.26; 95% CI, 0.09-0.73). In post hoc analyses, reductions exceeding 20% were associated with shorter PFS compared with the full-dose group (adjusted HR, 1.40; 95% CI, 1.01-1.95), although the overall 3-group comparison was not statistically significant. Conclusions and Relevance In this multicenter cohort study, physician-selected initial EV dose reduction was not significantly associated with survival or response outcomes. These findings do not establish equivalence or warrant routine initial dose reduction. The lower incidence of severe PN and the exploratory PFS signal with reductions exceeding 20% are hypothesis-generating and require prospective validation.