Dose modifications, toxicity, and survival with enfortumab vedotin plus pembrolizumab (EVP) in advanced urothelial carcinoma (aUC): Real-world experience in Alberta, Canada.

Abstract

188 Background: EVP has demonstrated a survival benefit in advanced urothelial carcinoma (aUC) clinical trials. However real-world toxicity patterns, timing of onset, and prognostic significance of treatment-related adverse effects (AEs) remain incompletely characterized. We evaluated outcomes, toxicity, and dose modifications among patients with aUC treated with first-line EVP in routine clinical practice. Methods: We conducted a retrospective, multicenter analysis of aUC patients treated with first-line EVP in Alberta, Canada (Sep 2024–Jan 2026). AEs were graded using CTCAE v5.0. Time to AE onset, dose modifications, and treatment discontinuation were assessed. Progression-free survival (PFS) and overall survival (OS) were analyzed. Results: Sixty patients were included (median age 69 years, 82% male). Primary tumor site was bladder in 68% and upper genitourinary tract in 23%. Histology was pure urothelial in 80% and mixed in 20%. Disease was metastatic in 80% (55% visceral, 25% nodal-only); 20% had locally advanced/unresectable disease. Median follow-up was 10.3 months. Initial enfortumab vedotin (EV) dose was 1.25 mg/kg in 76% of patients and 1 mg/kg in 23%; the median number of EVP cycles was 8. Six-month PFS was significantly higher with an initial EV dose of 1.25 mg/kg compared with 1 mg/kg (78% vs 51%; HR 0.35, 95% CI 0.15–0.83; p = 0.017). The most common AEs of any grade were rash (63%), fatigue (57%), and neuropathy (47%). Grade III–IV AEs included rash (15%), fatigue (8%), and mucositis (3%) with median onset at 16, 95, and 66 days. Thromboembolic events occurred in 10%. No patients died due to treatment toxicity. Dose reductions occurred in 62%, dose delays in 45%, and treatment discontinuation in 38% (EV alone 25%, pembrolizumab alone 8%, both 5%). Median cycles before treatment discontinuation were 5 for rash and fatigue, and 6 for neuropathy. One-year OS was significantly higher among patients who developed a rash compared with those who did not (72% vs 46%; p = 0.018). No significant OS differences were observed with development of neuropathy (69% vs 56%; p = 0.18) or fatigue (61% vs 64%; p = 0.62). Conclusions: In this real-world cohort, EVP demonstrated efficacy and safety consistent with clinical trial data. Toxicity-related dose modifications were common but generally manageable. Higher initial EV dosing was associated with improved PFS, and treatment-related rash correlated with superior OS, suggesting a potential role for rash as an early biomarker of treatment response. Treatment related AEs and outcomes. Toxicity n (%) Median days to Onset (IQR) Dose Reductionsn (%) Dose discontinuationn (%) 1yr OS (log rank p-value) Skin Rash 38 (63) 18 (10-75) 22 (36) 6 (12) 72% vs 46% (p=.018) Neuropathy 28 (46) 96 (69-132) 12 (20) 7 (11.6) 69% vs 56%(p=0.18) Fatigue 34 (56) 29 (12-89) 14 (23) 7 (11.6) 61% vs 64%(p=0.62)