Real-world outcomes of first-line enfortumab vedotin plus pembrolizumab in metastatic urothelial carcinoma.

e16595 Background: Metastatic urothelial carcinoma (mUC) is associated with poor prognosis. The approval of enfortumab vedotin plus pembrolizumab (EV+P) has established a new first-line standard of care. We report real-world outcomes of first-line EV+P, including efficacy, tolerability, and the impact of eligibility criteria. Methods: This retrospective cohort study included patients with advanced urothelial carcinoma treated with first-line EV+P at Alexandra Hospital since January 2024. Demographic, clinical, treatment, and safety data were collected from institutional records. Survival outcomes were estimated using Kaplan–Meier methods. Statistical analyses were performed with SPSS. Results: Sixty-two patients received first-line EV+P. Median age was 69.5 years (IQR 61.8–75.2); 12.7% had ECOG performance status (PS) ≥2, 38.1% had received prior (neo)adjuvant platinum-based chemotherapy, and 35.5% had de novo metastatic disease. Median follow-up was 13 months. At data cut-off, 36 patients (58.1%) had discontinued treatment, primarily due to disease progression. Disease control was achieved in 45 patients (72.6%), including complete response in 11 (17.7%), partial response in 22 (35.5%), and stable disease in 12 (19.4%). Median progression-free survival (mPFS) was 9.6 months (95% CI 7.1–12.2), and median overall survival (mOS) was 16.8 months (95% CI 12.9–20.6). Twenty-seven patients (43.5%) progressed on EV+P; 10 subsequently received platinum-based chemotherapy, achieving an mPFS of 6.1 months (95% CI 2.9–9.3). Eight patients did not meet EVITA eligibility criteria, mainly due to ECOG PS ≥2. These patients experienced rapid disease progression (mPFS 1.5 months, 95% CI 0.8–2.2), received no subsequent therapy, and had poor survival (mOS 3.9 months). Among EVITA-eligible patients (n = 54), mPFS was 13.2 months (95% CI 5.9–20.5), and mOS was not reached. Treatment-related adverse events occurred in 25 patients (40.3%), with grade ≥3 toxicity observed in 11 patients (17.7%). Pembrolizumab was permanently discontinued in 10 patients (16.0%) and EV in 13 patients (20.9%) due to toxicity. Treatment discontinuation for toxicity was associated with improved PFS and OS (p < 0.01) and remained significant on multivariable analysis adjusting for age, de novo metastatic disease, and EVITA eligibility (HR 0.32, 95% CI 0.12–0.89). Conclusions: Real-world first-line EV+P demonstrates meaningful clinical activity and manageable toxicity in mUC, with outcomes comparable to EV-302. Benefit appears independent of prior platinum exposure. Patients not meeting EVITA eligibility derive minimal benefit, highlighting the importance of appropriate patient selection.