Real-world effectiveness and safety of enfortumab vedotin plus pembrolizumab versus gemcitabine-platinum chemotherapy in first-line treatment of advanced urothelial carcinoma: A propensity-matched analysis from the TriNetX global network.

706 Background: Enfortumab vedotin plus pembrolizumab (EV+P) has demonstrated superior OS compared to platinum-based chemotherapy (gemcitabine-cisplatin or gemcitabine-carboplatin, collectively gemcitabine-platinum [GP]) in the EV-302 trial, establishing a new standard for first-line treatment of advanced urothelial carcinoma (aUC). However, real-world data (RWD) directly comparing these regimens remains limited. This study evaluates the RWD and safety of EV+P versus GP using a global electronic health record database. Methods: We conducted a retrospective cohort study using the TriNetX Global Health Research Network, comprising EMR data from 154 healthcare organizations. Patients with advanced or metastatic urothelial carcinoma receiving first-line EV+P or GP were identified. Propensity score matching (1:1) was performed based on age, sex, race, ECOG performance status, comorbidities, and baseline labs, yielding 836 patients per cohort. The primary outcome was all-cause mortality. Secondary outcomes included hospitalization and grade ≥3 adverse events (anemia, thrombocytopenia, neutropenia). Kaplan-Meier analysis and Cox proportional hazards models were used to assess 2-year overall survival (OS). Results: After matching, 836 patients per cohort were analyzed. Median follow-up was 203 days for EV+P and 460 days for GP. EV+P was associated with significantly lower all-cause mortality at 2 years (26.8% vs 47.7%; risk ratio [RR] 0.561, 95% CI 0.492–0.641; p < 0.0001), and higher 2-year survival probability (52.6% vs 44.0%; log-rank p = 0.0339). Hospitalization occurred in 44.5% (EV+P) vs 49.2% (GP; RR 0.905, p = 0.056). Grade ≥3 anemia (20.9% vs 50.7%), thrombocytopenia (2.2% vs 30.0%), and neutropenia (6.1% vs 27.8%) were all significantly less frequent in the EV+P group (p < 0.0001 for all). However, EV+P had higher rates of rash (26% vs 9%), pruritis (18% vs 5%), and peripheral neuropathy (16% vs 7%). In a histologic subtype analysis, EV+P consistently demonstrated longer median survival (626–719 days) and higher survival probabilities (47.6–48.4%) across clear cell, signet ring, squamous, and sarcomatoid urothelial carcinoma compared to GP (median survival 539–568 days; survival probabilities 40.8–44.3%), highlighting superior efficacy of EV+P in these aggressive variants. Conclusions: In this global, real-world cohort with 2-year follow-up, EV+P demonstrated significantly improved survival and reduced hematologic toxicity compared to GP chemotherapy in the first-line treatment of aUC. While EV+P was associated with more skin and neurologic adverse events, these results support the use of EV+P as a preferred frontline option in eligible patients.