Locally advanced(LAUC) or metastatic urothelial carcinoma (mUC) remains a formidable clinical challenge due to its poor prognosis. Although platinum-based chemotherapy remains the first-line standard of care, its therapeutic efficacy is limited. The advent of immune checkpoint inhibitors (ICIs), such as pembrolizumab, and antibody-drug conjugates (ADCs), such as enfortumab vedotin (EV), has significantly reshaped the treatment paradigm. Given their distinct yet complementary mechanisms of action, the combination of EV and pembrolizumab represents a promising first-line therapeutic strategy. While ongoing clinical trials, including the Phase 3 EV-302 study, are investigating this regimen, real-world evidence regarding its clinical application, safety profile, and effectiveness remains scarce.

We conducted a retrospective, multicenter study analyzing real-world outcomes of LA/mUC patients who received at least one cycle of EV + pembrolizumab. Key endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). Data were collected from electronic medical records and analyzed using Kaplan-Meier survival estimates and Cox proportional hazards models.

A total of 39 patients were included; 25 (64.1%) were males, 14 (35.9%) females. The median age was 65.6 years (IQR: 38-88).The ORR was 56.4%, 13 patients (33.3%) experienced PR, 9 (23%) CR, 9 (23%) PD and 8 (20.1%) experienced SD. Amount patient, 24 (61.5%) had lower tract urothelial carcinoma (LUTC), 15 (38.5%) had upper tract urothelial carcinoma (UTUC). The most common TRAEs were Skin reaction (33.3%), with 12% experiencing grade ≥3 toxicities. Compared to historical chemotherapy data, EV + pembrolizumab demonstrated a favorable efficacy and safety profile in a real-world setting.

Our findings suggest that EV + pembrolizumab is a viable treatment option for LA/mUC, with encouraging efficacy and manageable toxicity in a real-world population. Further prospective validation is warranted to confirm these outcomes and optimize patient selection.