Real-world safety and effectiveness of enfortumab vedotin plus pembrolizumab in locally advanced or metastatic urothelial carcinoma: A multicenter Japanese cohort study

Background Enfortumab vedotin plus pembrolizumab (EVP) has emerged as a standard first-line treatment for locally advanced or metastatic urothelial carcinoma (la/mUC). However, large-scale real-world data in Japanese patients remain limited. Methods We retrospectively analyzed consecutive patients with la/mUC who received first-line EVP across multiple Japanese centers. Oncologic outcomes including tumor response, progression-free survival (PFS), cancer-specific survival (CSS), overall survival (OS), and adverse events (AEs) were assessed. Survival was estimated using the Kaplan-Meier method, and exploratory analyses were performed to identify factors associated with OS, PFS and objective response rate (ORR). Results A total of 212 patients were included. The median age was 75 years, and 23 patients (10.8%) had ECOG performance status (PS) ≥2. Among 201 evaluable patients, ORR was 63% including 12.5% of complete response. Subgroup analysis of ORRs showed broadly consistent efficacy across diverse patient or cancer characteristics. The median PFS, CSS, and OS was 12.0, 15.0, and 12.9 months, respectively. Liver metastasis was associated with poor PFS (HR 2.35, P = 0.012), ECOG PS ≥ 2 was associated with poor OS (HR 2.84, P = 0.002), and variant histology was associated with poorer PFS (HR 3.19, P < 0.001) and OS (HR 2.6, P = 0.001). Any-grade AEs occurred in 87% of patients, and severe AEs occurred in 34%. Skin-related AEs were the most frequent toxicity, occurring in 59% of patients, with grade ≥3 skin-related AEs in 11%. Median time to onset of skin-related AEs was 15.5 days. Conclusions In this multicenter Japanese real-world cohort, first-line EVP demonstrated favorable antitumor activity with manageable but frequent toxicities, particularly early skin AEs. These findings support the effectiveness of EVP in routine practice while underscoring the importance of proactive AE management and careful risk stratification, including histologic subtype.