Neutrophil-to-Lymphocyte Ratio and Performance Status Are Associated With Increased Risk of Skin Toxicity in Patients Receiving Enfortumab Vedotin With or Without Pembrolizumab for Metastatic Urothelial Carcinoma

Introduction Enfortumab vedotin (EV) is widely used for metastatic urothelial carcinoma, either as monotherapy or in combination with pembrolizumab (EV + P). However, these regimens differ in patient characteristics, treatment lines, and intensity. Direct comparisons of adverse event profiles, particularly early toxicities and their risk factors, remain limited. Methods We conducted a multicenter retrospective cohort study including patients treated with EV monotherapy (n = 165) or EV + P (n = 76) at Osaka University Hospital and affiliated institutions between November 2021 and August 2025. A total of 221 patients with complete clinical and laboratory data were analyzed. The incidence and time-to-onset of adverse events were compared between regimens. Logistic regression and time-to-event analyses were performed to identify factors associated with skin toxicity. Results The incidence and time-to-onset of adverse events were comparable between EV and EV + P. Skin toxicity was the most frequent and early-onset adverse event in both groups. Multivariable analysis identified baseline performance status and neutrophil-to-lymphocyte ratio (NLR) as independent predictors of skin toxicity, whereas treatment regimen was not associated with risk. Patients with high NLR (≥6) and poor performance status showed a lower incidence of skin toxicity, whereas those with low NLR (<6) had a significantly higher risk. Conclusions EV and EV + P demonstrated similar safety profiles despite differences in treatment context. Host-related factors, particularly baseline NLR and performance status, rather than treatment regimen, primarily determine the risk of skin toxicity. These findings support risk-adapted monitoring and early intervention strategies for EV-based therapy.