Enfortumab vedotin cutaneous toxicity and peripheral neuropathy are associated with improved outcomes in urothelial carcinomaSkin Reactions and Nerve Issues Linked to Better Survival

Whether the reported associations between enfortumab vedotin (EV)-related toxicities and efficacy remain robust after appropriate adjustment for immortal time bias (ITB) remains unclear. We conducted a systematic review and meta-analysis to evaluate these associations while accounting for time-related bias. PubMed, Web of Science, CINAHL, and the Cochrane Library were searched from inception through November 15, 2025. Studies assessing EV-related adverse events (AEs) and clinical outcomes in advanced urothelial carcinoma (UC) were included. Studies were excluded if they included malignancies other than UC, evaluated EV in combination with other systemic therapies, did not report outcomes of interest, or lacked sufficient data for extraction. Pooled hazard ratios (HRs) were computed for overall survival (OS) and progression-free survival (PFS), and pooled odds ratios were calculated for objective response rate (ORR) and disease control rate (DCR). Risk of bias was assessed using the Newcastle-Ottawa Scale. Among 13 eligible retrospective studies, 12 were included in the meta-analysis; 10 evaluated EV-related cutaneous toxicity (5 ITB-adjusted), whereas 5 evaluated peripheral neuropathy (4 ITB-adjusted). Cutaneous toxicity was associated with improved OS; this association was attenuated in ITB-adjusted analyses, with a lower HR in unadjusted studies. Cutaneous toxicity was associated with improved PFS, ORR, and DCR, but demonstrated limited robustness for PFS. For peripheral neuropathy, improved OS was observed across 4 studies (3 ITB-adjusted). Associations with ORR and DCR were based on only 2 studies. PFS was not significantly associated; sensitivity analyses suggested limited robustness. Residual heterogeneity and variability in toxicity definitions and analytical approaches remained across studies. EV-related AEs, particularly cutaneous toxicity, were associated with favorable clinical outcomes. As evidence was limited by retrospective study designs, a small number of studies, and residual heterogeneity, these findings should be considered hypothesis-generating and require confirmation in prospective studies.