Incidence and Spectrum of Adverse Events With Enfortumab Vedotin Therapy in Advanced or Metastatic Urothelial Carcinoma: Evidence From a Systematic Review and Meta-Analysis.

Abstract

Background: Systemic treatment options for locally advanced or metastatic urothelial carcinoma (La/mUC), especially for patients resistant to chemotherapy and ineligible for immunotherapy, are a current research focus. Enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, has recently been introduced, necessitating attention to its potential adverse reactions for patient safety.

Methods: Databases were searched for publications up to 12 June 2025. Clinical trials and retrospective studies investigating EV therapy were included in the analysis. Adverse reactions and complications were primary outcomes, analyzed using Stata 14.0.

Results: 22 studies (including 3 randomized controlled trials (RCTs)) with 1715 patients were included. The most common adverse effect was fatigue (38.41%, 95% confidence interval [CI]: 31.10%-45.99%, I² = 85.2010, p < 0.001). Other common effects included rash, alopecia, peripheral sensory neuropathy, pruritus, dysgeusia, decreased appetite, and decreased weight, and the pooled incidence was 37.20% (95% CI: 30.45%-44.21%, I² = 86.2369, p < 0.001), 37.14% (95% CI: 30.15%-44.40%, I² = 79.0839, p < 0.001), 33.68% (95% CI: 29.44%-38.06%, I² = 59.0190, p = 0.0011), 30.24% (95% CI: 21.26%-40.01%, I² = 91.4944, p < 0.001), 27.50% (95% CI: 20.69%-34.87%, I² = 83.9947, p < 0.001), 27.17% (95% CI: 18.46%-36.81%, I² = 90.4200, p < 0.001) and 26.55% (95% CI: 20.16%-33.45%, I² = 0.0000, p = 0.8935), respectively. The average pooled incidence of grade ≥ 3 adverse events was below 7.0%, with severe complications like rash 6.99% (95% CI: 4.97%-9.28%, I² = 45.9297, p = 0.0267), anemia 5.53% (95% CI: 3.03%-8.60%, I² = 56.9147, p = 0.0132), and neutropenia 4.95% (95% CI: 3.35%-6.80%, I² = 6.7786, p = 0.3788).

Conclusions: EV offers a new second-line treatment for La/mUC after chemotherapy and immunotherapy failures. It shows a generally manageable safety profile. However, severe adverse events such as skin complications, peripheral neuropathy, hyperglycemia, fatigue, and decreased appetite require attention. Given the low quality of some included studies, further evidence from larger-scale studies is needed to confirm its long-term tolerability. PROSPERO registration number: The systematic analysis was conducted according to the guidelines of the PRISMA statement and registered on PROSPERO (CRD42022273772). (https://www.crd.york.ac.uk/PROSPERO/view/CRD42022273772).