Real-world use of enfortumab vedotin in metastatic urothelial carcinoma: efficacy, safety, and risk stratification

Background: Enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, has demonstrated efficacy in advanced urothelial carcinoma (UC) following platinum-based chemotherapy and immune checkpoint inhibitor (ICI) therapy. However, real-world evidence on its effectiveness and safety remains limited. Methods: We conducted a multicenter retrospective study across Italian oncology centers to evaluate EV in patients with metastatic UC (mUC) who had progressed after prior platinum-based chemotherapy and ICI. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. We also assessed prognostic factors, including a composite index (HERO score) based on baseline hemoglobin and neutrophil-to-lymphocyte ratio (NLR). Results: Fifty-three patients were included (median age 72 years; 41.5% ⩾75 years). The ORR was 34.0% (all partial responses), with a DCR of 58.5%. Median PFS and OS were 6.1 and 9.7 months, respectively. Multivariate analysis identified NLR ⩾ 4 and lung metastases as independent predictors of inferior PFS, while NLR ⩾ 4 remained independently associated with worse OS. Dose reductions and peripheral neuropathy were associated with improved outcomes. The HERO score significantly stratified patients by PFS and OS ( p = 0.017 and p < 0.001, respectively). EV was generally well tolerated, with most adverse events being low-grade. Conclusion: In this real-world cohort, EV confirmed its efficacy and manageable safety profile in mUC. The HERO score may provide a simple tool for risk stratification in clinical practice, though prospective validation is needed.