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Background: Urothelial carcinoma (UC) is a significant clinical problem, especially in locally advanced and metastatic stages, where the prognosis remains poor despite advances in immunotherapy. Enfortumab vedotin (EV), an antibody–drug conjugate (ADC) targeting Nectin-4, extends beyond direct cytotoxicity by actively modulating the immunosuppressive tumor microenvironment (TME) in preclinical models, creating a strong rationale for combination strategies. This systematic review aimed to evaluate the clinical efficacy, safety, and hypothesized immune-modulating potential of EV in the treatment of UC, particularly in combination with immunotherapy. Materials and Methods: The review was conducted in accordance with the PRISMA 2020 guidelines. PubMed, Web of Science, and ClinicalTrials.gov databases were searched to identify interventional clinical studies published between 2020 and 2026. Studies evaluating EV used as monotherapy or in combination with immunotherapy in adult patients with UC were analyzed. ORR, PFS, OS, and the incidence of treatment-related adverse events were evaluated. Individual publications originating from the same clinical trial programs were treated as linked records and analyzed collectively. Results: The analysis was primarily based on key clinical trial programs, including EV-103, EV-301, and EV-302, along with their subgroup analyses, follow-up reports, and patient-reported outcomes. EV demonstrated significant clinical efficacy in the treatment of locally advanced UC (laUC). In the EV-301 study, EV therapy significantly prolonged overall survival compared to chemotherapy (12.88 vs. 8.97 months). In the EV-302 study, EV combination therapy with pembrolizumab showed a significant improvement in progression-free survival and overall survival compared to platinum-based chemotherapy. Conclusions: EV represents a significant therapeutic advance not only as a cytotoxic agent but as a potent immune modulator with clinical efficacy that may be enhanced by its biologically hypothesized immunomodulatory mechanisms in mUC. Its clinical development reflects a critical shift from later-line monotherapy toward earlier-line combination strategies designed to target both tumor cells and the microenvironment. Further studies are needed to better define its role in the context of alternative treatment approaches and across different stages of disease.
Piekarz et al. (Sat,) studied this question.