Factors associated with primary resistance to enfortumab vedotin in previously treated patients with metastatic urothelial carcinoma: a multicenter retrospective study.

Background: To evaluate the primary resistance factors to enfortumab vedotin (EV) monotherapy by comparing treatment outcomes between the early progressive disease (EPD) group and non-EPD group.

Methods: We retrospectively analyzed 121 patients with advanced urothelial carcinoma who received EV monotherapy across five institutions between 2019 and 2024. The patients were categorized into the EPD group (n = 34), defined by radiologically confirmed progressive disease within 3 months of EV initiation, and the non-EPD group (n = 87). The clinical parameters and oncological outcomes were compared between groups. The emergence of new metastatic lesions was defined as the detection of metastases in organs not previously identified as metastatic sites at baseline, during prior chemotherapy or immune checkpoint inhibitors (ICIs) before the initiation of EV.

Results: The median overall survival was significantly shorter in the EPD group than in the non-EPD group (6.5 vs. 19.9 months, p < 0.001). The EPD group had a significantly higher incidence of new metastatic lesions and a lower prevalence of normal Hb levels. Multivariate analysis identified low Hb and the presence of new metastatic lesions as independent predictors of EPD. Among patients with new metastases in the EPD group, an average of 74% of lesions emerged during ICI treatment and 75% involved multiple foci. Notably, more than 50% of these new lesions showed progression at the same sites following EV therapy.

Conclusions: Patients with low hemoglobin levels and new metastatic lesions before EV treatment may be at increased risk for EPD. For these patients, alternative treatment strategies should be considered before initiating EV.