Durable Response to Enfortumab Vedotin Compared to Re-challenging Chemotherapy in Metastatic Urothelial Carcinoma After Checkpoint Inhibitors

Background Enfortumab vedotin (EV), an antibody–drug conjugate targeting Nectin-4, has been used for patients with metastatic urothelial carcinoma (mUC) after progressing on checkpoint inhibitors (CPIs). Re-challenging chemotherapy with platinum agents and continuing CPIs beyond progressive disease (PD) have often been chosen following PD on CPIs, and several studies indicate favorable treatment effects of re-challenging chemotherapy. There is little evidence for comparing EV and re-challenging chemotherapy in real-world clinical practice. Objective The aim was to reveal the real-world treatment outcomes of EV, re-challenging chemotherapy, and continuing CPIs beyond PD in mUC patients. Patients and Methods A multi-institutional dataset of 350 mUC patients treated with CPIs was utilized. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) were evaluated to compare the treatment arms. Results One hundred and nine mUC patients were treated with EV with a median follow-up of 6.4 months. The ORR and disease control rate (DCR) were 48% and 70%, respectively. The OS from PD on pembrolizumab exhibited significant differences among the three groups, with a median OS of 8, 14, and 29 months in continuing pembrolizumab beyond PD, re-challenging chemotherapy, and EV, respectively. When comparing the survival outcomes from the initiation of the treatment, there is neither a difference in OS ( p = 0.124), PFS ( p = 0.936), nor ORR ( p = 0.816) between EV and re-challenging chemotherapy. Notably, the DOR in patients who achieved an objective response was significantly longer in the EV group than the re-challenging chemotherapy group (a median of 11 and 5 months, p = 0.049). For OS, the difference was not statistically significant (27 and 11 months in EV and re-challenging chemotherapy, respectively: p = 0.05). Conclusions A superior effect of EV on patient survival compared to re-challenging chemotherapy and continuing pembrolizumab beyond PD was observed in our real-world analysis, which is attributed to the durable DOR in EV treatment despite the similar ORR to re-challenging chemotherapy. Plain Language Summary Enfortumab vedotin (EV) is an antibody–drug conjugate targeting Nectin-4 and is now utilized for patients with metastatic urothelial carcinoma following treatment with checkpoint inhibitors (CPIs). Until recently, repeating chemotherapy using platinum drugs or continuing CPIs were often the