Evaluating Effect of Prior Checkpoint Inhibitor Exposure on Disease Control with Enfortumab Vedotin Plus Pembrolizumab in First-Line Metastatic Bladder Cancer

Introduction: The combination of enfortumab vedotin and pembrolizumab (EVP) has become standard first-line therapy in metastatic urothelial carcinoma (mUC). Yet little is known regarding the impact of prior exposure to checkpoint inhibition (CPI) in the perioperative setting on efficacy of EVP. Methods: We evaluated a real-world cohort of patients with mUC treated with first-line EVP. Patients were categorized into three groups based on prior systemic therapy received before first-line EVP for metastatic disease: prior CPI, prior chemotherapy, or no prior therapy. Demographic characteristics, rwPFS, and OS were assessed. Kaplan–Meier methods and multivariable Cox regression were used to compare outcomes across groups. Results: Among 923 patients, 654 had no prior therapy, 148 had prior CPI exposure, and 121 had prior chemotherapy. Prior CPI exposure was independently associated with worse rwPFS on multivariable analysis (HR 1.43, 95% CI 1.10–1.86; p = 0.007), with significant differences across groups on Kaplan–Meier analysis (p = 0.017). OS from EVP initiation was similar across groups on univariable analysis (p > 0.05), although prior CPI exposure was associated with worse OS after multivariable adjustment (HR 1.42, 95% CI 1.07–1.89; p = 0.015). Limitations include the retrospective design and residual confounding. Conclusions: We find that among patients who progressed to metastatic disease, prior CPI exposure was associated with inferior outcomes following first-line EVP in a real-world experience. Further investigation is needed to determine whether prior CPI exposure directly compromises EVP efficacy, and if it warrants altering treatment strategies.