Adjusted Comparison of First-line Enfortumab Vedotin Plus Pembrolizumab Versus Platinum-based Chemotherapy ± Avelumab Maintenance for the Treatment of Locally Advanced/Metastatic Urothelial Carcinoma

Abstract

Background and objective

First-line (1L) treatment options for locally advanced or metastatic urothelial carcinoma (la/mUC) include enfortumab vedotin plus pembrolizumab (EV+P), based on EV-302, or platinum-based chemotherapy (PBC) with avelumab maintenance for patients without progression, based on JAVELIN-Bladder 100 (JB-100). Clinicians must choose between EV+P and PBC without knowing whether patients will respond to PBC and qualify for avelumab. In EV-302, avelumab maintenance was approved after trial initiation and therefore, was potentially underutilized among patients without progression. This modeling study facilitated a true 1L comparison of EV+P versus PBC ± avelumab.

Methods

Progression-free survival and overall survival were compared using EV-302 patient-level data and JB-100 study-level data. The JB-100 hazard ratio (HR) for avelumab versus best supportive care was applied to a comparable EV-302 PBC subgroup of patients without progression after a 22-week 1L period. This replaced EV-302 data for patients without progression to reflect outcomes assuming all EV-302 patients without progression received avelumab as observed in JB-100. Using a weighted hazard approach, patients without progression were combined with EV-302 patients with progression to obtain a hybrid PBC ± avelumab arm, which was compared with observed EV+P outcomes. Weighted average HRs with 95% confidence intervals (CIs) were calculated.

Key findings and limitations

EV+P improved progression-free survival (HR 0.51, 95% CI 0.44–0.59) and overall survival (HR 0.64, 95% CI 0.49–0.86) versus PBC ± avelumab. Results were consistent across sensitivity analyses. Limitations include assuming all patients without progression received avelumab, which may not reflect real-world patterns.

Conclusions and clinical implications

EV+P provides progression-free survival and overall survival benefits over PBC ± avelumab, reinforcing its position as the 1L standard of care in patients with la/mUC.