Induction enfortumab vedotin plus pembrolizumab followed by maintenance pembrolizumab in first-line metastatic urothelial carcinoma (IMPROEV).

Abstract

TPS893 Background: Enfortumab vedotin plus pembrolizumab (EV/P) is the preferred first-line regimen for metastatic urothelial carcinoma (mUC), demonstrating significant improvements in overall survival (OS) and progression-free survival (PFS) compared with platinum-based chemotherapy. However, continuation until disease progression or unacceptable toxicity leads to cumulative adverse events, particularly peripheral neuropathy, which is a common cause of treatment discontinuation. Post-hoc exposure–response analyses indicated that early EV dose intensity was associated with response, while declining serum EV concentrations over time did not compromise efficacy. In EV-103 and EV-201, 38–50% of patients who discontinued EV or EV/P maintained disease control for years, suggesting durable benefit after treatment cessation. These data support a finite-duration, induction–maintenance strategy over the traditional “treat-to-toxicity” approach. We hypothesize that induction EV/P followed by pembrolizumab maintenance in responders will preserve durable oncologic control while reducing cumulative toxicity and improving quality of life. Methods: IMPROEV is a single-arm, open-label, nonrandomized phase II trial enrolling 97 previously untreated patients with locally advanced or metastatic UC across four centers. Patients who received prior neoadjuvant or adjuvant checkpoint inhibitor therapy ≥12 months before enrollment are eligible. Patients receive EV 1.25 mg/kg IV on days 1 and 8 plus pembrolizumab 200 mg IV on day 1 of each 21-day cycle for 6 cycles (18 weeks). Patients achieving confirmed complete or partial response per RECIST v1.1 transition to P 400 mg IV every 6 weeks for up to 2 years. Those with stable disease may continue EV/P or transition to P alone at investigator discretion. The primary endpoint is 18-month PFS. Secondary endpoints include OS, duration of response, treatment-free interval, incidence of peripheral neuropathy, and quality of life (EORTC QLQ-C30, BLM30, CIPN20). Exploratory analyses will evaluate ctDNA dynamics from baseline through progression. The trials uses a one-arm, two-stage design testing the null hypothesis that the proportion of patients who progress or die within 18 months ( p 0 ) is ≤0.56 versus the alternative ( p a ) of 0.67, with 11.4% type I error and 80.3% power. Stage I will enroll 31 evaluable patients; if >22 progress or die within 18 months, accrual will stop. Otherwise, 66 additional patients will be enrolled in stage II. Enrollment is expected to begin in Fall 2025. Clinical trial information: NCT07221942 .