HCRN GU22-598: Phase 2 trial of enfortumab vedotin plus pembrolizumab with selective bladder sparing for treatment of muscle-invasive urothelial cancer of the bladder.

Abstract

TPS891 Background: Radical cystectomy is a standard potentially curative treatment for patients with muscle-invasive bladder cancer (MIBC). However, it is associated with challenges including the need for urinary diversion, a detrimental impact on patients’ psychosocial health and body image, and potential morbidity and mortality. Further, despite being performed with curative intent, a large subset of patients experience metastatic recurrence. Neoadjuvant systemic therapy has been integrated into treatment of MIBC in an attempt to eradicate micrometastatic disease and improve outcomes. With standard cisplatin-based neoadjuvant therapy, ~30-40% of patients achieve a pathological complete response (pCR). The KEYNOTE-905 trial further showed a 57.1% pCR rate among patients who were predominantly cisplatin-ineligible and who received neoadjuvant enfortumab vedotin (EV) plus pembrolizumab (Vulsteke et al, ESMO 2025). These findings have raised the question of whether cystectomy is needed in all patients to achieve cure. We previously showed that with a response-guided bladder-sparing approach, in which patients achieving a stringently defined clinical complete response (cCR) after systemic therapy could omit cystectomy, that durable bladder intact survival is achievable in a subset of patients (Galsky et al, Nature Medicine, 2023). Building on this approach requires integrating more effective and generalizable systemic therapy. The KEYNOTE-905 trial recently established a role for EV plus pembrolizumab as neoadjuvant therapy for MIBC. The current trial seeks to integrate this regimen into a response-guided bladder-sparing paradigm. Methods: The Hoosier Cancer Research Network GU22-598 is a single arm multi-center phase II trial, investigating the use of enfortumab vedotin and pembrolizumab with response-guided bladder sparing for the treatment of localized MIBC (cT2-T3N0M0). The study is enrolling at 5 institutions, with a planned sample size of 47 patients. The primary endpoint is clinical complete response rate, a stringently defined composite endpoint based on results of MRI of the bladder, urine cytology, and cystoscopy with TURBT of any visible tumor and/or resection site plus random biopsies using a recommended template. All patients receive three cycles of neoadjuvant EV and pembrolizumab, with patients achieving a cCR omitting cystectomy and proceeding with additional 14 cycles of maintenance pembrolizumab, with EV given along with the first 6 maintenance cycles. Patients without a cCR proceed with cystectomy. The planned sample size of 47 patients is based on a hypothesized cCR rate of 45%, ensuring the lower bound of the 95% confidence interval exceeds 30%. The study was open to accrual as of February 2025. Primary completion is estimated to be in November 2027. The ClinicalTrials.gov ID number is NCT06809140. Clinical trial information: NCT06809140 .