EV-PRIME: Phase Ib/II study of enfortumab vedotin and pembrolizumab combined with radiotherapy as a bladder-sparing trimodality therapy in muscle invasive bladder cancer.

TPS885 Background: Enfortumab vedotin and pembrolizumab (EVP) combination is highly effective for patients with metastatic urothelial cancer, with a response rate of 68% that includes many durable responses. This combination has also demonstrated activity in the perioperative setting for patients with muscle-invasive bladder cancer (MIBC), based on results of the KEYNOTE-905/EV-303 trial. Current standard of care treatment for patients with MIBC remains systemic therapy followed by radical cystectomy (RC). However, for selected patients who are either not RC candidates or prefer a bladder-sparing approach, trimodality therapy (TMT) with trans-urethral resection of bladder tumor (TURBT) followed by combined chemotherapy and radiation therapy (RT) constitutes an alternative treatment option. The efficacy and durable responses observed with EV/P support the rationale of combining this regimen with RT for patients with MIBC, allowing patients to potentially forego extensive surgery. Methods: This is a phase Ib/II, multi-center, investigator initiated trial of bladder sparing tri-modality therapy in MIBC, utilizing EVP in combination with standard fractionation bladder RT following TURBT (within 8 weeks of treatment start). Eligible patients have biopsy-confirmed MIBC (cT2-T4a) with component of urothelial histology, but no evidence of metastatic disease on imaging (M0) and have ECOG PS ≤1. Patients will be either ineligible for RC or declining surgery and will not have contraindications to receiving either EV or P. Enrolled patients will receive 2 cycles (6 weeks) of treatment with combination of EVP and concurrent conventionally fractionated RT (64Gy/32Fx), followed by adjuvant EV for 3 cycles (5 total cycles maximum) and pembrolizumab for 15 cycles (17 total cycles maximum). The trial will start with a phase Ib 3+3 dose escalation of EV at three dose levels (0.75 mg/kg, 1.00 mg/kg, 1.25 mg/kg) given on Days 1,8 of a 21-day cycle, in combination with standard dose of pembrolizumab 200 mg IV (Day 1 of 21-day cycle) and RT, to define the safety of this combination and determine the recommended phase II dose (RP2D) of EV as part of this regimen. In the phase II portion of the study, patients will be treated at the RP2D of EV in combination with standard dose of pembrolizumab and RT, to assess the efficacy of this combination. Primary efficacy endpoint is the 6-month clinical complete response (cCR) in the phase II portion of the study; important secondary endpoints include median recurrence-free survival, median cystectomy-free survival and median overall survival. The study is open and currently actively accruing patients in phase Ib dose escalation at UCSF. This trial will aim to enroll 35 patients at the RP2D, and up to 47 patients total at 3 high-volume centers. Clinical trial information: NCT06470282 .