Neoadjuvant (Neoadj) gemcitabine intravesical system (Gem-iDRS) plus cetrelimab (CET) or CET alone in patients (pts) with muscle-invasive bladder cancer (MIBC) ineligible for/refusing neoadj cisplatin-based chemotherapy (NAC): Updated perioperative outcomes from SunRISe-4.

748 Background: There is a high unmet need for effective neoadj treatments (tx) for MIBC that maintain overall health and do not delay or complicate planned radical cystectomy (RC). Gem-iDRS, previously TAR-200, is a novel intravesical drug-releasing system designed to provide sustained delivery of gemcitabine in the bladder. SunRISe-4 (NCT04919512) is a randomized phase 2 study evaluating neoadj Gem-iDRS and CET in pts with MIBC who are ineligible for or refuse NAC. This analysis from SunRISe-4 evaluated if neoadj Gem-iDRS plus CET (Cohort 1 [C1]) or CET alone (C2) impacted pre- and post-RC surgical, laboratory, or safety outcomes, including clinical declines, delay to RC, or increased perioperative complications. Methods: Pts (≥18 yr; ECOG PS 0-1) had histologically confirmed cT2-T4a N0M0 MIBC, were ineligible for or refused NAC, and planned for RC. Pts were randomized 5:3 to receive Gem-iDRS plus CET or CET alone Q3W for 12 wks, followed by RC (protocol-specified RC window: 11-15 wks). Perioperative outcomes included time to RC, 30- and 90-d post-RC morbidity and mortality, and changes on tx in ECOG PS, BMI, albumin, creatinine, and hemoglobin. ECOG PS was recorded on site at baseline and wks 6 and 36. Results: As of the May 9, 2025, data cutoff, 134 pts underwent RC (C1: 88; C2: 46). Median time to RC was 13.6 wks in C1 and 13.3 wks in C2. Most pts had RC within the window (C1: 85.2%; C2: 84.8%). 5/88 (5.7%) pts in C1 and 6/46 (13.0%) in C2 underwent RC after 15 wks (1 pt had a delay due to grade 2 hematuria,1%, during neoadj tx). 79.3% of C1 and 69.6% of C2 pts received ileal conduit. No clinically significant changes in ECOG, BMI, albumin, creatinine, and hemoglobin were noted on tx. At 30 and 90 d post RC, no significant increase in morbidity or mortality was observed (Table). Conclusions: In pts with MIBC ineligible for or refused NAC, neoadj Gem-iDRS plus CET and CET alone were not associated with declines in overall health, delays to RC, or significant increase in 30- and 90-d post-RC morbidity or mortality. Addition of Gem-iDRS to the checkpoint inhibitor CET did not worsen safety and post-RC morbidity compared with CET alone. Clinical trial information: NCT04919512 . Safety outcomes within 30 and 90 d post RC. Pts, n (%) ≤30 d post RC ≤90 d post RC Overall(N=118) Gem-iDRS + CET (n=76) CET alone (n=42) Overall (N=100) Gem-iDRS + CET (n=68) CET alone (n=32) Morbidity Serious AEs 46 (39.0) 32 (42.1) 14 (33.3) 49 (49.0) 37 (54.4) 12 (37.5) Grade ≥3 AEs 54 (45.8) 38 (50.0) 16 (38.1) 55 (55.0) 40 (58.8) 15 (46.9) Mortality a Any cause 3 (2.5) 1 (1.3) b 2 (4.8) c 4 (4.0) 2 (2.9) d 2 (6.3) c AE, adverse event. a No deaths that occurred ≤30 and 90 d post RC were related to neoadj tx with Gem-iDRS or CET. b Due to hypoxia. c Due to peritonitis and cardiac arrest in 1 pt each. d Due to hypoxia and cardio-respiratory arrest in 1 pt each.