Gemcitabine intravesical system (Gem-iDRS) in combination with cetrelimab (CET) versus chemoradiotherapy (CRT) in muscle-invasive bladder cancer (MIBC): SunRISe-2 final results.

635 Background: Bladder sparing is an important therapeutic goal in MIBC. Definitive treatment for localized MIBC is CRT or radical cystectomy (RC) with neoadjuvant chemotherapy. Gem-iDRS (previously TAR-200), approved for BCG-unresponsive non-MIBC with carcinoma in situ, is an intravesical drug-releasing system designed for sustained delivery of gemcitabine in bladder. CET is an investigational IgG4 anti–PD-1 antibody. We report final analysis of SunRISE-2 (NCT04658862), an open-label, randomized, phase 3 superiority study. Methods: Patients (pts; ≥18 yrs with cT2-T4a, N0, M0 MIBC, declined/ineligible for RC) were randomized 1:1 to Gem-iDRS + intravenous CET (arm 1) or concurrent CRT (cisplatin or gemcitabine plus RT, 64 or 55 Gy; arm 2). In arm 1, pts received Gem-iDRS every 3 wks (Q3W) for 18 wks, followed by Q12W until W144 and CET Q3W until W78. In arm 2, pts received CRT for up to 6.5 wks. Primary end point was bladder-intact event-free survival (BI-EFS; defined as time to muscle-invasive or distant relapse, RC or death). Secondary end points included overall response (OR; using biopsy and CT/MRI) at W18, metastasis-free survival (MFS), overall survival (OS), and safety. The study met the prespecified futility criteria. Final analysis was conducted after data collection was complete. Results: At July 7, 2025 data cutoff, 518 pts were randomized (arm 1, n=262; arm 2, n=256). Median follow-up was 11.3 months. Gem-iDRS + CET did not show superior BI-EFS over CRT (HR, 1.71 [95% CI, 1.16-2.53]); 24-mo rates were 58.5% vs 66.5%, respectively. At W18, OR rate was 56.7% in arm 1 and 65.3% in arm 2. In pts who achieved complete response (CR) at W18, 24-mo BI-EFS rates were 76.2% and 72.0% in arms 1 and 2 (Table). Incidence of any-grade and grade ≥3 treatment-related adverse events (TRAEs) is shown in Table. Most common grade ≥3 TRAE was urinary tract infection (6.3%) in arm 1 and neutropenia (8.7%) in arm 2. There was no treatment-related death in arm 1 and 1 death in arm 2. Conclusions: In SunRISe-2, Gem-iDRS + CET did not show superior BI-EFS over CRT in pts with MIBC not receiving RC. 24-mo BI-EFS rates in pts with CR at W18, and MFS and OS rates in all pts were similar in both arms. There were no unexpected safety findings in either arm. Clinical trial information: NCT04658862 . Efficacy [95% CI] Gem-iDRS + CET (n=262) CRT (n=256) Median BI-EFS, mo NE [22.9-NE] NE [26.6-NE] 24-mo BI-EFS rate, % 58.5 [49.4-66.5] 66.5 [55.6-75.4] OR rate at W18, n (%) a 122 (56.7) [49.8-63.5] 132 (65.3) [58.4-71.9] 24-mo BI-EFS rate in pts with CR at W18, % 76.2 [59.9-86.5] 72.0 [55.1-83.5] 24-mo MFS rate, % 65.5 [55.5-73.8] 70.2 [59.4-78.7] 24-mo OS rate, % 83.7 [76.3-88.9] 84.0 [73.7-90.5] TRAEs n=254 n=241 Any-grade | grade ≥3, n (%) 203 (79.9) | 68 (26.8) 212 (88.0) | 77 (32.0) a Gem-iDRS + CET, n=215; CRT, n=202; CR 50.7% and 59.4%, partial response 6.0% and 5.9%, non-response 43.3% and 34.7%, respectively. NE, not estimable.