A phase 2 trial of risk enabled therapy after neoadjuvant chemo-immunotherapy for muscle-invasive bladder cancer (RETAIN-2).

815 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) or chemoradiation (CRT) is the standard of care for patients (pts) with muscle invasive bladder cancer (MIBC). Mutations in DNA damage repair genes enrich for pathologic downstaging after NAC. In RETAIN-1, a risk-adapted approach was employed to identify patients for cystectomy-sparing active surveillance (AS) following NAC, reporting a 73% 2-year MFS rate. RETAIN-2 employs a similar approach but incorporates neoadjuvant chemoimmunotherapy. Methods: This is a phase II, multi-institutional trial in which pts with cT2-T3N0M0 MIBC, ECOG PS 0-1 and CrCl≥50 mL/min received neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) with nivolumab. Pre-NAC transurethral bladder resection (TURBT) specimens were sequenced for mutations (pathogenic or VUS) in ATM , ERCC2 or RB1 . Pts with >1 mutation and clinical complete response (cCR) post-NAC (based on restaging TUR, urine cytology and CT imaging) initiated active surveillance (AS). Remaining pts underwent bladder-directed therapy: intravesical therapy (< cT2 post-NAC), CRT or RC. The primary endpoint is 2-year metastasis-free survival (MFS) for ITT pts which is not mature. This interim analysis reports clinically meaningful secondary endpoint outcomes. Results: A total of 80 pts were treated over 40 months at four academic centers and 71 were evaluable per protocol. The median age was 69 years (range: 66-86), 77% were male, 80% had ECOG PS 0 and 87% were cT2. Of 80 treated pts, 60 (75%) completed 3 cycles of AMVAC with nivolumab; 7 tolerated only 1 cycle, and 2 died shortly after completing 3 cycles from treatment-related adverse events and were not evaluable for the primary endpoint. Grade 3-4 TRAEs occurred in 19% of all treated pts. Of 71 evaluable ITT pts, 31 (44%) had a mutation of interest and the cCR rate in those pts was 71%; 35 pts proceeded directly to RC, 10 received CRT, 3 received intravesical therapy and 23 pts started per protocol AS. Of 23 AS pts, 4 did not have mutation. Similarly, 3 pts with tumor mutation and cCR chose RC. In pts who underwent RC, pT0 rate was 46%, <T2 rate was 63%, and 5 (14%) developed metastases. Of the 23 pts on AS, 6 required salvage local tx (3 salvage RC, 2 intravesical tx and 1 CRT). At data cut-off (Sep 1, 2024), with a median follow-up of 18.4 mo (range: 6.1– 42.6 mo), 86% of all evaluable ITT pts remain metastasis free. A total of 10 pts developed metastases – 5 in the RC, 1 in the CRT, and 4 in the AS groups. Twenty-nine pts remain metastasis free with an intact bladder (78% of AS pts, 41% of ITT pts). Conclusions: Interim results of RETAIN-2 show a 46% pT0 rate in those allocated to cystectomy and a 78% metastasis-free bladder-preservation rate in those allocated to AS. Follow-up is ongoing for the primary endpoint of 2-year MFS. Clinical trial information: NCT04506554 .