Interim RETAIN-2 Results: Chemoimmunotherapy-Based Active Surveillance in MIBC

For patients with muscle-invasive bladder cancer (MIBC), the standard of care includes cisplatin-based neoadjuvant chemotherapy (NAC) followed by either radical cystectomy (RC) or chemoradiation (CRT). Sequence variants in DNA damage repair genes have been associated with increased pathologic downstaging after NAC.

The RETAIN-1 trial used a risk-adapted strategy to identify patients eligible for cystectomy-sparing active surveillance (AS) after NAC, reporting a 73% 2-year metastasis-free survival (MFS) rate. New findings from the interim analysis of the RETAIN-2 trial, presented at the American Society of Clinical Oncology 2025 Genitourinary Cancers Symposium, build on this approach by incorporating neoadjuvant chemoimmunotherapy, offering further insights into this bladder-preserving strategy.

The trial involved 80 patients with cT2-T3N0M0 MIBC, Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1, and creatinine clearance of 50 mL/min or greater. Each patient was administered neoadjuvant-accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) with nivolumab.

Transurethral bladder resection (TURBT) specimens obtained before NAC were analyzed for pathogenic sequence variants or variants of uncertain significance in  ATM, ERCC2, or RB1. Patients with one or more variants who achieved a clinical complete response (cCR) after NAC— determined by restaging TUR, urine cytology, and CT imaging—were enrolled in AS.

Patients who did not meet these criteria received bladder-directed therapy, including intravesical therapy for <cT2 disease after CRT, or RC. The primary endpoint is 2-year MFS in the intent-to-treat (ITT) population and is still maturing. This interim analysis presents clinically significant secondary endpoint findings.

Over a 40-month period, patients were treated at four academic centers. Among the 80 enrolled patients, 71 were evaluable per protocol, with 80% having an ECOG PS score of 0 and 87% presenting with cT2 disease. A total of 60 patients (75%) completed three cycles of AMVAC with nivolumab. Seven patients tolerated only one cycle, and two patients died shortly after completing three cycles due to treatment-related adverse events (TRAEs) and were not included in the primary endpoint analysis.

Grade 3-4 TRAEs were observed in 19% of all treated patients. Of the 71 evaluable ITT patients, 31 (44%) had a sequence variant of interest, with a cCR rate of 71% for the subgroup. A total of 35 patients proceeded directly to RC; 10 received CRT, three received intravesical therapy, and 23 started per-protocol AS. Of the patients in the AS group, four did not have sequence variants.

In addition, three patients with both a tumor sequence variant and cCR opted for RC. Among those who underwent RC, the pathologic complete response (pT0) rate was 46%, with a median follow-up of 42.6 months. A total of 86% of all evaluable ITT patients remained free of metastasis. Metastasis occurred in 10 patients: five in the RC group, one in the CRT group, and four in the AS group. A total of 29 patients (78% of AS patients and 41% of ITT patients) remained free of metastasis with an intact bladder.

This interim analysis of the RETAIN-2 trial demonstrated a 46% pT0 rate among those undergoing cystectomy and a 78% metastasis-free bladder preservation rate in the AS cohort. Follow-up is ongoing for the primary endpoint of 2-year MFS.