IMGeS study: A prospective, multicentre, phase II trial of sequential intravesical mitomycin-C and gemcitabine therapy in BCG-unresponsive high-risk NMIBC ineligible for or declining radical cystectomy.

TPS904 Background: High-risk non-muscle-invasive bladder cancer (HR-NMIBC) unresponsive to adequate Bacillus Calmette-Guérin (BCG) has a high risk of recurrence and progression. Although several novel bladder-preserving approaches such as immune checkpoint inhibitors, viral gene therapy, and cytokine-based regimens, are under investigation, their efficacy remains limited, financial toxicity is a concern, and current FDA approvals are restricted to carcinoma in situ (CIS). Radical cystectomy (RC) therefore remains the standard of care, but many patients are ineligible or decline surgery. Both intravesical mitomycin-C (MMC) and gemcitabine (GEM) have demonstrated efficacy in NMIBC, and sequential administration may offer synergistic benefit. No prospective data exist. Methods: The IMGeS study is an investigator-initiated, prospective, open-label, multicentre, single-arm phase II trial evaluating the efficacy and safety of sequential intravesical MMC and GEM in BCG-unresponsive HR-NMIBC. Eighty-two patients will be enrolled from eight Korean centres over 24 months, with 12 months of follow-up. Eligible patients have histologically confirmed BCG-unresponsive high-risk NMIBC per AUA criteria, including refractory or relapsing disease within 6–9 months of adequate BCG, and are unsuitable for or refuse RC. Key exclusions include muscle-invasive or metastatic disease, upper tract urothelial carcinoma, prior intravesical MMC or GEM within 2 years (except a single immediate postop dose), and other predominant histology. Following TURBT, patients receive induction with MMC 40 mg/20 mL intravesically retained for 1–2 hours, immediately followed by gemcitabine 2 g/50 mL retained for 1–2 hours, weekly for 6 weeks. Patients without recurrence at 3-month cystoscopy receive monthly maintenance instillations for 12 months. The primary endpoint is 1-year high-risk recurrence-free survival (HRFS); secondary endpoints include progression-free, cystectomy-free, cancer-specific, and overall survival, as well as safety and tolerability. Exploratory endpoints include biomarker analyses from tumor, urine, and blood. Clinical trial information: NCT06388720 .