A phase II trial of intravesical gemcitabine/docetaxel plus systemic pembrolizumab in high-risk non–muscle invasive bladder cancer unresponsive to BCG.

TPS888 Background: High-risk non–muscle invasive bladder cancer (NMIBC) unresponsive/exposed to Bacillus Calmette-Guérin (BCG) represents an area of significant unmet clinical need. Radical cystectomy remains the standard of care, yet many patients are ineligible or decline surgery. Intravesical chemotherapy with gemcitabine/docetaxel has shown promising activity, and immune checkpoint inhibition with pembrolizumab is approved in this setting. Preclinical and retrospective data suggest that combining intravesical chemotherapy with systemic PD-1 blockade may enhance antitumor efficacy. Methods: This is a multicenter, investigator initiated, open-label, single-arm Phase II trial evaluating pembrolizumab (400 mg IV every 6 weeks) in combination with sequential intravesical gemcitabine (1 g) and docetaxel (37.5 mg) in patients with high-risk NMIBC unresponsive/ exposed to BCG who are ineligible for or refuse radical cystectomy. Induction consists of six weekly intravesical instillations, followed by monthly maintenance for up to 12 months. Pembrolizumab is administered for up to nine cycles (1 year). The primary endpoint is complete response (CR) at 3 months, defined as absence of high-risk NMIBC or progressive disease. Secondary endpoints include duration of response, disease-free rate, time to and avoidance of cystectomy, and safety/tolerability. Exploratory objectives include biomarker analyses from tumor tissue, blood, and urine, and evaluation of patient-reported outcomes. Status: Enrollment is ongoing, with a planned sample size of up to 37 patients. Interim analyses will assess proof-of-concept, and study continuation will depend on observed safety and early efficacy signals. Correlative studies will explore immune and molecular predictors of response and resistance in the tumor, blood, and urine. Clinical trial information: NCT06972615 .