Introduction & Objectives: Standard of care for bladder-preserving treatment with MIBC is CRT. Pembrolizumab has clinical activity across many stages of bladder cancer, including metastatic bladder cancer, MIBC, and non–muscle-invasive bladder cancer (NMIBC). Two phase 2 studies (NCT02662062 and NCT02621151) to test pembrolizumab plus CRT for MIBC are ongoing, and initial data are promising. KEYNOTE-992 (NCT04241185) will further investigate the safety and efficacy of pembrolizumab plus CRT in patients with MIBC who opt for bladder preservation. Materials & Methods: KEYNOTE-992 is an ongoing, multicenter, double-blind, placebo-controlled, randomized, phase 3 trial to evaluate the efficacy and safety of first-line pembrolizumab versus placebo—both added to CRT—in patients with MIBC. Adults with confirmed cT2-T4a, nonmetastatic (N0M0) MIBC who opt to undergo bladder-preserving therapy will be eligible for enrollment. Approximately 636 patients will be randomly assigned 1:1 to receive CRT plus either pembrolizumab 400 mg IV Q6W or placebo. The study drug—ie, pembrolizumab or placebo—will be discontinued after 9 doses. The investigator must choose 1 of the following radiotherapy (RT) plans before study begins: conventional RT consisting of 64 Gy at 2 Gy/fraction over 6.5 weeks (whole bladder with or without pelvic nodes) or hypofractionated RT consisting of 55 Gy at 2.75 Gy/fraction over 4 weeks (whole bladder). Investigators must likewise choose 1 of the following radiosensitizing chemotherapy regimens: cisplatin monotherapy (35 mg/m2 IV weekly), 5-fluorouracil (500 mg/m2 on days 1-5 and days 22-26) plus mitomycin C (12 mg/m2 on day 1), and gemcitabine monotherapy (27 mg/m2 IV twice weekly). Efficacy will be assessed by cystoscopy (± biopsy); imaging (CT or MRI) with blinded independent central review; and urine cytology at 10 weeks after CRT, then Q12W until the end of year 2, and every 24 weeks thereafter. Enrollment will be stratified by ECOG PS (PS 0 or 1 vs 2), PD-L1 combined positive score (<10 vs ≥10), T stage (T2 vs T3 or T4), and geographic region (US vs Europe vs rest of world). Primary end point is bladder-intact event-free survival, defined as the time from randomization to first occurrence of the following: residual/recurrent MIBC, nodal or distant metastases, radical cystectomy, or death from any cause. Key secondary end point is overall survival. Other secondary end points include metastasis-free survival, time to any NMIBC, time to cystectomy, and safety. Adverse events (AEs) will be monitored from randomization through 30 days after last dose of study drug (90 days for serious AEs). Results: KEYNOTE-992 is enrolling at sites in Czech Republic, Denmark, Estonia, Guatemala, Italy, Israel, Republic of Korea, Latvia, Malaysia, Netherlands, Spain, Taiwan, Turkey, Ukraine, and the United States of America. Conclusions: KEYNOTE-992 will provide further clarity on the efficacy of pembrolizumab plus CRT in previously untreated MIBC.
No datasets are available for this submission.