Introduction & Objectives: Chemoradiotherapy is recommended for some patients with MIBC as a bladder-preserving treatment. Pembrolizumab has demonstrated clinical activity in metastatic bladder cancer, MIBC, and non-MIBC (NMIBC), and ongoing phase 2 trials of pembrolizumab plus chemoradiotherapy are promising. The randomized, double-blind, phase 3 KEYNOTE-992 trial (NCT04241185) will evaluate the safety and efficacy of pembrolizumab plus chemoradiotherapy compared with placebo plus chemoradiotherapy in patients with untreated MIBC who chose bladder preservation.
Materials & Methods: Patients eligible for enrollment will be aged ≥18 years, have histologically confirmed MIBC (T2-T4aN0M0) with predominant urothelial histology (≥50%) obtained via diagnostic or maximal transurethral resection of bladder tumor (TURBT) performed within 90 days before enrollment, have planned treatment with one of the radiosensitizing chemotherapy agents specified in the protocol, and have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0‑2. Approximately 636 patients will be randomly assigned 1:1 to receive pembrolizumab 400 mg every 6 weeks (up to 9 doses) plus chemoradiotherapy or placebo every 6 weeks (up to 9 doses) plus chemoradiotherapy. Patients will be stratified by EOCG PS (0 and 1 vs 2), PD-L1 (combined positive score [CPS] <10 vs CPS ≥10), T stage (T2 vs T3 and T4), and geographic region (United States vs European Union vs rest of the world). The investigator’s choice of chemotherapy must be specified prior to random assignment. Allowed radiosensitizing chemotherapy regimens were cisplatin monotherapy (35 mg/m2 intravenously [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/m2IV twice weekly).Conventional radiotherapy consisting of 64 Gy at 2 Gy/fraction over 6.5 weeks (whole bladder with or without pelvic nodes) or hypofractionated radiotherapy consisting of 55 Gy at 2.75 Gy/fraction over 4 weeks (whole bladder only) are permitted based on local standards of care. Imaging via CT (chest) and CT urography or magnetic resonance urography (abdomen/pelvis/urinary tract) will be performed at 10 weeks after completion of chemoradiotherapy, every 12 weeks until the end of year 2, then every 24 weeks thereafter. Adverse events (AEs) will be monitored throughout the study and up to 30 days after cessation of treatment (90 days for serious AEs). The primary end point is bladder-intact event-free survival (time from random assignment to first documented occurrence of residual/recurrent MIBC, nodal or distant metastases, radical cystectomy, or death from any cause). Secondary end points are overall survival, metastasis-free survival, time to cystectomy, time to occurrence of NMIBC, and safety.
Results: KEYNOTE-992 is enrolling in Asia, Australia, Europe, North America, and South America.
Conclusions: Results of KEYNOTE-992 will provide further clarity on the efficacy and safety of pembrolizumab plus chemoradiotherapy in patients with untreated MIBC.

Pembrolizumab plus chemoradiotherapy versus placebo plus chemoradiotherapy for muscle-invasive bladder cancer (MIBC): the phase 3 KEYNOTE-992 study