Abstract CT564: KEYNOTE-992: A randomized phase 3 trial of pembrolizumab versus placebo in patients with muscle-invasive bladder cancer receiving concurrent chemoradiotherapy

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Abstract Background: Concurrent chemoradiotherapy (CRT) is recommended as a bladder-preserving treatment option for selected patients with muscle-invasive bladder cancer (MIBC). Pembrolizumab has shown clinical activity across many stages of bladder cancer, and ongoing phase 2 studies (ANZUP 1502, NCT02662062; NCT02621151) of pembrolizumab + CRT are promising. The global, randomized, double-blind, placebo-controlled, multicenter, phase 3 KEYNOTE-992 study (NCT04241185) will be conducted to evaluate the safety and efficacy of pembrolizumab + CRT in patients with previously untreated MIBC who opt for bladder preservation. Methods: Key patient eligibility criteria are age ≥18 years, histologically confirmed cT2-T4a, nonmetastatic MIBC, and decision to pursue bladder-preserving therapy. Approximately 636 patients will be randomly assigned 1:1 to receive CRT + either pembrolizumab 400 mg or placebo. Pembrolizumab or placebo will be administered intravenously (IV) every 6 weeks for up to 9 doses. Patients will be stratified by Eastern Cooperative Oncology Group performance status (ECOG PS) score (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). CRT regimen must be determined before randomization. The following radiotherapy (RT) regimens are permitted: 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 only). The following radiosensitizing chemotherapy regimens are permitted: cisplatin monotherapy (35 mg/m2 IV weekly), 5-fluorouracil (500 mg/m2 on days 1-5 and days 22-26) + mitomycin C (12 mg/m2 on day 1), and gemcitabine monotherapy (27 mg/m2 IV twice weekly). Efficacy will be assessed by cystoscopy (± biopsy), by CT or MRI with blinded independent central review, and by urine cytology at 10 weeks after CRT, then every 12 weeks until the end of year 2, and every 24 weeks thereafter. The primary end point is bladder-intact event-free survival, defined as time from randomization to residual/recurrent MIBC, nodal or distant metastases, radical cystectomy, or death from any cause. The key secondary end point is overall survival. Additional secondary end points are metastasis-free survival, time to any non-muscle-invasive bladder cancer, time to cystectomy, and safety. The study is enrolling at sites in Asia, Australia, Europe, North America, and South America. Citation Format: Neal D. Shore, Nicholas D. James, Michiel Simon Van der Heijden, Arjun Vasant Balar, Xiao Fang, Ekta Kapadia, Jeff M. Michalski, Shahrokh F. Shariat, Andrew James Weickhardt. KEYNOTE-992: A randomized phase 3 trial of pembrolizumab versus placebo in patients with muscle-invasive bladder cancer receiving concurrent chemoradiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT564.