Pembrolizumab plus concurrent chemoradiotherapy is being investigated as a potential therapy in patients with muscle-invasive bladder cancer.
Pembrolizumab (Keytruda) plus concurrent chemoradiotherapy (CRT) is being investigated as a potential therapy in patients with muscle-invasive bladder cancer (MIBC), according to the study design of the phase 3 KEYNOTE-992 trial (NCT04241185) that was presented in a poster at the American Association for Cancer Research (AACR) Annual Meeting 2022.1
Pembrolizumab has previously shown clinical activity across various stages of bladder cancer, including metastatic bladder cancer, MIBC, and non–muscle-invasive bladder cancer (NMIBC). KEYNOTE-992 aims to evaluate the efficacy and safety of pembrolizumab plus CRT vs placebo plus CRT in patients with MIBC who choose bladder preservation treatment.
This global, multicenter, double-blind, placebo-controlled trial is currently seeking to enroll approximately 636 patients with MIBC who will be randomized 1:1 into 2 cohorts of 318 patients each.
Eligible patients will be at least 18 years of age with a histologically confirmed MIBC diagnosis with predominant urothelial histology as well as clinically nonmetastatic bladder cancer. Patients must also be eligible to receive CRT and radiosensitizing chemotherapy regimens, have an ECOG performance status (PS) between 0 and 2, and adequate organ function.
Patients will be excluded if they have diffuse carcinoma in situ (CIS) throughout the bladder or if they have small cell neuroendocrine components in their tumor tissue. Key exclusion criteria also include limited bladder function with frequency of small amounts of urine, urinary incontinence, or use of catheters. Additionally, patients who have received prior pelvic or local radiation therapy, antineoplastic treatment for MIBC, or prior therapy with PD-1, PD-L1, or PD-L2 inhibitors will be excluded. Other exclusion criteria includes those with additional known malignancies that are progressing or have progressed, or those with additional known malignancies that have required active treatment in the past 3 years.
Patients will receive either CRT plus intravenous (IV) pembrolizumab at a dose of 400 mg every 6 weeks (Q6W) or CRT plus IV placebo Q6W for approximately 1 year and a maximum of 9 doses.
Eligible patients will be stratified by their ECOG PS (0 or 1 vs 2), T stage (T2 vs T3/4), PD-L1 combined positive score (CPS; <10 vs ≥ 10), and geographic region (United States vs Europe vs the rest of the world).
Accepted radiotherapy regimens include conventional radiotherapy consisting of 64 Gy at 2 Gy per fraction over 6.5 weeks to the whole bladder with or without pelvic nodes, or hypofractionated radiotherapy consisting of 55 Gy at 2.75 Gy per fraction over 4 weeks to the whole bladder. Accepted concurrent radiosensitizing chemotherapy regimens include 5-fluorouracil at a dose of 500 mg/m2 on days 1 through 5 and days 22 through 26 plus mitomycin C at a dose of 12 mg/m2 on day 1; cisplatin monotherapy through weekly IV administration at a dose of 35 mg/m2; and gemcitabine monotherapy through twice weekly IV administration at a dose of 27 mg/m2.
The primary objective of this trial will be to compare the bladder-intact event-free survival (BI-EFS) with the combination of pembrolizumab and CRT vs the combination of placebo and CRT. For the purposes of this trial, BI-EFS is defined as the time from randomization to recurrent/residual MIBC, nodal or distant metastases, radical cystectomy, or death from any cause.
The key secondary end point will be overall survival (OS), defined as the time from randomization to death from any cause. Other secondary end points that will be investigated include metastasis-free survival (MFS), time from randomization to occurrence of NMIBC, time from randomization to date of cystectomy, patient-reported outcomes, safety, and tolerability. MFS is defined as the time from randomization to first histologic or radiologic evidence of metastatic disease.
Patient-reported outcomes include global health status/quality of life and physical functioning scale as rated through European Organization for Research and Treatment of Cancer questionnaires, as well as urinary, bowel, and sexual domains as defined by the Bladder Cancer Index.
The efficacy of each treatment in the study will be assessed by cystoscopy, imaging, and urine cytology beginning 10 weeks after CRT, then Q12W up to the end of year 2, then Q24W beyond that point.
Efficacy will be analyzed in all randomly assigned patients in the intention-to-treat population. The stratified log-rank test will be used to evaluate BI-EFS. The hazard ratio will be assessed using a stratified Cox proportional hazards model with the Efron method of handling ties.
Safety will be analyzed in all randomly assigned patients who received at least 1 dose of study drug. Adverse effects (AEs) will be graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. AEs will be monitored throughout the study and for 30 days during the follow-up period. Serious AEs will be monitored for 90 days during the follow-up period.
KEYNOTE-992 is currently enrolling patients at sites in Asia, Australia, Europe, and North America.