In the phase II KEYNOTE-057 study, pembrolizumab monotherapy demonstrated effective antitumor activity and acceptable safety in bacillus calmette-guerin (BCG)-unresponsive high-risk (HR) nonmuscle invasive bladder cancer (HR NMIBC) patients. Thus, the KEYNOTE-676 trial assesses the theory that combining pembrolizumab and BCG earlier in the disease course might provide anticancer activity superior to that of BCG monotherapy.
KEYNOTE-676 (NCT03711032) is, therefore, an open-label, comparator-controlled, phase III study of pembrolizumab + BCG vs BCG monotherapy in patients with HR NMIBC. The initial study (cohort A) is enrolling patients with persistent/recurrent HR NMIBC after BCG induction while Cohort B is a new, randomized cohort that will be used to evaluate patients who are BCG treatment-naive or treatment-remote (> 2 years prior).
The authors plan to accrue approximately 975 patients with a blinded independent central review–confirmed histologic diagnosis of HR NMIBC (T1, high-grade Ta, or carcinoma in situ [CIS]). Patients must have undergone cystoscopy/TURBT ≤12 weeks before random allocation, have provided tissue for biomarker analysis, and have an ECOG PS 0-2. Additionally, patients must not have been treated with BCG in the 2 years before randomization.
Patients will be randomly assigned 1:1:1 to receive pembrolizumab 400 mg IV Q6W + BCG reduced maintenance (BCG induction then 1 maintenance cycle); pembrolizumab 400 mg IV Q6W + BCG full maintenance (BCG induction then maintenance cycles up to 18 months); or BCG monotherapy (BCG induction then BCG maintenance up to 18 months). The randomization will be stratified by NMIBC stage (CIS ± papillary disease or papillary disease alone) and PD-L1 expression (combined positive score [CPS] ≥10 or CPS <10).
In terms of outcome assessment, disease status will be evaluated by use of cystoscopy, urine cytology, and biopsy (as appropriate per protocol) every 12 weeks from randomization through year 2, then every 24 weeks through year 5 as well as imaging with CTU will occur every 72 weeks. The primary endpoint is event-free survival (EFS) in all patients. Additionally, secondary endpoints include complete response rate, duration of response (DOR), and 12-month DOR rate for patients with CIS and recurrence-free survival, overall survival, disease-specific survival, time to cystectomy, 24-mo EFS rate, time to deterioration in health-related quality of life, safety, and tolerability.
Presented by: Shahrokh F. Shariat, MD, Professor, and Chairman of the Department of Urology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria