Keynote-676: Phase 3 study of bacillus calmette-guerin (BCG) with or without pembrolizumab (pembro) for high-risk (HR) non-muscle invasive bladder cancer (NMIBC) that is persistent or recurrent following BCG induction
Kamat AM, Shore ND, Hahn NM, Alanee S, Nishiyama H, Shariat S, Nam K, Kapadia E, Frenkl TL, and Steinberg GD. Keynote-676: Phase 3 study of bacillus calmette-guerin (BCG) with or without pembrolizumab (pembro) for high-risk (HR) non-muscle invasive bladder cancer (NMIBC) that is persistent or recurrent following BCG induction. J Clin Oncol 2019; 37.
J Clin Oncol
Background: Intravesical instillation of BCG is the standard of care for patients with HR NMIBC. However, many patients have persistent/recurrent HR NMIBC after BCG induction and are at a particularly increased risk for progression, representing a significant unmet need. Programmed cell death ligand 1 (PD-L1) expression in the tumor microenvironment may attenuate responses to BCG. KEYNOTE-676 is a randomized, comparator-controlled, phase 3 trial to evaluate the efficacy and safety of the PD-1 inhibitor pembro plus BCG in patients with persistent/recurrent HR NMIBC after BCG therapy. Methods:Adult (>18 years) patients with histologically confirmed persistent/recurrent HR NMIBC of the bladder after adequate BCG induction therapy are eligible. Patients are required to have undergone cystoscopy/transurethral resection of bladder tumor within 12 weeks prior to randomization, to have no concurrent extravesical disease, and to have ECOG performance status score 0-2, adequate organ function, and tissue for biomarker analysis. Patients will be randomly assigned 1:1 to continue on BCG therapy alone or receive BCG plus pembro 200 mg every 3 weeks. Treatment will be stratified by carcinoma in situ (CIS) histology (presence/absence), PD-L1 combined positive score (≥10/<10), and timing of NMIBC persistence/recurrence (0 to ≤6, >6 to ≤12, or >12 to ≤24 mo). Primary end point is complete response rate in participants with CIS. Secondary end points will include event-free survival, patient-reported outcomes, and safety. Responses will be assessed by cystoscopy and blinded independent central review of urine cytology and biopsy (as applicable) every 12 weeks for years 1-2 and every 24 weeks for years 3-5 and by computed tomography urography every 18 months through year 5. Treatment will continue with pembro for up to 2 years and BCG for 3 years or until pathology-confirmed HR NMIBC persistence, recurrence, or disease progression, unacceptable toxicity, or patient/physician decision to withdraw. Recruitment will begin November 2018 and will continue until ∼550 patients are enrolled.