Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA
Background
Intravesical instillation of BCG is a standard-of-care treatment for patients with HR NMIBC, but up to 50% of patients later experience disease recurrence or progression to muscle-invasive bladder cancer (MIBC) despite BCG treatment. In the phase 2 KEYNOTE-057 study (NCT02625961), pembrolizumab monotherapy was shown to have antitumor activity in patients with HR BCG–unresponsive NMIBC who had carcinoma in situ (CIS) with or without papillary tumors and in patients with only papillary tumors. In cohort A of the randomized, phase 3 KEYNOTE-676 trial (NCT03711032), pembrolizumab plus BCG versus BCG alone is being evaluated in patients with persistent/recurrent HR NMIBC after first BCG induction.
Methods
Key eligibility criteria include adults with histologically confirmed HR NMIBC (T1, high-grade Ta, and/or CIS) that is persistent/recurrent following 1 adequate course of BCG induction therapy, have no concurrent extravesical disease or history of extravesical disease that recurred within 2 years, have an ECOG PS score of 0 to 2, and have undergone cystoscopy/TURBT ≤12 weeks before randomization. Approximately 430 patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks plus BCG or BCG alone. BCG (50 mg) will be administered by intravesical instillation as induction therapy once weekly for 6 weeks and then as maintenance therapy once weekly for 3 weeks at weeks 13 and 25, then every 24 weeks (Q24W) thereafter. Treatment will continue for approximately 2 years (pembrolizumab) or 3 years (BCG), or until confirmed persistent/recurrent HR NMIBC or disease progression to MIBC or metastatic bladder cancer, unacceptable toxicity, or withdrawal. Randomization to treatment will be stratified by PD-L1 combined positive score (≥10 or ˂10), histology (CIS or non-CIS), and NMIBC disease history (persistence/recurrence 0 to ≤6 months or recurrence ˃6 to ≤12 months or recurrence ˃12 to ≤24 months). Response will be assessed by local cystoscopy and blinded independent central review of urine cytology and biopsy (as applicable) every 12 weeks for years 1 to 2 and Q24W for years 3 to 5. Computed tomography urography will occur every 72 weeks through year 5, then every 104 weeks thereafter. The primary end point is complete response rate in patients with CIS. Secondary end points are duration of response in patients with CIS, event-free survival, recurrence-free survival, time to cystectomy, overall survival, disease-specific survival, safety and tolerability, and patient-reported outcomes. Enrollment incohort A of KEYNOTE-676 is ongoing in Asia, Australia, Europe, and North America. Clinical trial information: NCT03711032.