Pembrolizumab with favezelimab or vibostolimab for patients with bacillus Calmette-Guérin (BCG)–unresponsive high-risk (HR) non–muscle-invasive bladder cancer (NMIBC): Phase 2 KEYNOTE-057 cohort C.

Abstract

TPS719 Background: In cohort A of the phase 2 KEYNOTE-057 study (NCT02625961), the PD-1 inhibitor pembrolizumab demonstrated antitumor activity (3-month complete response rate, 41%) in patients with BCG-unresponsive HR NMIBC with carcinoma in situ (CIS) ± papillary tumors who are ineligible for or declined radical cystectomy (RC). However, treatment combinations that improve outcomes and durability of response with pembrolizumab monotherapy are needed. Coinhibitory receptors LAG-3 and TIGIT contribute to immune tolerance in the tumor microenvironment, and co-blockade of PD-1 with LAG-3 or TIGIT has demonstrated antitumor activity in clinical studies. In cohort C of KEYNOTE-057, efficacy and safety of coformulations of pembrolizumab and the LAG-3 inhibitor favezelimab or the TIGIT inhibitor vibostolimab are being evaluated in patients with BCG-unresponsive HR NMIBC with CIS ± papillary tumors. Methods: Key eligibility criteria include adults with histologically confirmed HR NMIBC (CIS ± high-grade Ta or T1 at baseline) that is BCG-unresponsive (persistent or recurrent CIS ± Ta/T1 ≤12 month of completing adequate BCG therapy) who are ineligible for or declined RC and have an ECOG PS of 0-2. Enrollment is planned for 60 patients. Patients will be randomly assigned 1:1 to receive the coformulation of pembrolizumab 200 mg and vibostolimab 200 mg or the coformulation of pembrolizumab 200 mg and favezelimab 800 mg intravenously every 3 weeks for ≤35 cycles or until central pathology–confirmed ≥T1 at any time point, persistent or recurrent CIS or high-grade Ta at 24-week efficacy review or thereafter, unacceptable toxicity, patient or physician decision to withdraw, or administrative reasons to discontinue. Tumor assessment will be performed every 12 weeks for 2 years and every 24 weeks thereafter for up to 5 years. Primary end point is 12-month complete response rate of HR NMIBC by cystoscopy, cytology, biopsy, and radiologic imaging by central pathology and radiology review. Secondary end points include duration of response of HR NMIBC; overall complete response rate and complete response rates at 3 and 6 months; progression-free survival (PFS) to worsening of grade, stage, or death; PFS to muscle-invasive or metastatic disease or death; and overall survival. Efficacy will be evaluated in patients who receive ≥1 dose of treatment and have a baseline evaluation consisting of pre-enrollment cystoscopy, TURBT/biopsy, urine cytology, and baseline CTU imaging. Safety and tolerability will be evaluated in patients who receive ≥1 dose of treatment. Enrollment is ongoing in Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT02625961 .