The Society of Urologic Oncology (SUO) 2024 annual meeting featured the study design of Cohort C from the phase II KEYNOTE-057 trial, which investigates co-formulations of vibostolimab/pembrolizumab and favezelimab/pembrolizumab in patients with Bacillus Calmette-Guérin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC).
Background
Pembrolizumab, a PD-1 inhibitor, has demonstrated anti-tumor activity in NMIBC, leading to FDA approval for patients with BCG-unresponsive high-risk NMIBC with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo radical cystectomy. However, there is an urgent need for novel combinations to enhance pembrolizumab's efficacy.
Rationale for TIGIT and LAG-3 Inhibition
T-cell immunoglobulin and ITIM domain (TIGIT) and lymphocyte activation gene 3 (LAG-3) are immune checkpoints that contribute to treatment resistance in various cancers, including bladder cancer. Studies have shown increased TIGIT expression on NK, CD4+, and CD8+ T cells in NMIBC patients compared to healthy donors. Additionally, stromal LAG-3 expression correlates with poor prognosis in metastatic urothelial cancer, with expression in immune cell subsets correlating with PD-1 expression. Inhibiting TIGIT and LAG-3 may enhance pembrolizumab's effectiveness.
Study Design
Cohort C of KEYNOTE-057 is designed to evaluate the efficacy and safety of co-formulations of the TIGIT inhibitor vibostolimab with pembrolizumab and the LAG-3 inhibitor favezelimab with pembrolizumab in patients with high-risk, BCG-unresponsive NMIBC with CIS +/- papillary tumors. Sixty patients will be randomized 1:1 to receive either:
- Co-formulated vibostolimab 200 mg + pembrolizumab 200 mg IV every 3 weeks
- Co-formulated favezelimab 800 mg + pembrolizumab 200 mg IV every 3 weeks
Eligibility Criteria
Key inclusion criteria include BCG-unresponsive CIS +/- papillary disease. The primary objective is to evaluate the antitumor activity of the co-formulations, measured by the 12-month complete response rate of high-risk NMIBC, determined by cystoscopy, cytology, biopsy, and radiologic imaging by central pathology and radiology review.
Secondary Endpoints
Secondary endpoints include:
- Duration of response of high-risk NMIBC in responders
- Complete response rates at 3 and 6 months
- Overall complete response rate
- Progression-free survival to worsening of grade, stage, or death
- Progression-free survival to muscle-invasive or metastatic disease or death
- Overall survival
- Safety
The study is enrolling patients across Asia, Australia, Europe, North America, and South America.
