(UroToday.com) The 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between January 25th and 27th was host to a urothelial carcinoma trials in progress poster session. Dr. Girish Kulkarni presented the study design of the phase 2 KEYNOTE-057 (Cohort C) trial evaluating pembrolizumab with favezelimab or vibostolimab for patients with bacillus Calmette-Guérin (BCG)–unresponsive high-risk non–muscle-invasive bladder cancer (NMIBC).
Pembrolizumab is a programmed death protein 1 (PD-1) inhibitor that was demonstrated to have anti-tumor activity in cohort A of the open-label phase II KEYNOTE-057 study (NCT02625961). This resulted in the US FDA approval of pembrolizumab for the treatment of patients with BCG-unresponsive high-risk NMIBC with CIS +/- papillary tumors, who are ineligible for or refused radical cystectomy. This agent demonstrated a 3-months complete response rate of 41%, with about half of patients maintaining this response at the 12 months assessment.1 Given these findings, and the limited approved options for such patients, novel combinations that can further improve the efficacy of pembrolizumab are sorely needed.
The immune checkpoints T-cell immunoglobulin and ITIM domain (TIGIT) and lymphocyte activation gene 3 (LAG-3) have been shown to contribute to treatment resistance in many cancers and have been expressed in bladder cancer. Compared with healthy donors, increased peripheral blood total NK cells and higher TIGIT expression on NK, CD4+, and CD8+ T cells have been observed in patients with NMIBC3.2 Furthermore, stromal expression of LAG-3 has been shown to correlate with poor prognosis in metastatic urothelial cancer, and expression in immune cell subsets has been found to correlate with PD-1expression.3
Given that the inhibition of TIGIT and LAG-3 may improve the efficacy of pembrolizumab, KEYNOTE-057 Cohort C will evaluate the efficacy and safety of co-formulations (receiving both treatments as a single infusion) of pembrolizumab with the TIGIT inhibitor vibostolimab or with the LAG-3 inhibitor favezelimab in patients with high-risk, BCG-unresponsive NMIBC with CIS +/- papillary tumors.
The study design is illustrated below. In Cohort C, 60 patients will be randomized 1:1 to co-formulated pembrolizumab 200 mg + vibostolimab 200 mg IQ every 3 weeks versus co-formulated pembrolizumab 200 mg + favezelimab 800 mg IQ every 3 weeks.
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The patient eligibility criteria are summarized below:
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The study objectives are as follows:
- Primary
- To evaluate the antitumor activity of the pembrolizumab-vibostolimab co-formulation with the pembrolizumab-favezelimab co-formulation
- Using the 12-months complete response (CR) rate of high-risk NMIBC, as determined by cystoscopy, cytology, biopsy, and radiologic imaging by central pathology and radiology review
- To evaluate the antitumor activity of the pembrolizumab-vibostolimab co-formulation with the pembrolizumab-favezelimab co-formulation
- Secondary
- To evaluate the following for the co-formulations of pembrolizumab plus vibostolimab and pembrolizumab plus favezelimab
- Duration of response of high-risk NMIBC in responders
- CR rates at 3 and 6 months
- Overall CR rate
- Progression-free survival (PFS), defined by worsening of grade, stage, or death
- PFS, defined by progression to muscle-invasive or metastatic disease or death
- Overall survival
- To evaluate the following for the co-formulations of pembrolizumab plus vibostolimab and pembrolizumab plus favezelimab
- Safety
- To characterize safety and tolerability of the co-formulations of pembrolizumab with vibostolimab and embrolizumab with favezelimab in patients with NMIBC
The study assessments and follow-up are summarized below:
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Presented by: Girish Kulkarni, MD, PhD, Professor, Department of Surgery, Division of Urology, University of Toronto, Toronto, ON
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, January 25th – January 27th, 2024
References:1. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): An open-label, single-arm, multicenter, phase 2 study. Lancet Oncol. 2021 Jul;22(7):919-930.
2. Audenet F, Farkas AM, Anastos H, et al. Immune phenotype of peripheral blood mononuclear cells in patients with high-risk non-muscle invasive bladder cancer. World J Urol. 2018;36(11):1741-8.
3. Zeng H, Zhou Q, Wang Z, et al. Stromal LAG-3+ cells infiltration defines poor prognosis subtype muscle-invasive bladder cancer with immunoevasive contexture. J Immunother Cancer. 2020;8(1):e000651.