Phase 2 KEYNOTE-057 cohort C: Pembrolizumab (pembro) with vibostolimab or favezelimab for patients (pts) with high-risk (HR) bacillus Calmette-Guérin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC).
Authors: Shore Neal D. , Gupta Shilpa , Kulkarni Girish S. , Necchi Andrea , Dave Hema Kishore , Kapadia Ekta , Zhao Qing , Kamat Ashish M. 
Published: March 2023

TPS591 Background: The PD-1 inhibitor pembro showed antitumor activity in cohort A of the phase 2 KEYNOTE-057 study (NCT02625961), with 41% of pts with HR BCG-unresponsive carcinoma in situ (CIS) of the bladder ± papillary tumors achieving a CR at 3 months with a median DOR of 16.2 months. Based on these results, pembro was approved in the United States for treatment of pts with BCG-unresponsive HR NMIBC with CIS ± papillary tumors who are ineligible for or have elected not to undergo radical cystectomy (RC). However, novel combinations that improve the efficacy of pembro are needed. Immune checkpoints TIGIT and LAG-3 have been shown to contribute to treatment resistance in many cancers, and their inhibition may enhance the activity of pembro. Cohort C of KEYNOTE-057 will evaluate the efficacy and safety of coformulations of pembro and TIGIT inhibitor vibostolimab or LAG-3 inhibitor favezelimab in pts with HR BCG-unresponsive NMIBC with CIS ± papillary tumors. Methods: Key eligibility criteria include adults with histologically confirmed HR NMIBC that is unresponsive to BCG (defined as persistent or recurrent CIS alone or with Ta/T1 ≤12 months of completion of adequate BCG therapy) who are ineligible for or elect not to undergo RC, have CIS ± papillary tumors at baseline (CIS alone, Ta + CIS or T1 + CIS), and have an ECOG score of 0-2. Approximately 60 pts will be randomly assigned 1:1 to Arm 1 (coformulation of pembro 200 mg and vibostolimab 200 mg) or Arm 2 (coformulation of pembro 200 mg and favezelimab 800 mg) IV Q3W (≤35 administrations) until central pathology-confirmed ≥T1 at any time point or persistent or recurrent CIS or high-grade ≥Ta at the 24-week efficacy review or thereafter. Pts with central pathology–confirmed low-grade pTa at any time point may continue treatment following resection of visible tumors. In the absence of disease persistence/recurrence or progression, treatment will continue until unacceptable toxicity, decision to withdraw, or administrative reasons. Tumor evaluations will be performed Q12W until year 2, then Q24W thereafter for up to 5 years. The primary efficacy end point is 12-month CR rate of HR NMIBC as determined by cystoscopy, cytology, biopsy, and radiologic imaging by central pathology and radiology review. Secondary efficacy end points include DOR of HR NMIBC in responders; overall CR rate and CR rate at 3 and 6 months; PFS to worsening of grade, stage, or death; PFS to muscle-invasive or metastatic disease or death; and OS. The safety objective will characterize the safety and tolerability in all pts who received ≥1 dose of study treatment. Efficacy will be evaluated in all pts who received ≥1 dose of study treatment and have a baseline evaluation consisting of pre-enrollment cystoscopy, TURBT/biopsy, urine cytology, and baseline CT urography imaging. Clinical trial information: NCT02625961 .