Introduction:

Standard of care for high-risk non-muscle invasive bladder cancer (HR NMIBC) is transurethral resection of bladder tumor (TURBT) followed by intravesical Bacillus Calmette-Guerin (BCG) immunotherapy. Approximately 50% of patients become unresponsive to BCG. Cohort A of the phase 2 KEYNOTE-057 trial (NCT02625961) evaluated the efficacy and safety of pembrolizumab monotherapy in participants with HR NMIBC with carcinoma in situ (CIS) with or without papillary disease, unresponsive to BCG therapy who were ineligible for or declined radical cystectomy (RC). Prior results showed that 41% of participants in cohort A achieved a complete response (CR) at 3 months, leading to the approval of pembrolizumab by the US Food and Drug Administration for participants with the described indication. Updated results from cohort A after a median of 5 years of follow-up are presented.

Methods:

Participants aged ≥18 years with histologically confirmed BCG-unresponsive HR NMIBC with CIS and/or high-grade Ta or T1 disease and predominantly urothelial histology who were ineligible for or declined RC, and an ECOG PS 0-2 were enrolled. Participants with papillary disease had undergone complete TURBT ≤12 weeks before the first dose of trial treatment. Enrolled participants received pembrolizumab 200 mg IV every 3 weeks for up to 35 administrations (~2 years). The safety analysis population included all enrolled participants who received ≥1 dose of study medication by the enrollment cutoff date (April 1, 2018). The efficacy analysis population included participants from the safety analysis population who also met the 2018 FDA criteria for BCG-unresponsive NMIBC. The primary end point was the CR rate, defined as the absence of high-risk or progressive disease. Secondary end points included duration of response for high-risk disease and safety.

Results:

Cohort A included 96 participants in the efficacy population; 101 were in the safety population. Median time from first dose to data cutoff (May 25, 2022) in the efficacy population was 60.4 months (range, 50.2-72.5). Ninety-one participants (94.8%) declined RC, 70 (72.9%) had recurrent HR NMIBC, and 26 (27.1%) had persistent HR NMIBC. Thirty-nine participants (40.6%) achieved CR at 3 months. Median duration of CR was 16.2 months (range, 0.0+ to 57.7+); 9 responders (33.3%) experienced CR ≥45 months. Forty-three participants (44.8%) underwent subsequent RC (none with ongoing CR). Median time from last dose to RC was 4.7 months (range, 1.4-28.3) for participants with CR who later progressed and 2.8 months (range, 1.4-38.4) for participants without CR. Five of 42 participants (12%) who underwent RC progressed to muscle-invasive disease (Table). Three participants (7.1%) who delayed RC for ≥1 year after treatment discontinuation progressed to T3/T4. No treatment-related deaths occurred.

Conclusion:

After 5 years of follow-up, pembrolizumab continued to show clinically meaningful antitumor activity and a manageable safety profile in participants with BCG-unresponsive HR NMIBC with CIS with or without papillary disease. Furthermore, these data suggest that the window of opportunity for RC is largely preserved for participants who subsequently elect to undergo RC after recurrence. These long-term efficacy data support the use of pembrolizumab in participants with BCG-unresponsive HR NMIBC.

Funding: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA