ASCO GU 2021: Pembrolizumab for the Treatment of Patients with High-Risk Non-Muscle-Invasive Bladder Cancer Unresponsive to Bacillus Calmette-Guérin: Extended Follow-up of KEYNOTE-057 Cohort A

( Standard of care for high-risk non-muscle-invasive bladder cancer (NMIBC) is transurethral resection of the bladder tumor followed by intravesical Bacillus Calmette-Guérin (BCG) immunotherapy, although many patients will become BCG-unresponsive and experience recurrence within 12 months. Pembrolizumab was approved in January 2020 for treatment of patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected to not undergo cystectomy based on interim results from 96 patients in the open-label, single-arm, multicenter, Phase II KEYNOTE-057 (NCT02625961) study. At the 2021 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium, Dr. Arjun Balar and colleagues presented updated efficacy and safety results with an extended minimum follow-up of 26.3 months from KEYNOTE-057 cohort A.

KEYNOTE-057 enrolled patients aged ≥18 years with histologically confirmed BCG–unresponsive high-risk carcinoma in situ, with or without papillary tumors, who were ineligible for or declined radical cystectomy to receive pembrolizumab 200 mg Q3W for up to 24 months or until disease persistence, recurrence, progression, or unacceptable toxicity. The primary endpoint for this trial was complete response rate, and key secondary endpoints included duration of response and safety. The trial schema for KEYNOTE-057 is as follows:

trial schema for KEYNOTE 057

Overall, 101 patients received pembrolizumab and 96 were included in the efficacy analysis (five patients did not meet BCG-unresponsive criteria). The median age of patients was 73 years (range: 44-92), and patients received a median of 12.0 (range: 7.0-45.0) BCG instillations. In this updated analysis, the median time from enrollment to data cutoff date of May 25, 2020, was 36.4 months (range: 26.3-48.5). Of 96 patients, the complete response rate was 40.6% (95% confidence interval [CI] 30.7-51.1) at first evaluable disease assessment, and the median duration of response was 16.2 months (range: 0.0+ to 36.2). Among 39 responders, 13 (33.3%) remained in complete response ≥18 months and 9 (23.1%) remained in complete response ≥24 months as of the data cutoff date:

time to CR and recurrence of HR NMIBC in patients who have experienced CR

No patient progressed to muscle-invasive bladder cancer while on study treatment based on protocol-specified disease assessments. The complete response rate was generally consistent with the primary analysis across protocol-prespecified subgroups, including PD-L1 expression status. There were 40 patients (41.7%) that underwent radical cystectomy after discontinuation of pembrolizumab: 35 patients (88%) had no pathologic upstaging to muscle-invasive bladder cancer, two (5%) had no available pathology data, and three (8%) had evidence of muscle-invasive bladder cancer (all non-responders):

pathologic staging at time of radical cystectomy in patients who discontinued pembrolizumab

For other subsequent treatments, 30 of 96 patients (31.3%) received additional intravesical therapy (ie. BCG), 27 of 96 (28.1%) underwent local procedures (ie. transurethral resection of bladder tumor [TURBT]), and 10 of 96 (10.4%) received systemic therapy. In 101 patients, treatment-related adverse events occurred in 67 patients (66.3%), most frequently diarrhea, fatigue, and pruritus (10.9% each). Grade 3/4 treatment-related adverse events occurred in 13 patients (12.9%). Twenty-two patients (21.8%) experienced immune-related adverse events, of which 3.0% were grade 3-4. Seven patients (6.9%) discontinued due to treatment-related adverse events and there were no grade 5 events.

Dr. Balar concluded his presentation of updated data from the KEYNOTE-057 trial with the following conclusions:

  • With more than three years of follow-up data, pembrolizumab continues to show clinically meaningful, antitumor activity in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer with CIS (with or without papillary disease) who are ineligible for or have elected not to undergo radical cystectomy
  • The use of pembrolizumab did not seem to limit the opportunity to undergo radical cystectomy or other subsequent therapies
  • Rates of pathological upstaging to muscle-invasive bladder cancer were low for patients who underwent radical cystectomy after discontinuation of pembrolizumab
  • Pembrolizumab monotherapy had a manageable safety profile consistent with what has been reported
  • Results from this analysis provide compelling evidence that pembrolizumab should be considered an effective nonsurgical treatment option in patients with BCG-unresponsive CIS of the bladder who are ineligible for or decline to undergo radical cystectomy
Presented by: Arjun Balar, MD, Medical Oncologist, Director, Genitourinary Medical Oncology Program, Perlmutter Cancer Center, New York University Langone Health, New York, New York

Written by: Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, Georgia, Twitter: @zklaassen_md during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021