Pembrolizumab in BCG-Unresponsive High-Risk Non–Muscle Invasive Bladder Cancer: KEYNOTE-057

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As reported in The Lancet Oncology by Arjun V. Balar, MD, and colleagues, the phase II KEYNOTE-057 trial showed that pembrolizumab produced enduring responses in a cohort of patients with high-risk non–muscle invasive bladder cancer unresponsive to bacillus Calmette-Guérin (BCG) who were ineligible for or chose not to undergo cystectomy.

Findings in the study cohort supported the January 2020 approval of pembrolizumab for treatment of patients with BCG-unresponsive, high-risk, non–muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Arjun V. Balar, MD

Arjun V. Balar, MD

Study Details

In the multicohort trial, 101 patients (96 evaluable for efficacy) with BCG-unresponsive carcinoma in situ of the bladder, with or without papillary tumors, who were ineligible for or declined radical cystectomy (cohort A) were enrolled from sites in 14 countries between December 2015 and April 2018. Patients received pembrolizumab at 200 mg every 3 weeks for up to 24 months or until centrally confirmed disease persistence, recurrence, or progression, or unacceptable toxicity. The primary endpoint was rate of clinical complete response rate, defined as absence of high-risk non–muscle invasive bladder cancer or progressive disease, assessed by cystoscopy and urine cytology approximately 3 months after the first dose of pembrolizumab.


Median follow-up was 36.4 months (interquartile range = 32.0–40.7 months). Complete response at 3 months was observed in 39 (41%; 95% confidence interval [CI] = 30.7%–51.1%) of 96 evaluable patients. Median duration of complete response was 16.2 months (95% CI = 6.7–36.2 months), with 18 (46%) of 39 responders remaining in complete response for ≥ 12 months.

At 12 months, the estimated progression-free survival to worsening of grade or stage or death was 83% (95% CI = 70.2%–90.4%) and estimated progression-free survival to muscle-invasive or metastatic disease or death was 97% (95% CI = 86.0%–99.2%). Overall survival was 98% (95% CI = 91.9%–99.5%) at 12 months, 95% (95% CI = 87.8%–97.8%) at 24 months, and 91% (83.7%–95.7%) at 36 months.


  • Pembrolizumab produced complete response at 3 months in 41% of patients.
  • Median duration of complete response was 16.2 months, with 46% of responses lasting ≥ 12 months.

Adverse Events

Among the 101 patients include in the safety analysis, treatment-related adverse events of any grade occurred in 67 (66%) and were of grade 3 or 4 in 13 (13%); the most common grade 3 and 4 events were hyponatremia (3%) and arthralgia (2%). Serious treatment-related adverse events occurred in eight patients (8%). Treatment-related adverse events led to discontinuation of treatment in seven patients (7%), with causes consisting of pneumonitis in two patients and autoimmune nephritis, cholestatic hepatitis, hyponatremia, myalgia, and type 1 diabetes in one patient each. Immune-mediated adverse events occurred in 22 patients (22%; grade 3 or 4 in 3), with common events including hypothyroidism (8%) hyperthyroidism (5%), and pneumonitis (3%). No treatment-related deaths were reported. 

The investigators concluded, “Pembrolizumab monotherapy was tolerable and showed promising antitumor activity in patients with BCG-unresponsive non–muscle invasive bladder cancer who declined or were ineligible for radical cystectomy and should be considered a clinically active nonsurgical treatment option in this difficult-to-treat population.”

Dr. Balar, of the Genitourinary Medical Oncology Program, Perlmutter Cancer Center at NYU Langone Health, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Merck Sharp & Dohme. For full disclosures of the study authors, visit

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