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Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study


Standard treatment for high-risk non-muscle-invasive bladder cancer is transurethral resection of bladder tumour followed by intravesical BCG immunotherapy. However, despite high initial responses rates, up to 50% of patients have recurrence or become BCG-unresponsive. PD-1 pathway activation is implicated in BCG resistance. In the KEYNOTE-057 study, we evaluated pembrolizumab, a PD-1 inhibitor, in BCG-unresponsive non-muscle-invasive bladder cancer.


We did this open-label, single-arm, multicentre, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. In cohort A of the trial, adults aged 18 years or older with histologically confirmed BCG-unresponsive carcinoma in situ of the bladder, with or without papillary tumours, with an Eastern Cooperative Oncology Group performance status of 0-2, and who were ineligible for or declined radical cystectomy were enrolled. All enrolled patients were assigned to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 24 months or until centrally confirmed disease persistence, recurrence, or progression; unacceptable toxic effects; or withdrawal of consent. The primary endpoint was clinical complete response rate (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 study drug. Patient follow-ups were done every 3 months for the first 2 years and every 6 months thereafter for up to 5 years. Efficacy was assessed in all patients who received at least one dose of the study drug and met BCG-unresponsive criteria. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing.


Between Dec 9, 2015, and April 1, 2018, we screened 334 patients for inclusion. 186 patients did not meet inclusion criteria, and 47 patients were assigned to cohort B (patients with BCG-unresponsive high grade Ta or any grade T1 papillary disease without carcinoma in situ; results will be reported separately). 101 eligible patients were enrolled and assigned to receive pembrolizumab. All 101 patients received at least one dose of the study drug and were included in the safety analysis. Five patients had disease that did not meet the US Food and Drug Administration definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore not included in the efficacy analysis (n=96). Median follow-up was 36·4 months (IQR 32·0-40·7). 39 (41%; 95% CI 30·7-51·1) of 96 patients with BCG-unresponsive carcinoma in situ of the bladder with or without papillary tumours had a complete response at 3 months. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients; the most common were arthralgia (in two [2%] patients) and hyponatraemia (in three [3%] patients). Serious treatment-related adverse events occurred in eight (8%) patients. There were no deaths that were considered treatment related.


Pembrolizumab monotherapy was tolerable and showed promising antitumour activity in patients with BCG-unresponsive non-muscle-invasive bladder cancer who declined or were ineligible for radical cystectomy and should be considered a a clinically active non-surgical treatment option in this difficult-to-treat population.


Merck Sharp & Dohme.

Expert's summary

By Dr. Francesco Soria

The treatment of patients with NMIBC failing BCG is still a matter of debate. Standard treatment is usually represented by radical cystectomy, which is able to provide good long-term oncological outcomes at the cost of high perioperative morbidity and non-trivial mortality; thus probably representing an overtreatment in a non-negligible percentage of cases.

Since 2020, the only FDA-approved conservative therapy for CIS-patients failing BCG was intravesical Valrubicin, with a reported complete response rate of 18%. Several other conservative treatments including different intravesical chemotherapy regimens and device-assisted therapies have been evaluated, with reported conflicting results.

In this trial, Balar et al. tested the efficacy of pembrolizumab in patients with BCG unresponsive CIS of the bladder, with or without papillary tumour. The rationale of this trial relies on the efficacy of this PD-1 inhibitor in metastatic urothelial carcinoma (i.e. KN-052). Overall, 40% of patients experienced a complete response. Around 1 out of 2 patients who experienced a complete response, maintained their response for 12 months or longer, demonstrating the efficacy of pembrolizumab in this setting. At the beginning of 2020, pembrolizumab was granted FDA approval based on the results of this KN-057 trial.

At present, we are now supporting the emergence of different effective therapies for the treatment of BCG-unresponsive disease. Similar results of efficacy have been reported for the PD-L1 inhibitor atezolizumab (SWOG S1605, NCT02844816) as well and recently, for Nadofaragen-Firadenovec (3-months complete response of 53%, with a duration of response of 12 months or longer in 45% of the responders). With the hope that these results of efficacy will be confirmed, also in high-risk patients without CIS, the findings of these trials will revolutionize the paradigm of treatment of patients failing BCG.

The next challenge will be the selection of patients who will benefit from conservative treatment, and to reserve early radical cystectomy for patients who experience disease recurrence/progress despite therapy. Moreover, having available different effective therapies, there is an urgent need for accurate biomarkers able to ideally select the right treatment for the right patient.

Expert's comment

In this single-arm multicentre phase II trial patients with Bacillus Calmette-Guérin (BCG) unresponsive carcinoma in situ (CIS) of the bladder, with or without papillary tumour, were assigned to receive pembrolizumab (a PD-1 inhibitor) 200mg intravenously every 3 weeks up to 24 months or in case of disease recurrence. The primary endpoint was clinical complete response, defined as the absence of high-risk non-muscle-invasive Bladder Cancer (NMIBC) or disease progression at 3 months. Overall, 101 eligible patients were treated and included for safety analysis while 96 were available for the efficacy analysis. In accordance to the definition of the U.S. Food and Drug Administration (FDA), 5 patients were excluded as they were not BCG unresponsive.

Within a median follow-up of 36 months, 39 (41%) patients experienced complete response. The median duration of complete response was 16 months, and 48% of responders maintained the response for 12 months or longer. At 12 months, the estimated progression-free survival to worsening of grade or stage or death was 83%. Adverse events occurred in two-third of the patients, and grade 3-4 adverse events occurred in 13% of the population. No treatment-related deaths were reported.