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Split decision with published pembrolizumab data in bladder cancer


Results were mixed for 2 pembrolizumab (Keytruda) bladder cancer trials recently published in the Lancet Oncology. Findings from the KEYNOTE-0571 trial showed success with the PD-1 inhibitor in non-muscle invasive bladder cancer (NMIBC); however, combining the agent with chemotherapy in the KEYNOTE-3612 trial did not improve outcomes in metastatic urothelial carcinoma.

KEYNOTE-057 trial

The multicenter, open-label, single-arm, multicohort, phase 2 KEYNOTE-057 trial included 101 patients with BCG-unresponsive, high-risk NMIBC with carcinoma in situ (CIS) with or without papillary tumors who were ineligible for or did not undergo cystectomy (cohort A). A second cohort, Cohort B, enrolled patients with papillary disease without CIS.

Pembrolizumab was administered at 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC, or disease progression. Disease was assessed every 12 weeks, and those who did not have disease progression could receive treatment for up to 2 years.

The results published in Lancet Oncology were for cohort A. In this group, the median age was 73 years (interquartile range, 44-92), 84% of patients were male, and 16% of patients were female. The ECOG performance score was 0 for 73% of patients and 1 for 27% of patients.

The median number of prior BCG instillations was 12. Regarding PD-L1 status, 38% of patients had a combined positive score (CPS) ≥10, 57% had a CPS <10, and PD-L1 level was unknown for 5% of patients.

There were 96 patients in the efficacy evaluable population. In this group, the complete response rate at 3 months was 40.6% (n = 39). At the time of the study, none of the patients had progressed to stage T2 disease.

The response generated by pembrolizumab was durable. The median duration of response was 16.2 months and 18 (46%) of the 39 responding patients maintained their response for 1 year or more.

Forty patients at some point in time after the study underwent cystectomy. Of note, only 3 of these patients had pathological upstaging to muscle-invasive disease or higher. The remainder were organ-confined, non-muscle invasive tumors.

Immune-mediated adverse events (AEs) across all grades occurred in 22% of the overall group of 101 patients who received treatment. There were 3 cases of grade 3/4 immune-mediated AEs: adrenal insufficiency, severe skin reaction, and type 1 diabetes mellitus.

“Pembrolizumab monotherapy was tolerable and showed promising antitumor activity in patients with BCG-unresponsive NMIBC who declined or were ineligible for radical cystectomy and should be considered a clinically active nonsurgical treatment option in this difficult-to-treat population,” first study author Arjun Balar, MD, director, Genitourinary Medical Oncology Program, Medical Director – Clinical Trials Office, Perlmutter Cancer Center, NYU Langone Health, and coauthors wrote in their study conclusion.

Based on the KEYNOTE-057 trial, the FDA approved pembrolizumab in January 2020 for the treatment of patients with BCG-unresponsive, high-risk NMIBC with CIS with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.


The open-label, phase 3 KEYNOTE-361 trial (NCT02853305) randomized 1010 patients with advanced or metastatic urothelial carcinoma to frontline treatment with single-agent pembrolizumab (P), pembrolizumab plus chemotherapy (P + C), or chemotherapy (C) alone. Chemotherapy consisted of cisplatin or carboplatin plus gemcitabine. The coprimary end points for the trial were overall survival (OS) and progression-free survival (PFS). Secondary end points were response, disease control rate, and safety.

The study did not meet its coprimary end points. The median PFS was 8.3 months with P + C, compared with 3.9 months and 7.1 months with P alone and C alone, respectively. The hazard ratio for PFS for P + C versus C was 0.78 (P = .0033). The median OS was 17.0 months for P +C, compared with 15.6 months with P alone and 14.3 months with C alone. The hazard ratio for OS for P + C versus C was 0.86 (P = .0407). The objective response rates were 54.7%, 30.3%, 44.9% for P + C , P, and C, respectively.

Regarding safety, 75.1% of the P + C arm experienced grade 3-5 treatment-related adverse events, compared with 16.9% in the P arm and 71.6% in the C arm. The AE-related discontinuation rates of any drug were 30.9%, 15.9%, and 18.1% in the 3 arms, respectively.

“The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma,” first study author Thomas Powles, MBBS, MRCP, MD, director, Barts Cancer Institute, and coauthors wrote in their conclusion.


1.Balar AV, Kamat AM, Kulkarni GS, et al. 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 [published online ahead of print May 26, 2021]. Lancet Oncol. doi: 10.1016/S1470-2045(21)00147-9

2. Powles T, Csőszi T, Özgüroğlu M, et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial [published online ahead of print May 26, 2021]. Lancet Oncol. doi: 10.1016/S1470-2045(21)00152-2

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