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

Arjun V. Balar*, Ashish M. Kamat, Girish S. Kulkarni, Edward M. Uchio, Joost L. Boormans, Mathieu Roumiguié, Laurence E.M. Krieger, Eric A. Singer, Dean F. Bajorin, Petros Grivas, Ho Kyung Seo, Hiroyuki Nishiyama, Badrinath R. Konety, Haojie Li, Kijoeng Nam, Ekta Kapadia, Tara Frenkl, Ronald de Wit

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

120 Citations (Scopus)

Abstract

Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: Merck Sharp & Dohme.

Original languageEnglish
Pages (from-to)919-930
Number of pages12
JournalThe Lancet Oncology
Volume22
Issue number7
DOIs
Publication statusPublished - 1 Jul 2021

Bibliographical note

Funding Information:
AVB has received research funding from AstraZeneca/MedImmune, Genentech/Roche, Merck Sharp & Dohme, and Seattle Genetics; has been a consultant to AstraZeneca/MedImmune, Cerulean Pharma, Genentech/Roche, Incyte, Merck Sharp & Dohme, Pfizer/EMD Serono, and Seattle Genetics/Astellas; and has received honoraria from AstraZeneca/MedImmune, Genentech/Roche, and Merck Sharp & Dohme. AMK has received research funding from FKD Industries and Merck Sharp & Dohme; has received honoraria from UroToday Publishing and EAU (EU Oncology); has been a consultant to Merck Sharp & Dohme, Bristol Myers Squibb, Imagin, Eisai, Arquer, MDX Health, Photocure, AstraZeneca, Tesaro, Abbott Molecular, US Biotest, Ferring, and BioClinica; has received travel expenses from Pfizer Japan; holds patents for CyPRIT-Cytokine Panel for Response to Intravesical Immunotherapy; and is the president of the International Bladder Cancer Group and the International Bladder Cancer Network. GSK has served on advisory boards for Merck, Bristol Myers Squibb, Roche, Ferring, Janssen, and Theralase and has received honoraria from AbbVie, TerSera, Sanofi, and Biosyent. EMU has received research funding from Merck, Pfizer, Astellas, Dendreon, Myriad, Janssen, Bayer, and Blue Earth. JLB has received research funding from Decipher Biosciences and has been a consultant to Bristol Myers Squibb, Ismar Healthcare, Ambu, Roche, Merck Sharp & Dohme, and Janssen. MR has been a consultant to Invectys, Arquer, and Janssen, and has received honoraria from Ipsen, Ferring, AstraZeneca, Pierre Fabre, and Astellas. LEMK has received honoraria from and has been a consultant for Ipsen, Bristol Myers Squibb, Merck Sharp & Dohme, Astellas, Bayer, Novartis, and Pfizer; has provided expert testimony for Ipsen; has participated in a speakers' bureau for Merck Sharp & Dohme, Bristol Myers Squibb, and Ipsen; and has received travel expenses from Bristol Myers Squibb, Merck Sharp & Dohme, Ipsen, and Astellas. EAS has received research support (clinical trial) from Astellas/Medivation. PG has been a consultant to AstraZeneca, Bayer, Bristol Myers Squibb, Clovis Oncology, Driver, EMD Serono, Exelixis, Foundation Medicine, GlaxoSmithKline, Genentech, Genzyme, Heron Therapeutics, Janssen, Merck, Mirati Therapeutics, Pfizer, Roche, Seattle Genetics, and QED Therapeutics; has participated in an educational programme for Bristol Myers Squibb; and received institutional research funding from AstraZeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Clovis Oncology, Debiopharm, Genentech, GlaxoSmithKline, Immunomedics, Kure It Cancer Research, Merck, Mirati Therapeutics, Oncogenex, Pfizer, and QED Therapeutics. HKS has been a consultant to Merck Sharp & Dohme, Genentech/Roche, Bristol Myers Squibb, Boehringer Ingelheim, and Janssen; and has received research funding from Merck Sharp & Dohme, AstraZeneca, Genentech/Roche, Bristol Myers Squibb, Baselia, and Astellas. HN has received research funding from Astellas, Ono Pharmaceuticals, and Takeda Pharmaceuticals and has participated in speakers' bureaus for Merck Sharp & Dohme and Chugai Pharmaceuticals. BRK has received research funding from Genomic Health, Merck Sharp & Dohme, Bristol Myers Squibb, and Photocure and has been a consultant to Photocure, Pacific Edge, TARIS Biomedical, Boston Scientific, and NxTHERA. HL, KN, and EK are employed by Merck Sharp & Dohme. TF is an employee of Merck Sharp & Dohme; has stock ownership in Merck Sharp & Dohme, Amicus, GlaxoSmithKline, and AstraZeneca; and has a spouse who is an employee of Amicus Therapeutics and who is on the board of directors for VenatoRx. RdW has received research funding from Bayer and Sanofi; has been a consultant to Astellas, Merck Sharp & Dohme, Roche/Genentech, and Sanofi; and has received honoraria from Astellas, Bayer, Janssen, Merck Sharp & Dohme, Roche/Genentech, and Sanofi. DFB declares no competing interests.

Publisher Copyright:
© 2021 Elsevier Ltd

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this