학술논문
Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG (KEYNOTE-057): a single-arm, multicentre, phase 2 trial.
Document Type
Academic Journal
Author
Necchi A; Vita-Salute San Raffaele University, IRCCS San Raffaele Hospital, Milan, Italy. Electronic address: necchi.andrea@hsr.it.; Roumiguié M; Institut Universitaire du Cancer Toulouse-Oncopole CHU, Toulouse, France.; Kamat AM; The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Shore ND; Carolina Urologic Research Center, Myrtle Beach, SC, USA.; Boormans JL; Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands.; Esen AA; Dokuz Eylül University, Izmir, Turkey.; Lebret T; Hôpital Foch, Université Paris-Saclay, Université Versailles Saint-Quentin-en-Yvelines, Suresnes, France.; Kandori S; Department of Urology, University of Tsukuba, Tsukuba, Japan.; Bajorin DF; Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Krieger LEM; Genesis Care, St Leonards, NSW, Australia.; Niglio SA; Laura & Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health, New York, NY, USA.; Uchio EM; UCI Health, Orange, CA, USA.; Seo HK; National Cancer Center, Goyang, South Korea.; de Wit R; Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands.; Singer EA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.; Grivas P; University of Washington and Fred Hutchinson Cancer Center, Seattle, WA, USA.; Nishiyama H; Department of Urology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.; Li H; Merck & Co, Rahway, NJ, USA.; Baranwal P; Merck & Co, Rahway, NJ, USA.; Van den Sigtenhorst-Fijlstra M; MSD Netherlands, Haarlem, Netherlands.; Kapadia E; Merck & Co, Rahway, NJ, USA.; Kulkarni GS; University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.
Source
Publisher: Lancet Pub. Group Country of Publication: England NLM ID: 100957246 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1474-5488 (Electronic) Linking ISSN: 14702045 NLM ISO Abbreviation: Lancet Oncol Subsets: MEDLINE
Subject
Language
English
Abstract
Background: The KEYNOTE-057 trial evaluated activity and safety of pembrolizumab in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer who were ineligible for or declined radical cystectomy. In cohort A (patients with carcinoma in situ, with or without papillary tumours) of the KEYNOTE-057 study, pembrolizumab monotherapy led to a complete response rate of 41% at 3 months, and 46% of responders maintained a response lasting at least 12 months. Here, we evaluate pembrolizumab monotherapy in cohort B of patients with papillary tumours without carcinoma in situ.
Methods: KEYNOTE-057 is a single-arm, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. Cohort B eligible patients were aged 18 years and older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had BCG-unresponsive high-risk non-muscle-invasive bladder cancer with papillary tumours (high-grade Ta or any-grade T1) without carcinoma in situ. Transurethral resection of bladder tumour within 12 weeks of first pembrolizumab dose was required. Patients received pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles. Primary endpoint was 12-month disease-free survival of high-risk non-muscle-invasive bladder cancer or progressive disease as assessed by cystoscopy, cytology, and central pathology and radiology review. Activity was assessed in all patients who received at least one dose of the study drug and had a baseline evaluation. 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 April 12, 2016, and June 17, 2021, 132 patients (104 [79%] men and 28 [21%] women) who had received a median of ten (IQR 9-15) previous BCG instillations were enrolled into cohort B of the study. Patients received a median of 10 cycles (IQR 6-27) of pembrolizumab. At data cutoff date, Oct 20, 2022, median follow-up was 45·4 months (IQR 36·4-59·3) and five (4%) of 132 patients remained on treatment. The 12-month disease-free survival was 43·5% (95% CI 34·9-51·9). Treatment-related adverse events occurred in 97 (73%) of 132 patients; 19 (14%) had a grade 3 or 4 treatment-related adverse event; the most common grade 3 or 4 treatment-related adverse events were colitis (in three [2%] patients) and diarrhoea (in two [2%]). 17 (13%) of 132 patients experienced serious treatment-related adverse events, of which colitis (three patients [2%]) was most common. No treatment-related deaths occurred.
Interpretation: Pembrolizumab monotherapy showed antitumour activity and manageable toxicity in patients with BCG-unresponsive high-risk Ta or T1 bladder cancer without carcinoma in situ and could potentially be a suitable treatment option for patients who decline or are ineligible for radical cystectomy. Findings will need to be confirmed in a randomised controlled trial.
Funding: Merck Sharp & Dohme.
Competing Interests: Declaration of interests AN reports grants to his institution from Bristol Myers Squibb, Gilead, and Merck Sharp & Dohme (MSD); personal consulting fees from AstraZeneca, Bristol Myers Squibb, Catalym, Gilead, Janssen, MSD, and Roche; and support for attending meetings or travel from AstraZeneca, Bristol Myers Squibb, Catalym, Gilead, Janssen, MSD, and Roche. MR served as a consultant for Astellas Pharma, AstraZeneca, Pfizer, Janssen Oncology, Bayer, Ferring, Pierre Fabre, Photocure, Oncodiag, and Bristol Myers Squibb. AMK reports grants from Arquer Diagnostics, EnGene, Ferring, Patient-Centered Outcomes Research Institute, PhotoCure, Seagen, and SWOG; consulting fees from Astellas Pharma, Biological Dynamics, Bristol Myers Squibb, CG Oncology, Cystotech, Eisai, EnGene, Ferring, Imagin Medical, Imvax, Incyte, Janssen, Medac, MSD, Nonagen Bioscience, Pfizer, PhotoCure, Protara Therapeutics, Roche, Seagen, Sessen Bio, Theralase, Urogen Pharma, US Biotest, and Vivet Therapeutics; has a joint patent with MD Anderson Cancer Center for CyPRIT (Cytokine Predictors of Response to Intravesical Therapy); and holds a leadership or fiduciary role for a board or committee for European Urology Oncology, International Bladder Cancer Group (IBCG), International Bladder Cancer Network (IBCN), Journal of Urology, and UroToday. NDS reports consulting fees from AbbVie, Accord, Alessa Therapeutics, Amgen, Antev, Arquer, Asieris, Astellas, AstraZeneca, Aura Biosciences, Bayer, Bioprotect, Bristol Myers Squibb, Boston Scientific, CG Oncology, Clarity, Cold Genesys, Dendreon, Exact Imaging, Genetench/Roche, Ferring, Fize Medical, Foundation Medicine, Genesis Care, Immunity Bio, Incyte, Invitae, Janssen, Lantheus, Lilly, MDX Health, MSD, Minomic, Myovant, Myriad, Nonagen, Novartis Nymox, Palette Life, PlatformQ, Pacific Edge, Pfizer, Preview, Profound Medical, Promaxo, Protara, PhotoCure, Propella, Sanofi Genzyme, Speciality Networks, Telix, Tolmar, and Urogen; and holds a leadership or fiduciary role for a board or committee for Alessa and PhotoCure. JLB reports grants to his institution from Merck, MSD, and Vitroscan; consulting fees to his institution from AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck/Pfizer, and MSD; and honoraria to his institution from Astellas. TL reports personal honoraria from Ipsen and Bristol Myers Squibb and support for attending meetings or travel from Pfizer. DFB reports support for this manuscript from MSD; grants from Bristol Myers Squibb and MSD; consulting fees from Bristol Myers Squibb and MSD; honoraria from Bristol Myers Squibb; participation on a data safety monitoring board or advisory board for Bristol Myers Squibb and MSD; and NCI grant P30 CA008748. LEMK served on a speaker's bureau for MSD and received honoraria for speaker's bureau and lectures from MSD. EMU reports grants from Merck, Seagen, CG Oncology, and Pfizer and honoraria from Merck and Pfizer. HKS reports research support for this manuscript from MSD; consulting fees from MSD; and honoraria for lectures from MSD. RdW reports support to his institution for this manuscript from MSD; personal consulting fees from Astellas and MSD; personal honoraria for lectures from Astellas and Bayer; and participation on an advisory board for Astellas and MSD. EAS reports research support to his institution from Astellas/Medivation and participation on a data safety monitoring board or advisory board for Aura Biosciences, Johnson & Johnson, MSD, and Vyriad. PG reports support for this manuscript from MSD; consultancy role for 4D Pharma, Aadi Bioscience, AbbVie, Asieris Pharmaceuticals, Astellas, AstraZeneca, BostonGene, Bristol Myers Squibb, CG Oncology, Dyania Health, Exelixis, Fresenius Kabi, G1 Therapeutics, Genentech, Gilead Sciences, Guardant Health, ImmunityBio, Infinity Pharmaceuticals, Janssen, Lucence, Merck, Mirati Therapeutics, MSD, Pfizer, PureTech, QED Therapeutics, Regeneron, Roche, Seattle Genetics, Silverback Therapeutics, Strata Oncology, and UroGen Pharma; research support to his institution from ALX Oncology, Acrivon Therapeutics, Bavarian Nordic, Bristol Myers Squibb, Debiopharm Group, Genentech, G1 Therapeutics, Gilead Sciences, GSK, Merck, Mirati Therapeutics, MSD, Pfizer, and QED Therapeutics; and participation on a Data Safety Monitoring or Advisory Board for Bristol Myers Squibb and Strata Oncology. HN reports support for this manuscript from MSD; grants to his institution from Ono Pharmaceutical; contracts to his institution from Astellas and Chugai Pharma; consulting fees from AstraZeneca, Janssen, MSD, and Ono Pharmaceutical; and personal honoraria for speaker's bureaus from Astellas, AstraZeneca, Bristol Myers Squibb, Merck Biopharma, MSD, Nippon Kayaku, and Ono Pharmaceutical. HL is an employee of MSD and holds stock in Merck & Co, Rahway, NJ, USA. PB is a contractor for MSD, a subsidiary of Merck & Co, Rahway, NJ, USA. MVdS-F is an employee of MSD Netherlands and holds stock in Merck & Co, Rahway, NJ, USA. EK is an employee of MSD and holds stock in Merck & Co, Rahway, NJ, USA. GSK reports nonfinancial support for this manuscript from MSD; consulting fees from Astellas, AstraZeneca, Janssen, MSD, PhotoCure, TerSera, Tolmar, and Verity; honoraria from Bristol Myers Squibb, EMD Serono, Janssen, Knight Pharmaceuticals, MSD, Novartis, Pfizer, PhotoCure, Theralase, Verity; and a leadership role (vice chair research) for Bladder Cancer Canada. All other authors declare no competing interests.
(Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)
Methods: KEYNOTE-057 is a single-arm, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. Cohort B eligible patients were aged 18 years and older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had BCG-unresponsive high-risk non-muscle-invasive bladder cancer with papillary tumours (high-grade Ta or any-grade T1) without carcinoma in situ. Transurethral resection of bladder tumour within 12 weeks of first pembrolizumab dose was required. Patients received pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles. Primary endpoint was 12-month disease-free survival of high-risk non-muscle-invasive bladder cancer or progressive disease as assessed by cystoscopy, cytology, and central pathology and radiology review. Activity was assessed in all patients who received at least one dose of the study drug and had a baseline evaluation. 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 April 12, 2016, and June 17, 2021, 132 patients (104 [79%] men and 28 [21%] women) who had received a median of ten (IQR 9-15) previous BCG instillations were enrolled into cohort B of the study. Patients received a median of 10 cycles (IQR 6-27) of pembrolizumab. At data cutoff date, Oct 20, 2022, median follow-up was 45·4 months (IQR 36·4-59·3) and five (4%) of 132 patients remained on treatment. The 12-month disease-free survival was 43·5% (95% CI 34·9-51·9). Treatment-related adverse events occurred in 97 (73%) of 132 patients; 19 (14%) had a grade 3 or 4 treatment-related adverse event; the most common grade 3 or 4 treatment-related adverse events were colitis (in three [2%] patients) and diarrhoea (in two [2%]). 17 (13%) of 132 patients experienced serious treatment-related adverse events, of which colitis (three patients [2%]) was most common. No treatment-related deaths occurred.
Interpretation: Pembrolizumab monotherapy showed antitumour activity and manageable toxicity in patients with BCG-unresponsive high-risk Ta or T1 bladder cancer without carcinoma in situ and could potentially be a suitable treatment option for patients who decline or are ineligible for radical cystectomy. Findings will need to be confirmed in a randomised controlled trial.
Funding: Merck Sharp & Dohme.
Competing Interests: Declaration of interests AN reports grants to his institution from Bristol Myers Squibb, Gilead, and Merck Sharp & Dohme (MSD); personal consulting fees from AstraZeneca, Bristol Myers Squibb, Catalym, Gilead, Janssen, MSD, and Roche; and support for attending meetings or travel from AstraZeneca, Bristol Myers Squibb, Catalym, Gilead, Janssen, MSD, and Roche. MR served as a consultant for Astellas Pharma, AstraZeneca, Pfizer, Janssen Oncology, Bayer, Ferring, Pierre Fabre, Photocure, Oncodiag, and Bristol Myers Squibb. AMK reports grants from Arquer Diagnostics, EnGene, Ferring, Patient-Centered Outcomes Research Institute, PhotoCure, Seagen, and SWOG; consulting fees from Astellas Pharma, Biological Dynamics, Bristol Myers Squibb, CG Oncology, Cystotech, Eisai, EnGene, Ferring, Imagin Medical, Imvax, Incyte, Janssen, Medac, MSD, Nonagen Bioscience, Pfizer, PhotoCure, Protara Therapeutics, Roche, Seagen, Sessen Bio, Theralase, Urogen Pharma, US Biotest, and Vivet Therapeutics; has a joint patent with MD Anderson Cancer Center for CyPRIT (Cytokine Predictors of Response to Intravesical Therapy); and holds a leadership or fiduciary role for a board or committee for European Urology Oncology, International Bladder Cancer Group (IBCG), International Bladder Cancer Network (IBCN), Journal of Urology, and UroToday. NDS reports consulting fees from AbbVie, Accord, Alessa Therapeutics, Amgen, Antev, Arquer, Asieris, Astellas, AstraZeneca, Aura Biosciences, Bayer, Bioprotect, Bristol Myers Squibb, Boston Scientific, CG Oncology, Clarity, Cold Genesys, Dendreon, Exact Imaging, Genetench/Roche, Ferring, Fize Medical, Foundation Medicine, Genesis Care, Immunity Bio, Incyte, Invitae, Janssen, Lantheus, Lilly, MDX Health, MSD, Minomic, Myovant, Myriad, Nonagen, Novartis Nymox, Palette Life, PlatformQ, Pacific Edge, Pfizer, Preview, Profound Medical, Promaxo, Protara, PhotoCure, Propella, Sanofi Genzyme, Speciality Networks, Telix, Tolmar, and Urogen; and holds a leadership or fiduciary role for a board or committee for Alessa and PhotoCure. JLB reports grants to his institution from Merck, MSD, and Vitroscan; consulting fees to his institution from AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck/Pfizer, and MSD; and honoraria to his institution from Astellas. TL reports personal honoraria from Ipsen and Bristol Myers Squibb and support for attending meetings or travel from Pfizer. DFB reports support for this manuscript from MSD; grants from Bristol Myers Squibb and MSD; consulting fees from Bristol Myers Squibb and MSD; honoraria from Bristol Myers Squibb; participation on a data safety monitoring board or advisory board for Bristol Myers Squibb and MSD; and NCI grant P30 CA008748. LEMK served on a speaker's bureau for MSD and received honoraria for speaker's bureau and lectures from MSD. EMU reports grants from Merck, Seagen, CG Oncology, and Pfizer and honoraria from Merck and Pfizer. HKS reports research support for this manuscript from MSD; consulting fees from MSD; and honoraria for lectures from MSD. RdW reports support to his institution for this manuscript from MSD; personal consulting fees from Astellas and MSD; personal honoraria for lectures from Astellas and Bayer; and participation on an advisory board for Astellas and MSD. EAS reports research support to his institution from Astellas/Medivation and participation on a data safety monitoring board or advisory board for Aura Biosciences, Johnson & Johnson, MSD, and Vyriad. PG reports support for this manuscript from MSD; consultancy role for 4D Pharma, Aadi Bioscience, AbbVie, Asieris Pharmaceuticals, Astellas, AstraZeneca, BostonGene, Bristol Myers Squibb, CG Oncology, Dyania Health, Exelixis, Fresenius Kabi, G1 Therapeutics, Genentech, Gilead Sciences, Guardant Health, ImmunityBio, Infinity Pharmaceuticals, Janssen, Lucence, Merck, Mirati Therapeutics, MSD, Pfizer, PureTech, QED Therapeutics, Regeneron, Roche, Seattle Genetics, Silverback Therapeutics, Strata Oncology, and UroGen Pharma; research support to his institution from ALX Oncology, Acrivon Therapeutics, Bavarian Nordic, Bristol Myers Squibb, Debiopharm Group, Genentech, G1 Therapeutics, Gilead Sciences, GSK, Merck, Mirati Therapeutics, MSD, Pfizer, and QED Therapeutics; and participation on a Data Safety Monitoring or Advisory Board for Bristol Myers Squibb and Strata Oncology. HN reports support for this manuscript from MSD; grants to his institution from Ono Pharmaceutical; contracts to his institution from Astellas and Chugai Pharma; consulting fees from AstraZeneca, Janssen, MSD, and Ono Pharmaceutical; and personal honoraria for speaker's bureaus from Astellas, AstraZeneca, Bristol Myers Squibb, Merck Biopharma, MSD, Nippon Kayaku, and Ono Pharmaceutical. HL is an employee of MSD and holds stock in Merck & Co, Rahway, NJ, USA. PB is a contractor for MSD, a subsidiary of Merck & Co, Rahway, NJ, USA. MVdS-F is an employee of MSD Netherlands and holds stock in Merck & Co, Rahway, NJ, USA. EK is an employee of MSD and holds stock in Merck & Co, Rahway, NJ, USA. GSK reports nonfinancial support for this manuscript from MSD; consulting fees from Astellas, AstraZeneca, Janssen, MSD, PhotoCure, TerSera, Tolmar, and Verity; honoraria from Bristol Myers Squibb, EMD Serono, Janssen, Knight Pharmaceuticals, MSD, Novartis, Pfizer, PhotoCure, Theralase, Verity; and a leadership role (vice chair research) for Bladder Cancer Canada. All other authors declare no competing interests.
(Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)