Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up
- PMID: 36494006
- DOI: 10.1016/j.annonc.2022.11.012
Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up
Abstract
Background: Immune checkpoint inhibitors are a standard therapy in metastatic urothelial carcinoma (UC). Long-term follow-up is necessary to confirm durability of response and identify further safety concerns.
Patients and methods: In KEYNOTE-045, patients with metastatic UC that progressed on platinum-containing chemotherapy were randomly assigned 1:1 to receive pembrolizumab or investigator's choice of paclitaxel, docetaxel, or vinflunine. Primary endpoints were progression-free survival per RECIST version 1.1 by blinded independent central review (BICR) and overall survival. In KEYNOTE-052, cisplatin-ineligible patients with metastatic UC received first-line pembrolizumab. The primary endpoint was objective response rate per RECIST version 1.1 by BICR.
Results: A total of 542 patients (pembrolizumab, n = 270; chemotherapy, n = 272) were randomly assigned in KEYNOTE-045. The median follow-up was 62.9 months (range 58.6-70.9 months; data cut-off 1 October 2020). At 48 months, overall survival rates were 16.7% for pembrolizumab and 10.1% for chemotherapy; progression-free survival rates were 9.5% and 2.7%, respectively. The median duration of response (DOR) was 29.7 months (range 1.6+ to 60.5+ months) for pembrolizumab and 4.4 months (range 1.4+ to 63.1+ months) for chemotherapy; 36-month DOR rates were 44.4% and 28.3%, respectively. A total of 370 patients were enrolled in KEYNOTE-052. The median follow-up was 56.3 months (range 51.2-65.3 months; data cut-off 26 September 2020). The confirmed objective response rate was 28.9% (95% confidence interval 24.3-33.8), and the median DOR was 33.4 months (range 1.4+ to 60.7+ months); the 36-month DOR rate was 44.8%. Most treatment-related adverse events for pembrolizumab in either study were grade 1 or 2 and manageable, which is consistent with prior reports.
Conclusion: With ∼5 years of follow-up, pembrolizumab monotherapy continued to demonstrate durable efficacy with no new safety signals in patients with platinum-resistant metastatic UC and as first-line therapy in cisplatin-ineligible patients.
Clinical trial registry and id: With ClinicalTrials.gov NCT02256436 (KEYNOTE-045); https://clinicaltrials.gov/ct2/show/NCT02256436 and NCT02335424 (KEYNOTE-052); https://clinicaltrials.gov/ct2/show/NCT02335424.
Keywords: cisplatin resistant/refractory; cisplatin-ineligible; pembrolizumab; urothelial carcinoma.
Copyright © 2023 Merck Sharp & Dohme LLC., a subsidiary Merck & Co., Inc., The Author(s). Published by Elsevier Ltd.. All rights reserved.
Conflict of interest statement
Disclosure AVB has received personal fees for serving as a consultant/advisor from Genentech, Incyte, Bristol Myers Squibb, Janssen, Merck, Pfizer, AstraZeneca/MedImmune, Nektar, Seagen, Immunomedics/Gilead, and Istari Oncology; has received personal fees for speaking engagements from Genentech, Merck, and AstraZeneca/MedImmune; has received research funding paid to his institution from Genentech, Merck, AstraZeneca/MedImmune, Nektar, and Immunomedics/Gilead; has served on the Scientific Steering Committee for Merck and Nektar; and holds equity in and has served on the Scientific Advisory Board for EpiVax Oncology and GT Biopharma. DEC has served on the Data Safety Monitoring Board/Advisory Board for Bristol Myers Squibb, Pfizer, Roche, Janssen, Astellas, MSD, Novartis, Merck, and Bayer. PG has received personal fees for serving as a consultant/advisor from Aadi Bioscience, AstraZeneca, Astellas Pharma, Boston Gene, Bristol Myers Squibb, CG Oncology Inc., Dyania Health, EMD Serono, Exelixis, Fresenius Kabi, G1 Therapeutics, Genentech/Roche, Gilead Sciences, Guardant Health, Infinity Pharmaceuticals, Janssen, Lucence Health, MSD, Mirati Therapeutics, Pfizer, PureTech, QED Therapeutics, Regeneron Pharmaceuticals, Seattle Genetics, Silverback Therapeutics, 4D Pharma PLC, UroGen; and has received research funding paid to his institution from Bavarian Nordic, Bristol Myers Squibb, Clovis Oncology, Debiopharm, EMD Serono, G1 Therapeutics, Gilead Sciences, GlaxoSmithKline, MSD, Mirati Therapeutics, Pfizer, and QED Therapeutics. TP has received research funding paid to his institution from AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, and Eisai; has received personal fees for serving as a consultant/advisor from AstraZeneca, Roche, BMS, Exelixis, Ipsen, Incyte, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, and Mashup Ltd.; and has received travel expenses from Roche, Pfizer, MSD, AstraZeneca, and Ipsen. JV has received research funding paid to her institution from Agendia, Arvinas, Astellas Pharma, Blueprint Medicines, Bristol Myers Squibb, Celldex, Clovis Oncology, Deciphera, Eisai, Exelixis, Fortis Therapeutics, Ignyta, Incyte, Innocrin Pharma, Eli Lilly, Loxo, Merck, Novartis, Pfizer, Polyphor, Rgenix, and Roche/Genentech; and has received personal fees for serving as a consultant/advisor from Seattle Genetics/Astellas. YF has received personal fees for serving on advisory boards from Astellas, AstraZeneca, Ferring, Merck, Janssen, Sanofi, TerSera, and IMV Inc; has received research funding paid to his institution from Merck, TerSera, and IMV Inc.; and has received travel expenses from Sanofi and TerSera. JLL has received research funding paid to his institution from Pfizer, Ipsen, Bristol Myers Squibb, MSD, Merck, Roche, AstraZeneca, and Seagen; has served on the Data Safety Monitoring Board/Advisory Board for Pfizer Korea, Astellas Korea, Bristol Myers Squibb, Merck, MSD, and AstraZeneca; and holds stock or stock options in Myovant Sciences, Amgen, Johnson & Johnson, Merck, BeiGene, and Innovent. LF has received research funding paid to his institution from AbbVie, Bavarian Nordic, Bristol Myers Squibb, Dendreon, Janssen, Merck, and Roche/Genentech; and has served on the Data Safety Monitoring Board/Advisory Board for Bristol Myers Squibb, Merck, Merck KGaA, Sutro Biopharma, and Roche/Genentech. NJV has received grants and personal fees from Exelixis, Pfizer, Bristol Myers Squibb, Eisai, and Merck. MAC has received honoraria from Bristol Myers Squibb, Astellas, Janssen, MSD, Sanofi, Bayer, Roche, Pfizer, Novartis, and Ipsen; has received personal fees for serving as a consultant/advisor from Bristol Myers Squibb, MSD, Bayer, Ediciones Universidad de Navarra (EUNSA), Pfizer, Roche, Janssen, Pierre Fabre, and Ipsen; and has received travel expenses from Janssen, Astellas, Roche, Ipsen, and MSD. AN has received personal fees for serving as a consultant/advisor from MSD, Roche, Bayer, AstraZeneca, Clovis Oncology, Janssen, Incyte, Seattle Genetics/Astellas, Bristol Myers Squibb, Rainier Therapeutics, Bicycle Therapeutics, and Basilea Pharmaceutica; has received honoraria from Roche, MSD, AstraZeneca, Janssen, Foundation Medicine, and Astellas; and has received research funding paid to his institution from MSD, AstraZeneca, Gilead, and Bristol Myers Squibb. DPP has received research funding paid to his institution from Advanced Accelerator Applications, Agensys Inc., Astellas, AstraZeneca, Bayer, BioXcel Therapeutics, Bristol Myers Squibb, Clovis Oncology, Eisai, Eli Lilly, Endocyte, Genentech, Gilead Sciences, Innocrin, MedImmune, Medivation, Merck, Mirati, Novartis, Pfizer, Progenics, Replimune, Roche, Sanofi Aventis, and Seattle Genetics; has received personal fees for serving as a consultant from Advanced Accelerator Applications, Amgen, Astellas, AstraZeneca, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Eli Lilly, Exelixis, Gilead Sciences, Incyte, Ipsen, Janssen, Mirati, Monopteros, Pfizer, Pharmacyclics, Regeneron, Roche, Seattle Genetics, and UroGen; and formerly held stock or stock options in Bellicum and TYME. ERP has served on Scientific Advisory Committees for Astellas, AstraZeneca, Aveo, Bristol Myers Squibb, Calithera, Exelixis, Flatiron, Genentech, Janssen, MEI, Merck, Natera, Pfizer, Regeneron, Seattle Genetics, and Infinity Pharma; and has received research funding paid to her institution from Astellas, Bristol Myers Squibb, Genentech, and Merck. JZX and KI are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co Inc., Rahway, NJ, USA, and own stock in Merck & Co., Inc., Rahway, NJ, USA. BHM is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co Inc., Rahway, NJ, USA. JB has received personal fees for serving as a consultant/advisor from Pierre Fabre, Astellas Pharma, Pfizer, Merck, Genentech, Novartis, AstraZeneca/MedImmune, and Bristol Myers Squibb; has received research funding paid to his institution from Millennium, Sanofi, and Pfizer/EMD Serono; has received travel expenses from Pfizer, MSD Oncology, and Ipsen; has received honoraria from UpToDate; and owns stock in Rainier. RdW has received research funding paid to his institution from Bayer and Sanofi; has received personal fees for serving as a consultant/advisor for Merck, Orion, Astellas, Hengrui, Sanofi, and Bayer; has received honoraria from Bayer and Sanofi; and has served on the Data Safety Monitoring Board/Advisory Board for Bristol Myers Squibb, Eisai, Boehringer Ingelheim, and Basilea. PHO has received research funding paid to his institution from the National Institutes of Health, Boehringer Ingelheim, Merck, Genentech/Roche, AstraZeneca/MedImmune, Acerta Pharma, Janssen, Seagen, Astellas Pharma, and Bristol Myers Squibb; has received personal fees for consulting from Genentech/Roche, Merck, Astellas Pharma, Seagen, Atheneum Partners, First World Publications, Health Advances, Janssen, Dedham Group, Pfizer, CLD, Axiom Healthcare Strategies, EMD Serono, and IntrinsiQ Specialty Solutions; has received honoraria from the National Association of Managed Care Physicians, Med Learning Group, and Curio Science; has received travel expenses from Seagen, Astellas, Genentech/Roche, and Janssen; has served on the Data Safety Monitoring Board/Advisory Board for Jansen, Nektar, Dragonfly Therapeutics, and G1 Therapeutics; and formerly held stock or stock options in Allergan. DJV has declared no conflicts of interest. 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