Putative Biomarkers of Clinical Benefit With Pembrolizumab in Advanced Urothelial Cancer: Results from the KEYNOTE-045 and KEYNOTE-052 Landmark Trials

Joaquim Bellmunt*, Ronald de Wit, Yves Fradet, Miguel A. Climent, Daniel P. Petrylak, Jae Lyun Lee, Lawrence Fong, Andrea Necchi, Cora N. Sternberg, Peter H. O’Donnell, Thomas Powles, Elizabeth R. Plimack, Dean F. Bajorin, Arjun V. Balar, Daniel Castellano, Toni K. Choueiri, Stephane Culine, Winald Gerritsen, Howard Gurney, David I. QuinnJacqueline Vuky, Nicholas J. Vogelzang, Razvan Cristescu, Jared Lunceford, Assieh Saadatpour, Andrey Loboda, Junshui Ma, Mohini Rajasagi, James Luke Godwin, Blanca Homet Moreno, Petros Grivas

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)

Abstract

Purpose: In an exploratory analysis, we investigated the association between programmed death ligand 1 (PD-L1), tumor mutational burden (TMB), T-cell–inflamed gene expression profile (TcellinfGEP), and stromal signature with outcomes of pembrolizumab in urothelial carcinoma (UC). Patients and Methods: Patients with advanced UC received first-line pembrolizumab 200 mg every 3 weeks in the single-arm phase II KEYNOTE-052 trial (NCT02335424) and salvage pembrolizumab 200 mg every 3 weeks or chemotherapy (paclitaxel/docetaxel/vinflunine) in the randomized phase III KEYNOTE-045 trial (NCT02256436). The association of each biomarker (continuous variable) with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was evaluated using logistic regression (ORR) and Cox PH (PFS, OS), adjusted for ECOG PS; nominal P values were calculated without multiplicity adjustment (one-sided, pembrolizumab; two-sided, chemotherapy). Significance was prespecified at a ¼ 0.05. Results: In KEYNOTE-052, PD-L1, TMB, and TcellinfGEP were significantly associated with improved outcomes; stromal signature was significantly associated with worse outcomes. In KEYNOTE-045, although findings for TMB and TcellinfGEP with pembrolizumab were consistent with those of KEYNOTE-052, PD-L1 was not significantly associated with improved outcomes, nor was stromal signature associated with worse outcomes with pembrolizumab; chemotherapy was not associated with outcomes in a consistent manner for any of the biomarkers. Hazard ratio (HR) estimates at prespecified cutoffs showed an advantage for pembrolizumab versus chemotherapy regardless of PD-L1 or TMB, with a trend toward lower HRs in the combined positive score ≥10 and the TMB ≥175 mutation/exome subgroup. For TcellinfGEP, PFS and OS HRs were lower in the TcellinfGEP-nonlow subgroup regardless of treatment. Conclusions: Multiple biomarkers characterizing the tumor microenvironment may help predict response to pembrolizumab monotherapy in UC, and potential clinical utility of these biomarkers may be context-dependent.

Original languageEnglish
Pages (from-to)2050-2060
Number of pages11
JournalClinical Cancer Research
Volume28
Issue number10
DOIs
Publication statusPublished - 15 May 2022

Bibliographical note

Funding Information:
Patent 14/588,503) pending. D.F. Bajorin reports grants, personal fees, and other support from Merck, Inc. during the conduct of the study; grants and personal fees from BMS and AstraZeneca; personal fees from Dragonfly and Fidia Farmaceutici outside the submitted work. A.V. Balar reports grants from Merck during the conduct of the study; grants and personal fees from Merck, Genentech, BMS, Seagen, Immunomedics/Gilead, and Pfizer; personal fees from Incyte and Janssen outside the submitted work. D. Castellano reports personal fees from Pfizer, Roche, BMS, AstraZeneca, Novartis, MSD, Ipsen, Eisai, Astellas, Janssen, Bayer, and Sanofi outside the submitted work. T.K. Choueiri reports grants, personal fees, nonfinancial support, and other support from Merck, BMS, Pfizer, Roche, and EMD Serono during the conduct of the study; grants, personal fees, non-financial support, and other support from NCCN panel outside the submitted work; and has a patent for Biomarkers of activity/toxicity from IO pending and issued and a patent for ctDNA pending. T.K. Choueiri also reports institutional and personal, paid and unpaid support for research, advisory boards, consultancy, and honoraria from AstraZeneca, Aravive, Aveo, Bayer, BMS, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH and others), outside the submitted work; Institutional patents filed on molecular mutations and immunotherapy response, and ctDNA; Equity in Tempest, Pionyr, Osel, NuscanDx; Committees NCCN, GU Steering Committee, ASCO/ESMO; Medical writing and editorial assistance support may have been funded by Communications companies in part; No speaker’s bureau; Mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/foreign components; and the institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. T.K. Choueiri is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI; CV provided upon request for scope of clinical practice and research. S. Culine reports personal fees from Bayer, Merck, and Astellas outside the submitted work. W. Gerritsen reports other support from MSD during the conduct of the study; grants from Bayer and Astellas and other support from IqVia outside the submitted work. H. Gurney reports personal fees from BMS, MSD, Pfizer, Merck Serono, Roche, and Ipsen during the conduct of the study; personal fees from Astellas and Janssen outside the submitted work. D.I. Quinn reports personal fees from Astellas, Bayer, Pfizer, AstraZeneca, and Merck outside the submitted work; and employment with Abbvie Research and Development. J. Vuky reports grants from Merck during the conduct of the study; grants from Agendia, Arvinas, Astellas Pharma, Blueprint Medicines, BMS, Clovis Oncology, Deciphera, Eisai, Exelixis, Fortis, Genentech, Ignyta, Incyte, Innocrin Pharma, Lilly, Loxo, Novartis, Pfizer, Polyphor, and Rgenix outside the submitted work. N.J. Vogelzang reports personal fees from Merck (consulting regarding FDA submission; advisory board; and advisory board for Lenvima in collaboration with AstraZeneca), Aveo, Exelixis, Pfizer, BMS, and PER during the conduct of the study. R. Cristescu reports other support from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, during the conduct of the study, and owns stock in Merck & Co., Inc., Kenilworth, NJ, USA. J. Lunceford reports other support from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, outside the submitted work; also has a patent for Angiogenesis and mMDSC gene expression based biomarker of tumor response to PD-1 antagonists pending and a patent for patent WO 2020/167619 pending. A. Saadatpour reports personal fees and other support from Merck & Co., Inc., Kenilworth, NJ, USA, during the conduct of the study. A. Loboda reports other support from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, during the conduct of the study. J. Ma reports other support from Merck & Co, Inc., Kenilworth, NJ, USA, outside the submitted work. M. Rajasagi reports grants from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and stock in Merck & Co., Inc., Kenilworth, NJ, USA, outside the submitted work. J.L. Godwin reports other support from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Agenus outside the submitted work. B. Homet Moreno reports personal fees from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, outside the submitted work. P. Grivas reports grants from Merck during the conduct of the study; grants and personal fees from Merck; grants and personal fees

Funding Information:
The authors thank the patients and their families and caregivers as well as all primary investigators and site personnel for participating in the study. Medical writing and/or editorial assistance was provided by Holly C. Cappelli, PhD, CMPP, and Dana Francis, PhD, of ApotheCom. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding Information:
J. Bellmunt reports personal fees from Pfizer-Merck (Germany), Merck, Genen-tech, AstraZeneca, and BMS; grants from Pfizer-Merck and Takeda outside the submitted work; and author and section editor of UpToDate. R. de Wit reports personal fees from Merck during the conduct of the study; grants and personal fees from Sanofi and Bayer; personal fees from Astellas and Orion outside the submitted work. Y. Fradet reports grants and other support from Merck; personal fees from Astellas, Sanofi, Janssen, AstraZeneca, and Ferring; grants and personal fees from TerSera; and grants from IMV Inc. outside the submitted work. M.A. Climent reports personal fees from Pfizer, MSD, Roche, BMS, EUSA, Ipsen, Astellas, Janssen, Astra, and Merck outside the submitted work. D.P. Petrylak reports other support from Ada Cap (Advanced Accelerator Applications) Amgen, Astellas, AstraZeneca, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, BMS, Clovis Oncology, Eli Lilly, Exelixis, Gilead Sciences, Incyte, Ipsen, Janssen, Mirati, Monopteros, Pfizer, Pharmacyclics, Regeneron Pharmaceuticals, Roche, Seattle Genetics, and Urogen, grants from Ada Cap (Advanced Accelerator Applications), Agensys Inc, Astellas, AstraZeneca, Bayer, BioXcel Therapeutics, BMS, Clovis Oncology, Eisai, Eli Lilly, Endocyte, Genentech, Gilead Sciences, Innocrin, MedImmune, Medivation, Merck, Mirati, Novartis, Pfizer, Progenics, Replimune, Roche, Sanofi Aventis, and Seattle Genetics, and other support from Bellicum (Sold 7/2020), Tyme (sold 10/2019) during the conduct of the study. L. Fong reports grants and personal fees from Merck during the conduct of the study; grants from Abbvie, Bavarian Nordic, and Dendreon and grants and personal fees from BMS, Janssen, and Roche/Genentech outside the submitted work. A. Necchi reports grants from Merck and Gilead, personal fees from Roche and Bayer, Pfizer, BMS, and Ipsen, and grants and personal fees from AstraZeneca, Janssen, and Incyte during the conduct of the study; grants and personal fees from Merck, Janssen, AstraZeneca, and Incyte, and personal fees from Roche, Bayer, Pfizer, and BMS outside the submitted work. C.N. Sternberg reports personal fees from Pfizer, BMS, Sanofi-Genzyme, MSD, Merck, Roche-Genentech, Incyte, Foundation Medicine, Immunomedics, Medscape, UroToday, Janssen, CCO Clinical, NCI, Bayer, Astra-Zeneca, and IMPACT Therapeutics outside the submitted work. P.H. O’Donnell reports grants from Merck during the conduct of the study; grants, personal fees, and other support from Genetech/Roche, Astellas Pharma, Seattle Genetics, and Janssen; other support from Allergan, Nektar, NIH, Dragonfly Therapeutics, and G1 Therapeutics; personal fees from Atheneum Partners, Health Advances, Dedham Group, CLD, Axiom Healthcare Strategies, EMD Serono, IntrinsiQ Specialty Solutions, ISMIE, NAMCP, and Merck; grants and personal fees from Pfizer; grants from Boehringer Ingeleim, AstraZeneca/MedImmune, Acerta Pharma and BMS outside the submitted work. T. Powles reports personal fees from AstraZeneca, BMS, Exelixis, Incyte, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, and Roche; grants from AstraZeneca, Roche, BMS, Exelixis, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, and Eisai; other support from Roche, Pfizer, MSD, AstraZeneca, and Ipsen outside the submitted work. E.R. Plimack reports grants and personal fees from Merck during the conduct of the study; personal fees from AstraZeneca, Infinity Pharma, Pfizer, Astellas, AstraZeneca, Aveo, BMS, Calithera, Exelexis, Flatiron, Genentech, Janssen, MEI, Merck Natera, Pfizer, Regeneron Pharmaceuticals, and Seattle Genetics, and grants from Astellas, BMS, Genentech, and Merck outside the submitted work; also E.R. Plimack has a patent for Methods for screening muscle invasive bladder cancer patients for neoadjuvant chemotherapy responsiveness (US

Publisher Copyright:
©2022 American Association for Cancer Research

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