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

  • Joaquim Bellmunt
    Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, and IMIM-PSMAR Lab Harvard Medical School, Boston, Massachusetts.
  • Ronald de Wit
    Department of MedOnc, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
  • Yves Fradet
    Department of Surgery/Urology, Centre Hospitalier Universitaire de Québec–Université Laval, Quebec City, QC, Canada.
  • Miguel A. Climent
    Department of Medical Oncology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
  • Daniel P. Petrylak
    Department of Internal Medicine/Medical Oncology, Yale New Haven Health, Smilow Cancer Hospital, New Haven, Connecticut.
  • Jae-Lyun Lee
    Department of Oncology, Asan Medical Center and University of Ulsan College of Medicine, Seoul, South Korea.
  • Lawrence Fong
    Department of Medicine, UCLA, Los Angeles, California.
  • Andrea Necchi
    Department of Medical Oncology, Vita-Salute San Raffaele University and IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy.
  • Cora N. Sternberg
    Englander Institute for Precision Medicine, Department of Hematology and Oncology, Weill Cornell Medicine, Meyer Cancer Center, New York, New York.
  • Peter H. O'Donnell
    Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois.
  • Thomas Powles
    Department of Genitourinary Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
  • Elizabeth R. Plimack
    Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
  • Dean F. Bajorin
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Arjun V. Balar
    Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York.
  • Daniel Castellano
    Department of Medical Oncology, Hospital Universitario 12 de Octubre (CiberOnc), Madrid, Spain.
  • Toni K. Choueiri
    Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Stephane Culine
    Department of Medical Oncology, Hôpital Saint-Louis, Paris, France.
  • Winald Gerritsen
    Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.
  • Howard Gurney
    Department of Medical Oncology, Westmead Hospital and Macquarie University, Sydney, NSW, Australia.
  • David I. Quinn
    Department of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles, California.
  • Jacqueline Vuky
    Department of Medicine/Oncology, Oregon Health & Science University, Portland, Oregon.
  • Nicholas J. Vogelzang
    Department of Medical Oncology, Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada.
  • Razvan Cristescu
    Department of Translational Medicine, Merck & Co., Inc., Kenilworth, New Jersey.
  • Jared Lunceford
    Department of Translational Oncology Statistics, Merck & Co., Inc., Kenilworth, New Jersey.
  • Assieh Saadatpour
    Department of Genome and Biomarker Sciences, Merck & Co., Inc., Kenilworth, New Jersey
  • Andrey Loboda
    Department of Translational Medicine, Merck & Co., Inc., Kenilworth, New Jersey.
  • Junshui Ma
    Department of Translational Oncology Statistics, Merck & Co., Inc., Kenilworth, New Jersey.
  • Mohini Rajasagi
    Department of Oncology Early Development, Merck & Co., Inc., Kenilworth, New Jersey.
  • James Luke Godwin
    Department of Oncology, Merck & Co., Inc., Kenilworth, New Jersey.
  • Blanca Homet Moreno
    Department of Oncology, Merck & Co., Inc., Kenilworth, New Jersey.
  • Petros Grivas
    Department of Medicine, Division of Oncology, University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, Washington.

抄録

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>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).</jats:p> </jats:sec> <jats:sec> <jats:title>Patients and Methods:</jats:title> <jats:p>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 α = 0.05.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>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.</jats:p> </jats:sec>

収録刊行物

  • Clinical Cancer Research

    Clinical Cancer Research 28 (10), 2050-2060, 2022-03-03

    American Association for Cancer Research (AACR)

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