title: Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma.
abstract: OBJECTIVE
  Nivolumab, an anti-PD-1 immune checkpoint inhibitor, improved overall survival versus everolimus in a phase 3 trial of previously treated patients with metastatic renal cell carcinoma (mRCC). We investigated immunomodulatory activity of nivolumab in a hypothesis-generating prospective mRCC trial.
  
  
  METHODS
  Nivolumab was administered intravenously every 3 weeks at 0.3, 2, or 10 mg/kg to previously treated patients and 10 mg/kg to treatment-naïve patients with mRCC. Baseline and on-treatment biopsies and blood were obtained. Clinical activity, tumor-associated lymphocytes, PD-L1 expression (Dako immunohistochemistry; ≥5% vs. <5% tumor membrane staining), tumor gene expression (Affymetrix U219), serum chemokines, and safety were assessed.
  
  
  RESULTS
  In 91 treated patients, median overall survival [95% confidence interval (CI)] was 16.4 months [10.1 to not reached (NR)] for nivolumab 0.3 mg/kg, NR for 2 mg/kg, 25.2 months (12.0 to NR) for 10 mg/kg, and NR for treatment-naïve patients. Median percent change from baseline in tumor-associated lymphocytes was 69% (CD3+), 180% (CD4+), and 117% (CD8+). Of 56 baseline biopsies, 32% had ≥5% PD-L1 expression, and there was no consistent change from baseline to on-treatment biopsies. Transcriptional changes in tumors on treatment included upregulation of IFNγ-stimulated genes (e.g., CXCL9). Median increases in chemokine levels from baseline to C2D8 were 101% (CXCL9) and 37% (CXCL10) in peripheral blood. No new safety signals were identified.
  
  
  CONCLUSIONS
  Immunomodulatory effects of PD-1 inhibition were demonstrated through multiple lines of evidence across nivolumab doses. Biomarker changes from baseline reflect nivolumab pharmacodynamics in the tumor microenvironment. These data may inform potential combinations. Clin Cancer Res; 22(22); 5461-71. ©2016 AACR.
authors.affiliation: Kidney Cancer Center, Dana-Farber Cancer Institute Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts. Toni_Choueiri@dfci.harvard.edu.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: Moffitt Cancer Center, Tampa, Florida.
authors.forename: Mayer N
authors.initials: MN
authors.lastname: Fishman
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.affiliation: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and the Brady Urological Institute, Baltimore, Maryland.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Drake
authors.affiliation: Yale University School of Medicine and Yale Cancer Center, New Haven, Connecticut.
authors.forename: Harriet
authors.initials: H
authors.lastname: Kluger
authors.affiliation: University of Chicago School of Medicine, Chicago, Illinois.
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.affiliation: Clinica Universidad de Navarra, Pamplona, Navarra, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Perez-Gracia
authors.affiliation: University of Wisconsin at Carbone Cancer Center, Madison, Wisconsin.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: McNeel
authors.affiliation: Earle A. Chiles Research Institute, Portland, Oregon.
authors.forename: Brendan
authors.initials: B
authors.lastname: Curti
authors.affiliation: Duke University Medical Center, Durham, North Carolina.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Harrison
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Plimack
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Leonard
authors.initials: L
authors.lastname: Appleman
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fong
authors.affiliation: Kidney Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts, and Institut Gustave Roussy, Villejuif, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Albiges
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Lewis
authors.initials: L
authors.lastname: Cohen
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Tina C
authors.initials: TC
authors.lastname: Young
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Chasalow
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Petra
authors.initials: P
authors.lastname: Ross-Macdonald
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Shivani
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Maria
authors.initials: M
authors.lastname: Jure-Kunkel
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: John F
authors.initials: JF
authors.lastname: Kurland
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Simon
authors.affiliation: Yale University School of Medicine and Yale Cancer Center, New Haven, Connecticut.
authors.forename: Mario
authors.initials: M
authors.lastname: Sznol
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000276:immunology / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000628:therapy*; D054357:Chemokine CXCL10 / Q000276:immunology; D054370:Chemokine CXCL9 / Q000276:immunology; D000068338:Everolimus / Q000276:immunology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology* / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000276:immunology; D007680:Kidney Neoplasms / Q000276:immunology* / Q000628:therapy*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D000077594:Nivolumab; D011446:Prospective Studies; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D007155:Immunologic Factors; D000077594:Nivolumab; D007371:Interferon-gamma; D000068338:Everolimus