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Choueiri TK , Fishman MN , Escudier B , McDermott DF , Drake CG , Kluger H , Stadler WM , Perez-Gracia JL , McNeel DG , Curti B , Harrison MR , Plimack ER , Appleman L , Fong L , Albiges L , Cohen L , Young TC , Chasalow SD , Ross-Macdonald P , Srivastava S , Jure-Kunkel M , Kurland JF , Simon JS , Sznol M
Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma
Clin Cancer Res. 2016 Nov 15;22(22) :5461-5471
PMID: 27169994    PMCID: PMC5106340    URL: https://www.ncbi.nlm.nih.gov/pubmed/27169994
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PURPOSE: 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. EXPERIMENTAL DESIGN: 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-naive 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-naive 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 IFNgamma-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; 1-11. (c)2016 AACR.
Choueiri, Toni K Fishman, Mayer N Escudier, Bernard McDermott, David F Drake, Charles G Kluger, Harriet Stadler, Walter M Perez-Gracia, Jose Luis McNeel, Douglas G Curti, Brendan Harrison, Michael R Plimack, Elizabeth R Appleman, Leonard Fong, Lawrence Albiges, Laurence Cohen, Lewis Young, Tina C Chasalow, Scott D Ross-Macdonald, Petra Srivastava, Shivani Jure-Kunkel, Maria Kurland, John F Simon, Jason S Sznol, Mario Journal Article United States Clin Cancer Res. 2016 May 11.