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Choueiri TK, Fishman M, Escudier B, McDermott DF, Drake CG, Kluger HM, Stadler WM, Perez-Gracia JL, McNeel DG, Curti BD, Harrison MR, Plimack ER, Appleman L, Fong L, Albiges L, Cohen LJ, 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) In process.
Abstract
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, 2.0, 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; {greater than or equal to}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% CI) was 16.4 months (10.1-not reached [NR]) for nivolumab 0.3 mg/kg, NR for 2 mg/kg, 25.2 months (12.0-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 {greater than or equal to}5% PD-L1 expression, and there was no consistent change from baseline to on-treatment biopsies. Transcriptional changes in tumors on treatment included up-regulation of interferon-gamma-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.
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Publication Date: 2016-05-11.
PMCID: PMC5106340
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Last updated on Friday, December 06, 2019