Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma

Toni K. Choueiri, Mayer N. Fishman, Bernard Escudier, David F. McDermott, Charles G. Drake, Harriet Kluger, Walter M. Stadler, Jose Luis Perez-Gracia, Douglas G. McNeel, Brendan Curti, Michael R. Harrison, Elizabeth R. Plimack, Leonard Appleman, Lawrence Fong, Laurence Albiges, Lewis Cohen, Tina C. Young, Scott D. Chasalow, Petra Ross-Macdonald, Shivani SrivastavaMaria Jure-Kunkel, John F. Kurland, Jason S. Simon, Mario Sznol

Research output: Contribution to journalArticlepeer-review

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, 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 was69%(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.

Original languageEnglish (US)
Pages (from-to)5461-5471
Number of pages11
JournalClinical Cancer Research
Volume22
Issue number22
DOIs
StatePublished - Nov 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma'. Together they form a unique fingerprint.

Cite this