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Clin Cancer Res. 2016 Nov 15;22(22):5461-5471. doi: 10.1158/1078-0432.CCR-15-2839. Epub 2016 May 11.

Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma.

Author information

1
Kidney Cancer Center, Dana-Farber Cancer Institute Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts. Toni_Choueiri@dfci.harvard.edu.
2
Moffitt Cancer Center, Tampa, Florida.
3
Institut Gustave Roussy, Villejuif, France.
4
Beth Israel Deaconess Medical Center, Boston, Massachusetts.
5
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and the Brady Urological Institute, Baltimore, Maryland.
6
Yale University School of Medicine and Yale Cancer Center, New Haven, Connecticut.
7
University of Chicago School of Medicine, Chicago, Illinois.
8
Clinica Universidad de Navarra, Pamplona, Navarra, Spain.
9
University of Wisconsin at Carbone Cancer Center, Madison, Wisconsin.
10
Earle A. Chiles Research Institute, Portland, Oregon.
11
Duke University Medical Center, Durham, North Carolina.
12
Fox Chase Cancer Center, Philadelphia, Pennsylvania.
13
University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
14
University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California.
15
Kidney Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts, and Institut Gustave Roussy, Villejuif, France.
16
Bristol-Myers Squibb, Princeton, New Jersey.

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 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.

PMID:
27169994
PMCID:
PMC5106340
DOI:
10.1158/1078-0432.CCR-15-2839
[Indexed for MEDLINE]
Free PMC Article

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