PUBLICAÇÕES científicas

Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma

Choueiri TK (1), Fishman M (2), Escudier B (3), McDermott DF (4), Drake CG (5), Kluger HM (6), Stadler WM (7), Perez-Gracia JL [ES] (8), McNeel DG (9), Curti BD (10), Harrison MR (11), Plimack ER (12), Appleman L (13), Fong L (14), Albiges L (15), Cohen LJ (16), Young TC (17), Chasalow SD (18), Ross-MacDonald P (19), Srivastava S (20), Jure-Kunkel M (21), Kurland JF (22), Simon JS (23), Sznol M (24).
(1) Medical Oncology, Dana-Farber Cancer Centee
(2) GU Oncology MMG, Moffitt Cancer Center, Genitourinary Program.
(3) Genitourinary Oncology, Institut Gustave Roussy.
(4) Division of Hematology-Oncology, Beth Israel Deaconess Medical Center.
(5) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine.
(6) Medical Oncology, Yale University School of Medicine.
(7) Department of Medicine/Section of Hematology/Oncology, University of Chicago.
(8) Oncology Department, Clinica Universidad de Navarra. University of Navarra.
(9) Medicine, University of Wisconsin- Madison.
(10) Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute.
(11) Divisions of Medical Oncology and Urology, Duke University, Duke Cancer Institute.
(12) Department of Medical Oncology, Fox Chase Cancer Center.
(13) Dept of Medicine/Division of Hematology-Oncology, University of Pittsburgh Medical Center.
(14) Medicine, University of California, San Francisco.
(15) Medical Oncology, Kidney Cancer Center, Dana-Farber Cancer Institute.
(16) Early Clinical Research, Bristol-Myers Squibb.
(17) Biostatistics, Bristol-Myers Squibb.
(18) Global Biometrics & Science, Bristol-Myers Squibb Company.
(19) Oncology, Bristol-Myers Squibb.
(20) Medical Affairs, Bristol-Myers Squibb.
(21) Bristol-Myers Squibb Company.
(22) Research and Development, Bristol-Myers Squibb.
(23) Immuno-Oncology, Bristol-Myers Squibb.
(24) Section of Medical Oncology, Yale University School of Medicine.

Revisão:Clinical Cancer Research

Data: 11/Mai/2016

Oncologia Médica

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-naïve 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-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 {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-γ-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.

CITAÇÃO DO ARTIGO  Clin Cancer Res. 2016 May 11. pii: clincanres.2839.2015

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