TY - JOUR
T1 - Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma
AU - Choueiri, Toni K.
AU - Fishman, Mayer N.
AU - Escudier, Bernard
AU - McDermott, David F.
AU - Drake, Charles G.
AU - Kluger, Harriet
AU - Stadler, Walter M.
AU - Perez-Gracia, Jose Luis
AU - McNeel, Douglas G.
AU - Curti, Brendan
AU - Harrison, Michael R.
AU - Plimack, Elizabeth R.
AU - Appleman, Leonard
AU - Fong, Lawrence
AU - Albiges, Laurence
AU - Cohen, Lewis
AU - Young, Tina C.
AU - Chasalow, Scott D.
AU - Ross-Macdonald, Petra
AU - Srivastava, Shivani
AU - Jure-Kunkel, Maria
AU - Kurland, John F.
AU - Simon, Jason S.
AU - Sznol, Mario
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/11/15
Y1 - 2016/11/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84995919524&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-15-2839
DO - 10.1158/1078-0432.CCR-15-2839
M3 - Article
C2 - 27169994
AN - SCOPUS:84995919524
SN - 1078-0432
VL - 22
SP - 5461
EP - 5471
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 22
ER -