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Markers of inflammation are associated with clinical outcomes in patients with metastatic renal cell carcinoma treated with nivolumab
Journal for ImmunoTherapy of Cancervolume 3, Article number: P197 (2015)
In previously treated patients with metastatic renal cell carcinoma (mRCC), the programmed death-1 (PD-1) inhibitor antibody nivolumab demonstrated objective response rates of 20%–22% and median overall survival (OS) of 18.2– 25.5 months. An exploratory biomarker analysis of baseline and on-therapy changes was conducted to investigate the relationship between the clinical and immunomodulatory activity of nivolumab.
Patients with 1–3 prior therapies for mRCC received nivolumab 0.3, 2, or 10 mg/kg IV every 3 weeks (Q3W); treatment-naïve patients received 10 mg/kg IV Q3W. Biopsies and peripheral blood mononuclear cells were obtained at baseline and cycle 2 day 8. Tumor burden reduction was defined as a ≥20% decrease. Gene expression data were obtained on Affymetrix U219. OS parameters were estimated by the Kaplan-Meier method or by Cox proportional hazards regression. PD-1 ligand 1 (PD-L1) expression was measured by tumor membrane immunohistochemical staining (28-8 antibody; Dako) in baseline biopsies. Serum-soluble factors were quantified using a Luminex multiplex panel (Myriad Rules-Based Medicine). T cell receptor sequencing was conducted with the immunoSEQ assay (Adaptive Biotechnologies).
91 patients were treated. 59 baseline and 55 on-therapy biopsies were evaluable for gene expression, with 42 matched samples. Patients with tumor burden reduction had differential expression (>1.3-fold, P < 0.01, q-value < 0.16) of 311 genes at baseline (n = 13) and 779 genes on-therapy (n = 11) compared with patients without tumor burden reduction, including higher expression of transcripts associated with cell-mediated immunity. CTLA-4, TIGIT, and PD-L2 transcripts were present at higher levels on-therapy in patients with tumor burden reduction. Table 1 summarizes OS and OS by PD-L1 expression. 18/56 biopsies (32%) had ≥5% PD-L1 expression. Among serum-soluble factors, recognized prognostic markers (VEGF, ICAM1, VCAM1, TIMP1) were associated with OS. Based on T cell sequencing, increased tumor T cell counts and decreased blood T cell clonality at baseline were associated with longer OS.
Immune markers at baseline and on-therapy suggest pre-existing adaptive immunity is associated with nivolumab-induced tumor regression. Upregulation of immune checkpoint molecules provides rationale for study of nivolumab and ipilimumab combination in mRCC. A minimal difference in OS by PD-L1 expression was observed for up to 2 years.
ClinicalTrials.gov identifier NCT01358721.
Motzer RM, et al: Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015, 33: 1430-1437.
Dako, for collaborative development of the automated PD-L1 immunohistochemistry assay. Adaptive Biotechnologies, for T cell repertoire analysis.