Use of a multiplatform analysis of plasma cytokines and angiogenic factors (CAFs) to identify baseline CAFs associated with pazopanib response and tumor burden in renal cell carcinoma (RCC) patients.

Abstract

4522 Background: In a phase II RCC study of pazopanib (VEG102616) a response rate of 34.7% and disease control rate (CR + PR +SD) of 80% were observed (Hutson, JCO 2009). Previous analysis using AVANTRAT Biochips (Decision Biomarkers) in a subset of 129/215 patients (pts) with greatest versus least tumor shrinkage (TS) identified that lower baseline levels of plasma HGF, IL-6, and IL-8 were significantly correlated with greater TS, while elevated E-Selectin and lower IL-6 were associated with longer progression-free survival (PFS) (Heymach, ACCR-NCI-EORTC 2009). The validation was conducted using Searchlight (SL) (Aushon) and ELISA (EL) assays. Methods: Candidate markers (HGF, IL-6, IL-8, E-Selectin, and VEGF) were validated in 215 pts including the initial 129 pts. Spearman correlations were performed across the three platforms. CAF levels were correlated with maximum change from baseline in TS by linear regression; PFS by Cox regression; baseline tumor burden using baseline sum of longest tumor diameter by Spearman. Results: CAF levels were highly correlated among the three platforms (R>0.70, p <0.0001 across all comparisons). Lower levels of HGF (SL p=0.0477, EL p=0.0104), IL8 (SL p=0.0328, EL not performed (NP)) and IL-6 (SL p=0.0415, EL p=0.0251) were significantly correlated with greater TS. Higher levels of E-Selectin (SL p=0.0410, EL NP), lower IL-6 (SL p=0.0019, EL p=0.0052) and HGF (SL p=0.0234, EL p=0.0354) have a longer median PFS 83.9 versus 39.29 weeks for the overall study population (215 pts). Higher levels of IL-6 (SL p <0.0001), IL-8 (SL p= 0.0003), and VEGF (SL p <0.0001) were significantly correlated with greater baseline tumor burden. Conclusions: The three platforms demonstrated consistent results that lower baseline levels of HGF and IL-6 are correlated with greater TS. Elevated levels of E-Selectin, lower levels of IL-6 and HGF are correlated with longer PFS. Higher levels of IL-6 and IL-8 correlated with greater tumor burden. CAF profiling is a feasible approach to assess pts who may derive benefit from pazopanib. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline