Analyses of plasma cytokine/angiogenic factors (C/AFs) profile during preoperative treatment with pazopanib (GW786034) in early-stage non-small cell lung cancer

Abstract

7568 Background: Pazopanib is an oral angiogenesis inhibitor targeting VEGFR, PDGFR and c-kit. In a single-arm phase II trial (NCT00367679; VEG105290), patients received pazopanib 800 mg QD for 2–6 weeks before scheduled surgery. Tumor volume measurements were performed using high resolution CT images before and after treatment. An exploratory analysis was planned to describe the modulation of C/AFs during pazopanib treatment and identify potential predictive plasma markers. Methods: Plasma samples were collected pre- treatment and on the last day of pazopanib dosing. Levels of 52 C/AFs were measured by suspension bead multiplex assays (BioRad) or ELISA. Results were correlated with change in tumor volume. Statistical analyses included Wilcoxon tests and Pearson correlation tests. Results: 19 paired samples have been analyzed. Pazopanib treatment was associated with a significant modulation of 13 C/AFs, including a decrease in soluble VEGFR-2 (p<0.001) and increases in PlGF, IFN-α2 and HGF; chemokines/monokines: SDF1-α, CTACK, CXCL-10, CXCL-9, RANTES; and further factors: IL-12; M-CSF and TRAIL (all with p<0.05). PlGF showed the highest up-regulation during treatment with an average 15.9 fold increase, whereas changes compared to baseline for the remaining factors varied between 5 and 60%. The exploratory correlation of C/AF changes with tumor changes indicated an association with 6 factors (sVEGFR-2 (r = 0.77), VEGF (r = - 0.68), IL-16, IL-1RA, MCP-3, and IL-4; all with p<0.05). A significant correlation between baseline levels of C/AFs and tumor reduction was observed for 8 factors (PlGF, IL-2R, IL-12, IL-16, TRAIL, SCF, IL-3 and CTACK). Conclusions: Pazopanib treatment was associated with decreases in sVEGFR2 and increases in an additional 12 C/Afs, with PlGF demonstrating a particularly striking increase. The exploratory analysis identifies that baseline levels of several C/Afs may have predictive value for pazopanib treatment. Moreover a strong correlation between sVEGFR-2 changes during pazopanib treatment and tumor shrinkage was observed making this factor a potentially attractive marker of response. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline, Pneum Rx, General Electric GlaxoSmithKline, Pneum Rx GlaxoSmithKline GlaxoSmithKline