Distinct patterns of cytokine and angiogenic factor modulation and markers of benefit for vandetanib and/or chemotherapy in patients with non-small-cell lung cancer

Abstract

Purpose: There is an unmet need for biomarkers for identifying patients likely to benefit from anticancer treatments, selecting dose, and understanding mechanisms of resistance. Plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptor 2 (sVEGFR-2) are known to be modulated by VEGF pathway inhibitors. It is unknown whether chemotherapy or VEGFR inhibitor/chemotherapy combinations induce changes in these or other cytokines and angiogenic factors (CAFs) and whether such changes could be markers of benefit.

Methods: Thirty-five plasma CAFs were analyzed using multiplexed bead arrays and enzyme-linked immunosorbent assays from 123 patients with non-small-cell lung cancer in a randomized phase II study who received vandetanib, a VEGFR and epidermal growth factor receptor inhibitor, monotherapy carboplatin and paclitaxel (CP), or the combination (VCP). Changes in CAFs at days 8, 22, and 43 from baseline were correlated with progression risk.

Results: VEGF increased and sVEGFR-2 decreased by day 43 in the vandetanib arm, whereas a distinct pattern was observed in the CP and VCP arms, with significant decreases in interleukin (IL) -12, IL-1 receptor antagonist, and matrix metalloproteinase 9 (MMP-9) and increased macrophage chemoattractant protein 1. In each treatment arm, changes in different markers were associated with progression risk. For example, increases in IL-8 with VCP, MMP-9 with CP, and VEGF with vandetanib monotherapy were associated with increased progression risk, and increase in intercellular adhesion molecule 1 with vandetanib was associated with decreased risk.

Conclusion: Vandetanib and chemotherapy treatment led to distinct patterns of CAF changes; the combination resembled chemotherapy alone. Changes in specific CAFs correlated with clinical outcome, but markers differed for each treatment arm. CAF profiling may provide insights into the biologic effects of treatment and identify drug-specific markers of activity and clinical benefit.

Fig 1.

(A-F) Changes in concentrations of cytokines and angiogenic factors (CAFs) during treatment (% baseline indicates the median of the ratios of CAF concentration at each time point to baseline concentration expressed as a percentage, not the ratio of the median concentration at each time point to the median baseline concentration). These figures are based on raw data. The P values in the text are based on the analysis of log₂ transformed data in mixed linear models and adjusted for sex. For figures generated from the log₂ transformed data with error bars, please see Figure A1. CP, carboplatin and paclitaxel; VCP, vandetanib, carboplatin, and paclitaxel; VEGF, vascular endothelial growth factor; IL-12, interleukin-12; MMP-9, matrix metalloproteinase-9; sVEGFR-2, soluble vascular endothelial growth factor receptor 2; IL-1RA, interleukin-1 receptor antagonist; MCP-1, macrophage chemoattractant protein 1.

Fig 2.

Kaplan-Meier curves of progression-free survival (PFS) based on extent of change in (A) intercellular adhesion molecule 1 (ICAM-1) and (B) vascular endothelial growth factor (VEGF) concentrations (≤ median indicates increase ≤ the median increase in concentration of that cytokine and angiogenic factor [CAF]; > median indicates increase > the median increase in concentration of that CAF). Note that the P values are from a log-rank test for the comparison of the Kaplan-Meier curves, whereas the P values shown in the text are from a Cox model with the change of the markers as continuous variables adjusting for sex and smoking status. Change in ICAM-1 at day 8 by treatment interaction, P = .021; change in VEGF at day 8 by treatment interaction, P = .009. V, vandetanib; CP, carboplatin and paclitaxel; VCP, vandetanib, carboplatin, and paclitaxel; HR, hazard ratio.

Fig A1.

Changes in plasma levels of cytokines and angiogenic factors during treatment (log₂ transformed data). VCP, vandetanib, carboplatin, and paclitaxel; CP, carboplatin and paclitaxel; V, vandetanib; sVEGFR-2, soluble vascular endothelial growth factor receptor 2; B, baseline; IL-12, interleukin-12; MMP-9, matrix metalloproteinase-9; VEGF, vascular endothelial growth factor; interleukin-1 receptor antagonist; MCP-1, macrophage chemoattractant protein 1.