Circulating cytokine and angiogenic factors as predictive biomarkers of glioblastoma response to aflibercept (VEGF Trap)

Abstract

2029 Background: Aflibercept is a recombinant fusion protein that scavenges both vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). In a single-arm phase II study (NABTC06–01; NCT00369590 ), a 22% response rate was seen in recurrent glioblastoma patients receiving aflibercept 4 mg/kg iv every 2 weeks. We performed detailed analyses of circulating and urinary cytokine and angiogenic factors to describe the modulation of markers in response to aflibercept and to identify potential predictive markers. Methods: Plasma samples were collected from 31 of 32 enrolled patients at baseline, 24 hours and every 2–4 weeks until progression. Urine samples were collected at baseline and every 4 weeks. Levels of 41 circulating factors were measured using suspension bead multiplex assays (BioRad) or ELISA. Free VEGF and PlGF levels were determined following sample immunodepletion. Baseline and changes in marker levels over time were correlated with response and progression using logistic regression and Cox proportion hazard models. Results: Treatment with aflibercept resulted in significant increases in total VEGF and PlGF at 24 hours and 28 days (p ≤ 0.001). Free VEGF was rapidly sequestered by 24 hours and remained significantly decreased at 28 days (p = 0.001). However, free PlGF levels rose over time and by 28 days were 45-fold higher than baseline (p < 0.001). Additional modulation of 4 factors at 24 hours included decreases in Groα and MIF (p = 0.001) and increases in urinary VEGF and MIP1β (p ≤ 0.001). At 28 days, levels of IL-18 were significantly decreased (p = 0.02) while SCGFβ and urinary VEGF levels increased (both p < 0.02). Comparing baseline biomarker levels between response groups (PD, SD, and PR), patients with lower levels of GROα, HGF, SCGFβ and higher levels of free VEGF were more likely to have a PR (all p < 0.05). Conclusions: In recurrent glioblastoma, aflibercept resulted in rapid and sustained decreases in free VEGF levels. Although greater than 95% of PlGF remained bound, free PlGF levels significantly increased over time. Treatment significantly modulated multiple cytokine and angiogenic factors with striking increases in MIF and SCGFβ. Potential biomarkers predictive of response to aflibercept include Groα, HGF and SCGFβ. No significant financial relationships to disclose.