Analysis of circulating biomarkers of sunitinib malate in patients with unresectable neuroendocrine tumors (NET): VEGF, IL-8, and soluble VEGF receptors 2 and 3

Abstract

4045 Background: Sunitinib malate (SU11248) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity that specifically inhibits VEGFR, PDGFR, KIT, RET, and FLT3. In a phase II trial of 109 patients with metastatic neuroendocrine tumors (NET), sunitinib treatment was associated with ORR and high rates of SD in patients with carcinoid and pancreatic islet cell tumors (Kulke et al, ASCO 2005). To characterize potential biomarkers of biological response to sunitinib, we analyzed plasma levels of a panel of soluble proteins from patients in this trial. Methods: Patients received sunitinib in 6-week cycles comprised of 50 mg/day for 4 weeks followed by 2 weeks off treatment. Pre-dose plasma samples from 106 patients were obtained on days 1 and 28 of multiple cycles. Plasma levels of VEGF, soluble VEGF receptor 2 (sVEGFR-2), interleukin-8 (IL-8), and a novel biomarker, sVEGFR-3, were measured via ELISA analysis. Results: Plasma levels of each protein were frequently modulated during the course of treatment. At the end of cycle 1, VEGF levels were increased more than 3-fold over baseline in ∼50% of all patients. Average baseline VEGF levels were higher in the islet cell group (62 vs. 40 pg/ml, P = 0.06). In cycle 1, sVEGFR-2 and sVEGFR-3 levels were significantly decreased by ≥30% in ∼60% and 70% of all patients, respectively (P < 0.0001). Levels tended to return to near-baseline after 2 weeks off treatment. The reduction in sVEGFR-3 levels in cycle 1 was, on average, greater in the subset of patients with PR (n=11) compared to others (45% vs. 38%). Overall, there was a 2.2-fold average increase in IL-8 levels by the end of cycle 1, and a larger proportional increase in IL-8 levels in patients exhibiting decreases in tumor size, patients who also tended to have lower baseline IL-8 levels. Further analysis of correlations with pharmacokinetic and clinical parameters is ongoing. Conclusions: Our results suggest that this panel of circulating proteins may be of utility as pharmacodynamic biomarkers of sunitinib activity in patients with advanced NET. sVEGFR-3 may be a novel biomarker of the biological activity of sunitinib in NET, and IL-8 may be of particular interest as a potential predictor of response. [Table: see text]