Circulating biomarkers of sunitinib in patients with unresectable hepatocellular carcinoma (HCC): Analysis of correlations with outcome and tumor imaging parameters

Abstract

4593 Background: Sunitinib malate (SU) is a multikinase inhibitor with antitumor activity in patients (pts) with HCC (Faivre et al, ASCO 2007). To assess potential biomarkers of SU response, we investigated plasma levels of soluble (s) proteins (VEGF-A, VEGF-C, sVEGFR-2 and -3, and sKIT) with roles in angiogenesis and SU target pathways. Methods: Pts (n=37) received SU 50 mg/d for 4 wks on, 2 wks off, every 6 wks. Pre-dose plasma samples were obtained on days (D) 1, 14, and 28 of cycle (C) 1 and D1 and 28 of C2. Soluble protein levels were measured by ELISA. Baseline levels and changes from baseline were analyzed for association with efficacy measures (time to progression [TTP], overall survival [OS], objective response, and tumor density changes [Choi criteria]). Results: Plasma protein levels were modulated in most pts during treatment. By the end of C1, VEGF-A levels increased >3-fold relative to baseline; sVEGFR-2, -3 and sKIT levels decreased (↓) by ∼50%, 70%, and 30%, respectively. VEGF-C levels ↓ by 30% by end of C2. Pretreatment VEGF-C levels correlated with TTP and OS, with levels above the median (>822 pg/mL) associated with longer times (TTP, p=0.004; OS, p=0.05). Pretreatment VEGF-C levels were also significantly higher in pts with partial response or stable disease >3 months (n=14) vs pts with progressive disease (n=13; p=0.02). Pts with largest ↓ in sKIT (< median) at C1D14 had longer TTP (p=0.018); sKIT ↓ also correlated with response according to Choi criteria (p=0.012) and with higher tumor necrosis, based on volumetric measurement (p=0.02; n=21). Choi criteria response correlated with larger ↓ in sVEGFR-3 (p=0.005). Higher tumor necrosis correlated with larger increases in VEGF-A (p=0.03) and larger ↓ in sVEGFR-2 (p=0.036). Conclusions: In HCC pts, SU is associated with modulation of plasma proteins involved in VEGF and KIT pathways. Baseline VEGF-C exhibited the strongest correlation with outcome. Additional correlations between biomarkers and various measures of antitumor activity were observed. Analysis of these biomarkers in larger studies of SU in HCC may be warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer Pfizer