VEGF, sVEGFR-2, bFGF, and IL-8 as biomarkers of the pharmacological activity of BAY 57–9352, an oral VEGFR-2 receptor tyrosine kinase inhibitor, in patients with solid tumors

Abstract

3035 Background: BAY 57–9352 (BAY) is a potent anti-angiogenic drug that inhibits VEGFR-2, as well as VEGFR-1, VEGFR-3, PDGFR-β, and c-Kit tyrosine kinases. Molecular biomarkers of angiogenesis (VEGF165, soluble VEGFR-2 [sVEGFR-2], basic FGF [bFGF], and interleukin-8 [IL-8]) were used to assess the pharmacodynamic effects of BAY. Methods: Patients with advanced solid tumors from two Phase I studies received oral BAY on either an intermittent 21 day cycle (14 days on drug, 7 days off drug) or continuous schedule (21 day cycle). Doses were escalated from 20 mg once daily (od) to 1500 mg twice daily (bid). Molecular biomarkers were measured at baseline, pre-dose, and 8 hours post-dose on Days 1 and 14 of each cycle. Pharmacokinetic parameters of BAY were also assessed. Results: Plasma samples from 130 patients were analyzed for angiogenic biomarkers. Increased VEGF165 and decreased sVEGFR-2 clearly correlated with the dose of BAY, respectively. All clinical responders (as shown by tumor shrinkage) were located within the upper 10% of the total response distribution for these markers. Subgroup analysis in the three more prevalent tumors showed that patients with colorectal, renal cell, and hepatocellular carcinoma all showed biomarker responses exceeding the mean overall responses. Biomarker levels reached a plateau at daily doses of approximately 900 mg bid or 1800 mg, suggesting a saturated pharmacodynamic effect. There were no consistent changes in bFGF and IL-8. Conclusions: Both VEGF and sVEGFR-2 demonstrated a dose-dependent change with BAY 57–9352. VEGF and sVEGFR-2 may be appropriate biomarkers of the therapeutic effects of BAY, and may be useful as potential predictors of early response. [Table: see text]