Vandetanib in patients with inoperable hepatocellular carcinoma: A phase II, randomized, double-blind, placebo-controlled study

Background & Aims: Inhibitors of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) have shown anti-tumor activities in advanced hepatocellular carcinoma (HCC). The present study evaluated the efficacy and safety of vandetanib, an oral inhibitor of both VEGFR and EGFR, in patients with unresectable advanced HCC. Methods: Eligible patients were randomized 1:1:1 to receive vandetanib 300 mg/day, vandetanib 100 mg/day, or placebo. Upon disease progression, all patients had the option to receive open-label vandetanib 300 mg/day. The primary objective was to evaluate tumor stabilization rate (complete response + partial response + stable disease >= 4 months). Secondary assessments included progression-free survival (PFS), overall survival (OS) and safety. Biomarker studies included circulating pro-angiogenic factors and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: Sixty-seven patients were randomized to vandetanib 300 mg (n = 19), vandetanib 100 mg (n = 25) or placebo (n = 23) groups. Twenty-nine patients entered open-label treatment. Vandetanib induced a significant increase in circulating VEGF and decrease in circulating VEGFR levels. In both vandetanib arms, tumor stabilization rate was not significantly different from placebo: 5.3% (vandetanib 300 mg), 16.0% (vandetanib 100 mg) and 8.7% (placebo). DCE-MRI did not detect significant vascular change after vandetanib treatment. Although trends of improved PFS and OS after vandetanib treatment were found, they were statistically insignificant. The most common adverse events were diarrhea and rash, whose incidence did not differ significantly between treatment groups. Conclusions: Vandetanib has limited clinical activity in HCC. The safety profile was consistent with previous studies. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.