Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study

Abstract

Purpose: To assess the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) and explore biomarkers for sunitinib response.

Patients and methods: We conducted a multidisciplinary phase II study of sunitinib, an antivascular endothelial growth factor receptor tyrosine kinase inhibitor, in advanced HCC. Patients received sunitinib 37.5 mg/d for 4 weeks followed by 2 weeks of rest per cycle. The primary end point was progression-free survival (PFS). We used functional magnetic resonance imaging to evaluate vascular changes in HCC after sunitinib treatment. Circulating molecular and cellular biomarkers were evaluated before and at six time points after sunitinib treatment.

Results: Thirty-four patients were enrolled. The objective response rate was 2.9%, and 50% of patients had stable disease. Median PFS was 3.9 months (95% CI, 2.6 to 6.9 months), and overall survival was 9.8 months (95% CI, 7.4 months to not available). Grade 3 or 4 toxicities included leukopenia/neutropenia, thrombocytopenia, elevation of aminotransferases, and fatigue. Sunitinib rapidly decreased vessel leakiness, and this effect was more pronounced in patients with delayed progression. When evaluated early (at baseline and day 14) as well as over three cycles of treatment, higher levels of inflammatory molecules (eg, interleukin-6, stromal-derived factor 1alpha, soluble c-KIT) and circulating progenitor cells were associated with a poor outcome.

Conclusion: Sunitinib shows evidence of modest antitumor activity in advanced HCC with manageable adverse effects. Rapid changes in tumor vascular permeability and circulating inflammatory biomarkers are potential determinants of response and resistance to sunitinib in HCC. Our study suggests that control of inflammation might be critical for improving treatment outcome in advanced HCC.

Fig 1.

Kaplan-Meier survival distributions. (A) Progression-free survival and (B) overall survival in 34 advanced hepatocellular carcinoma patients receiving sunitinib. On the x-axis is the number of patients at risk at each time point.

Fig 2.

Measurement of the effects of sunitinib using dynamic contrast-enhanced magnetic resonance imaging (MRI). (A) Sunitinib significantly decreased forward volume transfer constant (K^trans; red boxes) and reverse reflux rate constant between extracellular space and plasma (K_ep; blue boxes) in advanced hepatocellular carcinoma (HCC) patients (*P < .0001, data shown as medians with 95% CIs). (B) Representative MRI images of T1-weighted tumor enhancement (left) and maps of K^trans (center) and K_ep (right, two measures of tumor vessel permeability) before and after sunitinib demonstrating a dramatic radiographic tumor response within 2 weeks of treatment. (C) Correlation between the extent of K^trans decrease at day 14 in HCC patients with partial response (PR) or stable disease (SD) versus patients with progressive disease (PD) after sunitinib (*P < .05).

Fig A1.

Target validation by immunohistochemistry in hepatocellular carcinoma biopsies. (A) To identify endothelial cells, we used immunostaining with the anti-CD31 antibody. (B, C) As expected, vascular endothelial growth factor receptor 2 (VEGFR2) and platelet-derived growth factor receptor (PDGFR)α are expressed in the tumor endothelial cells. Interestingly, PDGFRβ is also highly expressed in endothelial cells (arrows) as well as in stromal cells (arrowheads in D). Bar represents 50 μm for all images.