Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma

Abstract

BACKGROUND.Epidermal growth factor receptor (EGFR) and ligand expression is frequently seen in hepatocellular carcinoma (HCC). A phase 2 study was performed with cetuximab, a chimeric monoclonal antibody that binds specifically to EGFR, in patients with advanced HCC.METHODS.Eligibility criteria included unresectable or metastatic measurable HCC, an Eastern Cooperative Oncology Group performance status ≤2, Cancer of the Liver Italian Program (CLIP) score ≤3, and adequate organ functions. The initial dose of cetuximab was 400 mg/m2 given intravenously followed by weekly intravenous infusions at 250 mg/m2. Each cycle was defined as 6 consecutive weekly treatments. EGFR expression was assayed by immunohistochemistry and trough serum concentrations of cetuximab were determined during the first cycle.RESULTS.Thirty patients were enrolled and assessable for efficacy and toxicity. No responses were seen. Five patients had stable disease (median time, 4.2 months; range, 2.8–4.2 months). The median overall survival was 9.6 months (95% confidence interval [CI], 4.3–12.1 months) and the median progression‐free survival (PFS) was 1.4 months (95% CI, 1.2–2.6 months). The treatment was generally well tolerated. No treatment‐related grade 4–5 toxicities occurred. Grade 3 (according to the National Cancer Institute's Common Terminology Criteria for Adverse Events [version 3.0]) aspartate aminotransferase, hypomagnesemia, and fever without neutropenia were noted in 1 patient (3.3%) each. On Week 6 of Cycle 1, arithmetic mean serum cetuximab concentrations for patients with Child‐Turcotte‐Pugh (CTP) A and CTP B disease were 47.6 mcg/mL and 66.9 mcg/mL, respectively.CONCLUSIONS.Although cetuximab could be safely administered with tolerable toxicity profiles, it demonstrated no antitumor activity in HCC in this phase 2 study. Cetuximab trough concentrations were not notably altered in patients with mild to moderate hepatic dysfunction. © 2007 American Cancer Society. Cancer 2007. ©2007 American Cancer Society.

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

“…Results of EGFR expression in HCC tumor tissues, mainly by immunohistochemistry, varied in different studies [365], and activating mutation of EGFR, the major determinant of efficacy of EGFR inhibitors in lung cancer [366], was rarely found in HCC tumor tissue [367]. Both small-molecule EGFR inhibitors and monoclonal anti-EGFR antibodies have been tested in small-scale trials for the treatment of advanced HCC, and the response rates and patient survival were not consistent among the studies [368][369][370][371]. Correlation of tumor response with expression of EGFR yielded inconclusive results [368,369].…”

The role of signaling pathways in the development and treatment of hepatocellular carcinoma

“…As with gefitinib, clinical results have so far been disappointing. In a phase II study of 30 patients with unresectable or metastatic HCC, cetuximab (400 mg/m 2 initial dose followed by 250 mg/m 2 given weekly) produced no CRs or PRs, and only five patients achieved SD (Zhu et al, 2007). Moreover, median PFS was just 1.4 months.…”

Review: Current status of therapy for hepatocellular carcinoma

“…Cetuximab is a chimeric immunoglobulin G1 monoclonal antibody that binds to epidermal growth factor receptors and may prevent the growth of EGFR-positive tumor cells [Asnacios et al 2008;Zhu et al 2007]. HCC cells demonstrate increased expression of EGFR and may be a target for cetuximab.…”