Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma

Bert H. O'Neil, Laura W. Goff, John Sae Wook Kauh, Jonathan R. Strosberg, Tanios Bekaii-Saab, Ruey Min Lee, Aslamuzzaman Kazi, Dominic T. Moore, Maria Learoyd, Richard M. Lush, Said M. Sebti, Daniel M. Sullivan

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101 Scopus citations

Abstract

Purpose: Hepatocellular carcinoma (HCC) is a common and deadly malignancy with few systemic therapy options. The RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is activated in approximately 50% to 60% of HCCs and represents a potential target for therapy. Selumetinib is an orally available inhibitor of MEK tyrosine kinase activity. Patients and Methods: Patients with locally advanced or metastatic HCC who had not been treated with prior systemic therapy were enrolled on to the study. Patients were treated with selumetinib at its recommended phase II dose of 100 mg twice per day continuously. Cycle length was 21 days. Imaging was performed every two cycles. Biopsies were obtained at baseline and at steady-state in a subset of patients, and pharmacokinetic (PK) analysis was performed on all patients. Results: Nineteen patients were enrolled, 17 of whom were evaluable for response. Most (82%) had Child-Pugh A cirrhosis. Toxicity was in line with other studies of selumetinib in noncirrhotic patients. PK parameters were also comparable to those in noncirrhotic patients. No radiographic response was observed in this group, and the study was stopped at the interim analysis. Of 11 patients with elevated α-fetoprotein, three (27%) had decreases of 50% or more. Median time to progression was 8 weeks. Inhibition of ERK phosphorylation was demonstrated by Western blotting. Conclusion: In this study of selumetinib for patients with HCC, no radiographic responses were seen and time to progression was short, which suggests minimal single-agent activity despite evidence of suppression of target activation.

Original languageEnglish (US)
Pages (from-to)2350-2356
Number of pages7
JournalJournal of Clinical Oncology
Volume29
Issue number17
DOIs
StatePublished - Jun 10 2011
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

O'Neil, B. H., Goff, L. W., Kauh, J. S. W., Strosberg, J. R., Bekaii-Saab, T., Lee, R. M., Kazi, A., Moore, D. T., Learoyd, M., Lush, R. M., Sebti, S. M., & Sullivan, D. M. (2011). Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma. Journal of Clinical Oncology, 29(17), 2350-2356. https://doi.org/10.1200/JCO.2010.33.9432