Originally published as JCO Early Release 10.1200/JCO.2005.01.3441 on August 14 2006

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Phase II Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma

Ghassan K. Abou-Alfa, Lawrence Schwartz, Sergio Ricci, Dino Amadori, Armando Santoro, Arie Figer, Jacques De Greve, Jean-Yves Douillard, Chetan Lathia, Brian Schwartz, Ian Taylor, Marius Moscovici, Leonard B. Saltz

From the Memorial Sloan-Kettering Cancer Center, New York, NY; Bayer Pharmaceuticals Corporation, West Haven, CT; Ospedale S. Chiara, Pisa; Ospedale Morgagni Pierantoni, Forli; Istituto Clinico Humanitas, Rozzano (MI); Bayer S.p.A. PH/Medical Department, Milan, Italy; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; AZ-VUB, Brussels, Belgium; and the Centre René Gauducheau, Nantes, France

Address reprint requests to Ghassan K. Abou-Alfa, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10022; e-mail: abou-alg{at}mskcc.org

Purpose This phase II study of sorafenib, an oral multikinase inhibitor that targets Raf kinase and receptor tyrosine kinases, assessed efficacy, toxicity, pharmacokinetics, and biomarkers in advanced hepatocellular carcinoma (HCC) patients.

Methods Patients with inoperable HCC, no prior systemic treatment, and Child–Pugh (CP) A or B, received continuous, oral sorafenib 400 mg bid in 4-week cycles. Tumor response was assessed every two cycles using modified WHO criteria. Sorafenib pharmacokinetics were measured in plasma samples. Biomarker analysis included phosphorylated extracellular signal regulated kinase (pERK) in pretreatment biopsies (immunohistochemistry) and blood-cell RNA expression patterns in selected patients.

Results Of 137 patients treated (male, 71%; median age, 69 years), 72% had CP A, and 28% had CP B. On the basis of independent assessment, three (2.2%) patients achieved a partial response, eight (5.8%) had a minor response, and 46 (33.6%) had stable disease for at least 16 weeks. Investigator-assessed median time to progression (TTP) was 4.2 months, and median overall survival was 9.2 months. Grade 3/4 drug-related toxicities included fatigue (9.5%), diarrhea (8.0%), and hand–foot skin reaction (5.1%). There were no significant pharmacokinetic differences between CP A and B patients. Pretreatment tumor pERK levels correlated with TTP. A panel of 18 expressed genes was identified that distinguished "nonprogressors" from "progressors" with an estimated 100% accuracy.

Conclusion Although single-agent sorafenib has modest efficacy in HCC, the manageable toxicity and mechanisms of action support a role for combination regimens with other anticancer agents.

published online ahead of print at www.jco.org on August 14, 2006.

Presented at the 4th International Meeting on Hepatocellular Carcinoma: Eastern and Western Experiences, Hong Kong, December 14-16, 2004; European Organisation for Research and Treatment of Cancer–National Cancer Institute–American Association for Cancer Research Meeting, September 28-October 1, 2004, Geneva, Switzerland.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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