Sorafenib improves markers associated with survival in liver cancer

SAN FRANCISCO (Reuters Health) - The multiple kinase inhibitor sorafenib (Nexavar; Bayer) lowers levels of hepatocyte growth factor (HGF) and increases levels of vascular endothelial growth factor (VEGF), two markers that are associated with poor survival in hepatocellular carcinoma (HCC).

Findings of the phase 3 SHARP (Sorafenib HCC Assessment Randomized Protocol) study were presented here at the Presidential Plenary of The Liver Meeting 2008, the annual meeting of the American Association for the Study of Liver Diseases, by principal investigator Dr. Josep Llovet of the Hospital Clinic Barcelona, Spain, and Mt. Sinai School of Medicine in New York, NY.

In SHARP, 602 patients with advanced HCC were randomized to oral sorafenib 400 mg twice a day or placebo. ELISA was performed on plasma samples collected at baseline and after 12 weeks of treatment, assessing six plasma biomarkers (VEGF, soluble VEGF Receptor-2, soluble VEGFR-3, soluble c-Kit, HGF, and Ras p21) and one tumor biomarker (pERK).

Sorafenib significantly decreased the levels of c-Kit by 33.9%, HGF by 7.4%, sVEGFR-2 by 25.7% and sVEGFR-3 by 14.1%.

Sorafenib nearly doubled levels of VEGF, with an increase of 195.7% at 12 weeks.

"VEGF and c-Kit were independently associated with overall survival," Dr. Llovet told meeting attendees. "Low HGF levels and high c-Kit levels were associated with longer survival in patients treated with sorafenib."

Specifically, VEGF had a hazard ratio (HR) of 1.52 and c-Kit had a HR=0.76 for HCC survival. VEGF was also independently associated with survival (HR=1.98) and time to disease progression (HR=2.65) in the placebo cohort.

Low HGF levels were associated with improved survival (HR=1.681), as were high c-Kit levels (HR=0.56) in patients receiving sorafenib.

"This is the first drug to show positive findings in hepatocellular carcinoma," AASLD President Arthur J McCullough, MD, of Case Western Reserve University in Cleveland, Ohio, said in introductory remarks before Dr. Llovet's presentation.

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