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Regulatory Issues: FDA

Sorafenib for the Treatment of Unresectable Hepatocellular Carcinoma

Office of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA

Key Words. Sorafenib • Hepatocellular carcinoma • Regular approval

Correspondence: Robert C. Kane, M.D., Office of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Room 2109, Silver Spring, Maryland 20993-0004, USA. Telephone: 301-796-2330; Fax: 301-796-9845; e-mail: robert.kane{at}fda.hhs.gov

Received August 21, 2008; accepted for publication December 9, 2008; first published online in THE ONCOLOGIST Express on January 14, 2009.

Disclosures

Robert C. Kane: None; Ann T. Farrell: None; Rajanikanth Madabushi: None; Brian Booth: None; Somesh Chattopadhyay: None; Rajeshwari Sridhara: None; Robert Jsutice: None; Richard Pazdur: None

Section editors René Adam and Kenneth K. Tanabe have disclosed no financial relationships relevant to the content of this article. Andrew X. Zhu discloses a consultant/advisory role with Bayer (sorafenib).

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias.

Target audience: Physicians who wish to advance their current knowledge of clinical cancer medicine in hepatobiliary cancer.

Purpose. To describe the U.S. Food and Drug Administration (FDA) review and approval of sorafenib (Nexavar®; Bayer Pharmaceuticals Corp., Montville, NJ, and Onyx Pharmaceuticals Corp., Emeryville, CA), an oral kinase inhibitor, for the treatment of patients with unresectable hepatocellular carcinoma (HCC).

Experimental Design. The FDA independently analyzed an international, double-blind, placebo-controlled trial comparing the effect of best supportive care plus sorafenib or matching placebo on overall survival. Eligible patients had unresectable, biopsy-proven HCC and had not received prior systemic therapy.

Results. Among the 602 randomized patients (placebo, 303; sorafenib, 299), baseline characteristics were well balanced, and 97% were Child-Pugh score A. HCC was "advanced" in 70% overall, as defined by extrahepatic metastases or by tumor radiographically visible in venous structures outside the liver. Underlying liver diseases included hepatitis B (18%), hepatitis C (28%), and alcohol-related (26%). The trial was stopped following a prespecified second interim analysis showing a statistically significant survival advantage for sorafenib [median, 10.7 vs 7.9 months; hazard ratio, 0.69 (95% confidence interval, (0.55, 0.87)), p = 0.00058]. Adverse events in sorafenib-treated patients included diarrhea in 55% (grade 3, 10%), hand–foot syndrome in 21% (grade 3, 8%), rash in 19% (grade 3, 1%), and cardiac ischemia or infarction in 2.7% (versus 1.3% for placebo). On sorafenib, treatment-emergent hypertension occurred in 9% of patients (placebo, 4%) and was grade 3 in 4% (placebo, 1%); elevated serum lipase occurred in 40% (placebo, 37%); hypophosphatemia occurred in 35% (placebo, 11%).

Conclusions. Sorafenib is the first systemic therapy to demonstrate a survival benefit in a randomized trial for unresectable HCC and has received FDA approval for this indication.

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