Sorafenib for the Treatment of Unresectable Hepatocellular Carcinoma

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 analyzedaninternational,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),baselinecharacteristicswerewellbalanced, 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 alcoholrelated (26%). The trial was stopped following a prespecifiedsecondinterimanalysisshowingastatistically 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-treatedpatientsincludeddiarrheain55%(grade3, 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