Safety and Efficacy of Sorafenib in Patients with Hepatocellular Carcinoma (HCC) and Child-Pugh A versus B Cirrhosis

摘要

Background: We performed a retrospective analysis of data from a phase II study evaluating sorafenib in patients with advanced hepatocellular carcinoma (HCC) to assess differences in safety and efficacy based on Child-Pugh (CP) status (A/B). Methods: Patients received sorafenib 400 mg PO bid. We analyzed safety, pharmacokinetic (PK), and efficacy data in the two CP groups. Results: Ninety-eight patients were CP A; 38 were CP B, with a median duration of therapy of 4 and 1.8 months, respectively. Grade 3/4 adverse events in the CP A and B groups, respectively, included hyperbilirubinemia (14% and 53%), ascites (3% and 5%), and encephalopathy (3% and 13%). Median overall survival (OS) in the CP A group was 9.5 months, compared with 3.2 months in the CP B population. Responses were limited in both groups. AUC and C_max values were comparable between the two groups. Conclusions: Due to the lack of randomization against placebo or no therapy in this study, it is unclear if the more frequent worsening of liver cirrhosis and outcome of CP B patients are drug related or due to disease progression, or both. As expected, outcome was poorer in patients with CP B than in those with CP A cirrhosis. The hyperbilirubinemia seen in both groups may be at least partly related to inhibition of UGT1A1 by sorafenib. PK profiles were similar in the two groups. More data are needed to confirm and more fully understand the safety and efficacy of sorafenib in patients with advanced HCC and CP B cirrhosis. Sorafenib, an oral multikinase inhibitor, has been studied extensively in patients with hepatocellular carcinoma (HCC). A large phase III study evaluated sorafenib versus placebo in patients with advanced HCC. 1 Eligibility for this trial was restricted to patients with a Child-Pugh (CP) designation no worse than A ( Table 1 ). 2 , 3 This phase III trial demonstrated an overall survival advantage for sorafenib compared with placebo (10.7 vs. 7.9 months, P 4 , 5 Table 1. Child-Pugh scoring Although the phase III trial was limited to patients with a CP A status, the FDA approval of sorafenib was not. The safety and efficacy of sorafenib in patients with CP B or CP C cirrhosis has not been as fully defined as it has in those with CP A cirrhosis and needs to be further evaluated in the more severe CP strata. The pivotal phase III study was preceded by a large, nonrandomized phase II trial that evaluated sorafenib in patients with advanced HCC who had either CP A or B disease. 6 We performed a retrospective, exploratory subanalysis of data from the phase II trial to evaluate safety and efficacy outcomes in patients with CP A versus CP B cirrhosis to understand better the effects of sorafenib in patients with CP B disease.