Phase II study of sorafenib in patients with advanced hepatocellular carcinoma
Phase II study of sorafenib in patients with advanced hepatocellular carcinoma
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DOI：
10.1200/jco.2005.01.3441
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发表时间：
2006-09-10
影响因子：
45.3
通讯作者：
Saltz, Leonard B.
中科院分区：
文献类型：
--
作者：
Abou-Alfa, Ghassan K.;Schwartz, Lawrence;Saltz, Leonard B.
PurposeThis第二阶段研究索拉非尼B，口服多激酶抑制剂，目标Raf激酶和受体酪氨酸激酶，评估疗效，毒性，药代动力学，和生物标志物在晚期肝细胞癌（HCC）patients.MethodsPatients不可手术的HCC，没有以前的全身治疗，和Child-Pugh（CP）A或B，连续，口服索拉非尼B 400 mg bid在4周的周期。每两个周期使用改良的WHO标准评估肿瘤缓解。在血浆样品中测量索拉非尼的药代动力学。生物标志物分析包括磷酸化细胞外信号调节激酶（pERK）在预处理活检（免疫组化）和血细胞RNA表达模式在选定patients.ResultsOf 137例治疗（男性，71%，中位年龄，69岁），72%的CP A，28%的CP B。根据独立评估，3例（2.2%）患者达到部分缓解，8例（5.8%）患者出现轻微缓解，46例（33.6%）患者病情稳定至少16周。研究者评估的中位疾病进展时间（TTP）为4.2个月，中位总生存期为9.2个月。3/4级药物相关毒性包括疲乏（9.5%）、腹泻（8.0%）和手足皮肤反应（5.1%）。CP A和B患者之间的药代动力学无显著差异。治疗前肿瘤pERK水平与TTP相关。一组18个表达的基因被确定为区别于“nonprogressors”与“progressors”估计100% accuracy.ConclusionAlthough单药索拉非尼在HCC中具有适度的疗效，可管理的毒性和作用机制支持与其他抗癌药物的联合治疗方案的作用。
PurposeThis 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.MethodsPatients 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.ResultsOf 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.ConclusionAlthough 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.