BACKGROUND & AIMS Sorafenib, an oral multikinase inhibitor, significantly prolonged overall survival (OS) vs. placebo in patients with unresectable hepatocellular carcinoma (HCC) in two phase III studies, SHARP (Sorafenib HCC Assessment Randomized Protocol) and Asia Pacific (AP). To assess prognostic factors for HCC and predictive factors of sorafenib benefit, we conducted a pooled exploratory analysis from these placebo-controlled phase III studies. METHODS To identify potential prognostic factors for OS, univariate and multivariate (MV) analyses were performed for baseline variables by Cox proportional hazards model. Hazard ratios (HRs) and median OS were evaluated across pooled subgroups. To assess factors predictive of sorafenib benefit, the interaction term between treatment for each subgroup was evaluated by Cox proportional hazard model. RESULTS In 827 patients (448 sorafenib; 379 placebo) analyzed, strong prognostic factors for poorer OS identified from MV analysis in both treatment arms were presence of macroscopic vascular invasion (MVI), high alpha-fetoprotein (AFP), and high neutrophil-to-lymphocyte ratio (NLR; ⩽ vs. >median [3.1]). Sorafenib OS benefit was consistently observed across all subgroups. Significantly greater OS sorafenib benefit vs. placebo was observed in patients without extrahepatic spread (EHS; HR, 0.55 vs. 0.84), with hepatitis C virus (HCV) (HR, 0.47 vs. 0.81), and a low NLR (HR, 0.59 vs. 0.84). CONCLUSIONS In this exploratory analysis, presence of MVI, high AFP, and high NLR were prognostic factors of poorer OS. Sorafenib benefit was consistently observed irrespective of prognostic factors. Lack of EHS, HCV, and lower NLR were predictive of a greater OS benefit with sorafenib. LAY SUMMARY This exploratory pooled analysis showed that treatment with sorafenib provides a survival benefit in all subgroups of patients with HCC; however, the magnitude of benefit is greater in patients with disease confined to the liver (without extrahepatic spread), or in those with hepatitis C virus, or a lower neutrophil-to-lymphocyte ratio, an indicator of inflammation status. These results help inform the prognosis of patients receiving sorafenib therapy and provide further refinements for the design of trials testing new agents vs. sorafenib. Clinical Trial Numbers: NCT00105443 and NCT00492752.

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肝细胞癌患者索拉非尼获益的预后因素和预测因素：两项 III 期研究的分析

背景与目的 索拉非尼是一种口服多激酶抑制剂，与安慰剂相比，在两项 III 期研究、SHARP（索拉非尼 HCC 评估随机方案）和亚太 (AP) 研究中，与安慰剂相比显着延长了不可切除肝细胞癌 (HCC) 患者的总生存期 (OS)。为了评估 HCC 的预后因素和索拉非尼获益的预测因素，我们对这些安慰剂对照的 III 期研究进行了汇总探索性分析。方法 为了确定 OS 的潜在预后因素，通过 Cox 比例风险模型对基线变量进行单变量和多变量 (MV) 分析。跨合并亚组评估风险比 (HR) 和中位 OS。为了评估索拉非尼获益的预测因素，通过 Cox 比例风险模型评估每个亚组治疗之间的相互作用项。结果 在分析的 827 名患者（448 名索拉非尼；379 名安慰剂）中，从两个治疗组的 MV 分析中确定的较差 OS 的强预后因素是存在肉眼可见的血管侵犯 (MVI)、高甲胎蛋白 (AFP) 和高中性粒细胞-淋巴细胞比率（NLR；⩽ vs. >中值 [3.1]）。在所有亚组中一致观察到索拉非尼 OS 获益。在没有肝外扩散（EHS；HR，0.55 对 0.84）、丙型肝炎病毒（HCV）（HR，0.47 对 0.81）和低 NLR（HR，0.59）的患者中，索拉非尼的 OS 获益显着高于安慰剂与 0.84)。结论 在该探索性分析中，MVI、高 AFP 和高 NLR 的存在是较差 OS 的预后因素。无论预后因素如何，始终观察到索拉非尼的益处。缺乏 EHS、HCV、较低的 NLR 预示着索拉非尼的 OS 获益更大。初步总结 本次探索性汇总分析表明，索拉非尼治疗可在所有 HCC 患者亚组中提供生存获益；然而，对于局限于肝脏的疾病（没有肝外扩散）、丙型肝炎病毒或中性粒细胞与淋巴细胞比率较低的患者（炎症状态的一个指标），获益的幅度更大。这些结果有助于告知接受索拉非尼治疗的患者的预后，并为测试新药与索拉非尼的试验设计提供进一步的改进。临床试验编号：NCT00105443 和 NCT00492752。然而，对于局限于肝脏的疾病（没有肝外扩散）、丙型肝炎病毒或中性粒细胞与淋巴细胞比率较低的患者（炎症状态的一个指标），获益的幅度更大。这些结果有助于告知接受索拉非尼治疗的患者的预后，并为测试新药与索拉非尼的试验设计提供进一步的改进。临床试验编号：NCT00105443 和 NCT00492752。然而，对于局限于肝脏的疾病（没有肝外扩散）、丙型肝炎病毒或中性粒细胞与淋巴细胞比率较低的患者（炎症状态的一个指标），获益的幅度更大。这些结果有助于告知接受索拉非尼治疗的患者的预后，并为测试新药与索拉非尼的试验设计提供进一步的改进。临床试验编号：NCT00105443 和 NCT00492752。索拉非尼。临床试验编号：NCT00105443 和 NCT00492752。索拉非尼。临床试验编号：NCT00105443 和 NCT00492752。