Background: The mammalian target of rapamycin (mTOR) pathway is upregulated in nearly half of hepatocellular carcinoma (HCC) tumors and is associated with poor prognosis. In preclinical models of HCC, the combination of mTOR pathway inhibition with the multikinase inhibitor sorafenib improves treatment efficacy. A prior phase I study of the allosteric mTOR inhibitor temsirolimus combined with sorafenib demonstrated acceptable safety at the recommended phase II dose. Methods: We conducted a single-arm, multicenter phase II trial of the combination of temsirolimus 10 mg intravenously weekly plus sorafenib 200 mg b.i.d. The primary endpoint was time to progression (TTP) with efficacy target of median TTP of at least 6 months; secondary endpoints included overall survival (OS), objective response rate, safety, and alpha-fetoprotein (AFP) tumor marker response. Next-generation tumor sequencing was performed as an exploratory endpoint. Results: Twenty-nine patients were enrolled, including 48% with hepatitis C virus infection and 28% with hepatitis B virus; 86% had Barcelona clinic liver cancer stage C disease. Among 28 patients evaluable for efficacy, the median TTP was 3.7 (95% confidence interval [CI]: 2.2, 5.3) months, with 14% of patients achieving TTP of at least 6 months. The median OS was 8.8 (95% CI: 6.8, 14.8) months. There were no complete or partial responses; 75% of patients had stable disease as best response. AFP decline by at least 50% was associated with prolonged TTP and OS. Serious adverse events occurred in 21%; the most common treatment-related adverse events of CTCAE grade 3 or higher were hypophosphatemia (36%), thrombocytopenia (14%), and rash (11%). There were no grade 5 events attributed to sorafenib or temsirolimus. Tumor next-generation sequencing (NGS) was performed in a subgroup of 24 patients with adequate tumor samples. Tumor mTOR pathway mutations were identified in 42%. There was no association between tumor mutation profile and OS or TTP. Conclusions: The combination of temsirolimus and sorafenib demonstrated acceptable safety but did not achieve the target threshold for efficacy in this phase II study. Tumor NGS including the presence of mTOR pathway mutations was not associated with treatment response in an exploratory subgroup analysis.
Liver Cancer

中文翻译：

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替西罗莫司和索拉非尼联合治疗晚期肝细胞癌肿瘤突变分析的 II 期试验

背景：哺乳动物雷帕霉素靶蛋白 ( mTOR ) 通路在近一半的肝细胞癌 (HCC) 肿瘤中上调，并且与预后不良有关。在 HCC 的临床前模型中， mTOR通路抑制与多激酶抑制剂索拉非尼的组合提高了治疗效果。变构 mTOR 抑制剂 temsirolimus 联合索拉非尼的先前 I 期研究表明，在推荐的 II 期剂量下，安全性可接受。方法：我们进行了一项单臂、多中心 II 期试验，联合使用每周 10 mg 静脉注射的 temsirolimus 和 200 mg bid 的索拉非尼。主要终点是进展时间（TTP），疗效目标中位 TTP 至少为 6 个月；次要终点包括总生存期（OS）、客观反应率、安全性和甲胎蛋白（AFP）肿瘤标志物反应。下一代肿瘤测序作为探索性终点进行。结果：入组 29 名患者，其中 48% 感染丙型肝炎病毒，28% 感染乙型肝炎病毒；86% 患有巴塞罗那临床肝癌 C 期疾病。在可评估疗效的 28 名患者中，中位 TTP 为 3.7（95% 置信区间 [CI]：2.2, 5.3）个月，14% 的患者达到至少 6 个月的 TTP。中位 OS 为 8.8 (95% CI: 6.8, 14.8) 个月。没有完全或部分反应；75%的患者病情稳定作为最佳反应。AFP 下降至少 50% 与 TTP 和 OS 延长有关。21% 发生严重不良事件；CTCAE 3 级或更高级别最常见的治疗相关不良事件是低磷血症 (36%)、血小板减少症 (14%) 和皮疹 (11%)。没有归因于索拉非尼或替西罗莫司的 5 级事件。在具有足够肿瘤样本的 24 名患者的亚组中进行了肿瘤下一代测序 (NGS)。瘤mTOR通路突变在 42% 中被发现。肿瘤突变谱与 OS 或 TTP 之间没有关联。结论：在这项 II 期研究中，西罗莫司和索拉非尼的组合表现出可接受的安全性，但未达到疗效的目标阈值。在探索性亚组分析中，包括存在mTOR通路突变的肿瘤 NGS 与治疗反应无​​关。
肝癌