Background The objectives of this phase II study were to determine the clinical activity of the MET tyrosine kinase inhibitor capmatinib (INC280) in patients with MET-dysregulated advanced hepatocellular carcinoma (HCC) and to assess the safety, pharmacokinetics, and correlation of biomarkers with the response. Methods This phase II, open-label, single-arm study evaluated twice daily (BID) oral capmatinib in a dose-determining stage, utilizing a Bayesian Logistic Regression Model (BLRM) subject to Escalation with Overdose Control criteria, safety, pharmacokinetics, and pharmacodynamic information to determine a recommended dose for expansion (RDE) evaluating efficacy in patients with MET-dysregulated HCC. Results A total of 38 patients received treatment. In the dose-determining stage, patients received capmatinib 300 mg BID capsules (n = 8), and in the expansion, patients received 600 mg BID capsules (n = 28) or 400 mg BID tablets (n = 2) based on the BLRM and other relevant clinical data. No predefined qualifying adverse events (AEs) were observed during the first 28 days of treatment, and the RDE was 600 mg BID capsules (equivalent pharmacokinetics to 400 mg BID tablets). The most common any causality AEs were nausea (42%), vomiting (37%), and diarrhea (34%). In the expansion stage, in a subgroup of 10 patients with MET-high HCC, the overall response rate was 30%, including 1 durable complete response (>600 days) and 2 partial responses [1 durable (>600 days)]. Conclusions Single agent capmatinib at the RDE is tolerable with a manageable safety profile. Antitumor activity was seen in a subset of patients with MET-dysregulated (MET-high) HCC. Trial registration ClinicalTrials.gov: NCT01737827. https://clinicaltrials.gov/ct2/show/NCT01737827.

中文翻译：

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MET 抑制剂卡马替尼 (INC280) 在晚期肝细胞癌患者中的疗效和安全性的 II 期研究。

背景这项 II 期研究的目的是确定 MET 酪氨酸激酶抑制剂卡马替尼 (INC280) 在 MET 失调的晚期肝细胞癌 (HCC) 患者中的临床活性，并评估生物标志物的安全性、药代动力学和相关性。回复。方法 这项 II 期、开放标签、单臂研究在剂量确定阶段使用贝叶斯逻辑回归模型 (BLRM) 评估每日两次 (BID) 口服卡马替尼，该模型受过量控制标准、安全性、药代动力学和药效学信息以确定扩展推荐剂量 (RDE)，以评估 MET 失调 HCC 患者的疗效。结果共38例患者接受治疗。在剂量确定阶段，患者接受了卡马替尼 300 mg BID 胶囊（n = 8），在扩展中，根据 BLRM 和其他相关临床数据，患者接受了 600 mg BID 胶囊（n = 28）或 400 mg BID 片剂（n = 2）。在治疗的前 28 天内未观察到预定义的合格不良事件 (AE)，RDE 为 600 mg BID 胶囊（药代动力学与 400 mg BID 片剂等效）。最常见的任何因果 AE 是恶心 (42%)、呕吐 (37%) 和腹泻 (34%)。在扩展阶段，在 10 名 MET 高 HCC 患者的亚组中，总体反应率为 30%，包括 1 名持久完全反应（>600 天）和 2 名部分反应[1 名持久（>600 天）]。结论 RDE 的单药卡马替尼是可耐受的，安全性可控。在一部分 MET 失调（MET 高）HCC 患者中观察到抗肿瘤活性。试验注册 ClinicalTrials.gov：NCT01737827。https://clinicaltrials.gov/ct2/show/NCT01737827。