Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
Institute of Clinical Pharmacology, GCP Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
Oncologist. 2021 Aug;26(8):649-e1313. doi: 10.1002/onco.13760. Epub 2021 Apr 24.
MET overexpression is uncommon, and positive MET immunohistochemistry (1+/2+) was an independent positive prognostic factor for response rate and progression-free survival. Whether MET overexpression can be considered a potential predictive biomarker and be used as an inclusion criterion is worth investigating in a future study.
Metatinib tromethamine tablet (metatinib) is a small molecule receptor kinase inhibitor targeting both c-MET and vascular endothelial growth factor receptor 2. This phase I trial aimed to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD), pharmacokinetics, safety, and efficacy of metatinib in patients with advanced solid tumors.
Eligible patients received a single dose of metatinib in a 3 + 3 dose-escalation design with dose levels of 25-800 mg/day, after a single dose on day 1, then 2 days off, and then a multidose schedule of once-daily doses for 25 consecutive days (days 4-28). Primary endpoints were MTD and safety; secondary and exploratory endpoints included pharmacokinetics (PK), efficacy, and biomarkers.
Eighteen patients (including nine patients with hepatocellular carcinoma [HCC]) received at least one dose of study drug (one patient quit the study without continuous multiple-dose administration after receiving a single dose of metatinib). Hand-foot skin reaction, diarrhea, and liver dysfunction were the DLTs, and 200 mg/day was the MTD. The most common treatment-related adverse events (TRAEs) were skin toxicity (50%), diarrhea (33.3%), and liver dysfunction (27.8%). Three patients (only one of six in the 200 mg/day cohort; the other two in the 300 mg/day cohort) experienced severe TRAEs: one patient with severe liver dysfunction and two patients with severe liver dysfunction and skin toxicity, respectively. Pharmacokinetics assessment indicated that metatinib was rapidly absorbed and metabolized to the formation of reactive metabolite, SCR-1510, after single-dose administration. The mean time taken to achieve maximum concentration and terminal elimination half-life of SCR-1510 was approximately 2.0-3.0 hours and ranged from 8 to 14 hours. Two patients had partial responses. The objective response rate and disease control rate (DCR) were 11.1% and 61.1%, respectively. The median progression-free survival (PFS) was 2.75 months.
Metatinib administration of 200 mg/day was well tolerated, safe, and effective. The MTD was 200 mg/day, which should be recommended in further investigations.
MET 过表达并不常见，MET 免疫组化阳性（1+/2+）是反应率和无进展生存期的独立阳性预后因素。MET 过表达是否可以被认为是一种潜在的预测生物标志物，并作为纳入标准，值得在未来的研究中进行探讨。
盐酸替泊替尼片（替泊替尼）是一种针对 c-MET 和血管内皮生长因子受体 2 的小分子受体激酶抑制剂。这项 I 期试验旨在确定替泊替尼在晚期实体瘤患者中的剂量限制性毒性（DLT）和最大耐受剂量（MTD）、药代动力学、安全性和疗效。
符合条件的患者在 3+3 剂量递增设计中接受单次剂量替泊替尼治疗，剂量水平为 25-800mg/天，在第 1 天单次给药后，停药 2 天，然后进行 25 天的每日一次连续剂量方案（第 4-28 天）。主要终点为 MTD 和安全性；次要和探索性终点包括药代动力学（PK）、疗效和生物标志物。
18 名患者（包括 9 名肝细胞癌 [HCC] 患者）接受了至少一剂研究药物（1 名患者在接受替泊替尼单次剂量后停止研究，未连续多次给药）。手足皮肤反应、腹泻和肝功能障碍是 DLT，200mg/天是 MTD。最常见的治疗相关不良事件（TRAEs）是皮肤毒性（50%）、腹泻（33.3%）和肝功能障碍（27.8%）。3 名患者（仅在 200mg/天组的 6 名患者中的 1 名；另外 2 名在 300mg/天组的患者）发生严重 TRAE：1 名患者出现严重肝功能障碍，2 名患者出现严重肝功能障碍和皮肤毒性。药代动力学评估表明，替泊替尼在单次给药后迅速吸收并代谢形成活性代谢物 SCR-1510。SCR-1510 达到最大浓度和终末消除半衰期的平均时间约为 2.0-3.0 小时，范围为 8-14 小时。2 名患者有部分缓解。客观缓解率和疾病控制率（DCR）分别为 11.1%和 61.1%。中位无进展生存期（PFS）为 2.75 个月。
替泊替尼 200mg/天的给药耐受良好，安全有效。MTD 为 200mg/天，应在进一步研究中推荐。
