First-in-Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors
First-in-Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors
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DOI：
10.1158/1078-0432.ccr-19-2860
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发表时间：
2020-03-01
影响因子：
11.5
通讯作者：
Hong, David S.
中科院分区：
文献类型：
--
作者：
Falchook, Gerald S.;Kurzrock, Razelle;Hong, David S.
目的：Tepotinib是一种口服、强效、高选择性MET抑制剂。这项首次人体I期试验研究了tepotinib的MTD，以确定推荐的II期剂量（RP2D）。患者和方法：患者按照三种剂量递增方案（R）之一口服tepotinib，21天为一个周期：R1，30 - 400 mg oncedeline，持续14天; R2，30 - 315 mg，每日一次，每周3次;或R3，300 - 1，400 mg，每日一次。两个周期后，病情稳定的患者可继续治疗，直至疾病进展或出现不可接受的毒性。主要终点是剂量限制性毒性（DLT）和治疗后出现的不良事件（TEAE）的发生率。次要终点包括安全性、耐受性、药代动力学、药效学和抗肿瘤作用。结果：149例患者接受tepotinib治疗（R1：n = 42; R2：n = 45; R3：n = 62）。尽管6例患者报告了DLT [R1（115 mg）中1例患者，R2（60、100、130 mg）中3例患者，R3（1，000、1，400 mg）中2例患者]，但在最高试验剂量1，400 mg每日一次时未达到MTD。tepotinib的RP2D被确定为500 mg每日一次，翻译建模数据支持足以在>= 90%的患者中实现>= 95%的MET抑制。治疗相关TEAE大多为1级或2级疲乏、外周水肿、食欲下降、恶心、呕吐和脂肪酶升高。R3中的最佳总体缓解是两名患者的部分缓解，均伴有MET过表达。结论：Tepotinib在MET失调的肿瘤中具有良好的耐受性和临床活性。tepotinib的RP2D确定为500 mg每日一次。MET异常可以驱动肿瘤发生。这项首次人体试验表明，强效、高选择性MET抑制剂tepotinib可以降低或稳定肿瘤负荷，并且在高达1，400 mg每日一次的剂量下耐受性良好。正在进行的临床试验中使用了500 mg每日一次的RP2D，该RP2D是通过整合肿瘤活检中人群药代动力学和药效学数据的转化建模和模拟确定的。
Purpose: Tepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D).Patients and Methods: Patients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30-400 mg oncedaily for 14 days; R2, 30-315 mg once daily 3 times/week; or R3, 300-1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects.Results: One hundred and forty-nine patients received tepotinib (R1: n = 42; R2: n = 45; R3: n = 62). Although six patients reported DLTs [one patient in R1 (115 mg), three patients in R2 (60, 100, 130 mg), two patients in R3 (1,000, 1,400 mg)], the MTD was not reached at the highest tested dose of 1,400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modeling data as sufficient to achieve >= 95% MET inhibition in >= 90% of patients. Treatment-related TEAEs were mostly grade 1 or 2 fatigue, peripheral edema, decreased appetite, nausea, vomiting, and lipase increase. The best overall response in R3 was partial response in two patients, both with MET overexpression.Conclusions: Tepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily. MET abnormalities can drive tumorigenesis. This first-in-man trial demonstrated that the potent, highly selective MET inhibitor tepotinib can reduce or stabilize tumor burden and is well tolerated at doses up to 1,400 mg once daily. An RP2D of 500 mg once daily, as determined from translational modeling and simulation integrating human population pharmacokinetic and pharmacodynamic data in tumor biopsies, is being used in ongoing clinical trials.