START Madrid-FJD, Hospital Fundación Jímenez Díaz, Madrid, Spain.
IIIrd Medical Department, Paracelsus Medical University, Salzburg Cancer Research Institute, Salzburg, Austria.
Clin Ther. 2021 Jun;43(6):1092-1111. doi: 10.1016/j.clinthera.2021.04.006. Epub 2021 May 27.
In the Phase II GEOMETRY mono-1 study, the potent and selective mesenchymal-epithelial transition (MET) inhibitor capmatinib exhibited considerable efficacy in MET exon 14 skipping (METex14)-mutated metastatic non-small cell lung cancer at a dose of 400 mg BID. The current recommended dose is 400 mg BID in tablet formulation, with or without food. This article reports the pharmacokinetic (PK) profile, safety, and tolerability of capmatinib 300 and 400 mg BID given with food in MET-dysregulated advanced solid tumors.
This multicenter, open-label, Phase I study enrolled adult patients with MET-dysregulated advanced solid tumors. In the dose escalation phase, capmatinib tablets were orally administered at a dose of 300 mg BID with food; if tolerated, the dose escalation cohort of 400 mg BID was to be opened to enrollment. In the expansion phase, patients were to be enrolled at the higher of the tolerated doses. Tablets were taken within 30 minutes of an unrestricted meal type, except on cycle 1 day 1 (C1D1) and cycle 1 day 7 (C1D7), when they were given with a high-fat meal. The primary objectives were to determine the higher of the tolerated study doses and assess PK variables, with a secondary objective of safety.
Overall, 35 patients (300 mg BID, n = 8; 400 mg BID, n = 27) with MET-dysregulated advanced solid tumors were enrolled; all patients had received prior antineoplastic therapy, and the most common primary site was lung (45.7%). Among PK-evaluable patients, the median T for capmatinib after administration with a high-fat meal (on C1D1/C1D7) was 4.0 to 5.6 hours across doses. At steady state (C1D7), capmatinib accumulation was low across dose levels (geometric mean of accumulation ratios, 1.29-1.69), with an increase in exposure (AUC and C) from 300 to 400 mg BID. There were no occurrences of dose-limiting toxicity. All patients experienced at least 1 adverse event, and treatment-related adverse events occurred in 28 patients (80%; 300 mg BID, n = 6; 400 mg BID, n = 22), the most frequent of which were fatigue (37.1%) and nausea (34.3%).
Capmatinib tablet formulation at a dose of up to 400 mg BID with food is well tolerated in patients with MET-dysregulated advanced solid tumors, with safety observations consistent with the existing profile under fasted conditions. These findings support the capmatinib dosing recommendation of 400 mg BID with or without food. ClinicalTrials.gov identifier: NCT02925104.
在 II 期 GEOMETRY mono-1 研究中，高选择性的间质上皮转化（MET）抑制剂卡马替尼在剂量为 400mg，每日两次（BID）时，在 MET 外显子 14 跳跃（METex14）突变的转移性非小细胞肺癌中显示出显著疗效。目前推荐的剂量为 400mg，每日两次，片剂形式，无论是否与食物同服。本文报告了 MET 失调的晚期实体瘤患者中，卡马替尼 300mg 和 400mg BID 随食物给药的药代动力学（PK）特征、安全性和耐受性。
这项多中心、开放标签、I 期研究纳入了 MET 失调的晚期实体瘤患者。在剂量递增阶段，卡马替尼片剂每日随食物口服 300mg BID；如果耐受，将开放剂量递增队列至 400mg BID。在扩展阶段，将以耐受的较高剂量入组患者。片剂应在不受限制的餐型后 30 分钟内服用，除非在第 1 周期第 1 天（C1D1）和第 1 周期第 7 天（C1D7），此时需要与高脂肪餐同服。主要目标是确定可耐受的较高研究剂量，并评估 PK 变量，次要目标是安全性。
总体而言，35 名（300mg BID，n=8；400mg BID，n=27）MET 失调的晚期实体瘤患者入组；所有患者均接受过抗肿瘤治疗，最常见的原发部位是肺部（45.7%）。在可进行 PK 评估的患者中，高脂肪餐给药（在 C1D1/C1D7）后卡马替尼的中位 T 为 4.0 至 5.6 小时，剂量间存在差异。在稳态（C1D7）时，卡马替尼在各剂量水平的蓄积较低（几何均数蓄积比为 1.29-1.69），从 300mg BID 增加至 400mg BID 时，暴露量（AUC 和 C）增加。未发生剂量限制毒性。所有患者至少发生 1 次不良事件，28 例（80%；300mg BID，n=6；400mg BID，n=22）患者发生与治疗相关的不良事件，最常见的不良事件是疲劳（37.1%）和恶心（34.3%）。
MET 失调的晚期实体瘤患者中，卡马替尼片剂剂量高达 400mg BID 时，随食物给药具有良好的耐受性，安全性观察结果与禁食条件下的现有情况一致。这些发现支持卡马替尼 400mg BID，无论是否与食物同服的推荐剂量。临床试验注册编号：NCT02925104。
