Takeda Masayuki, Ota Masahide, Iwama Eiji, Sugawara Shunichi, Shukuya Takehito, Umemura Shigeki, Tanaka Hiroshi, Oki Masahide, Takahama Takayuki, Masuda Takeshi, Nogami Naoyuki, Shimokawa Mototsugu
Department of Cancer Genomics and Medical Oncology, Nara Medical University, Nara, Japan.
Department of Cancer Genomics and Medical Oncology, Nara Medical University, Nara, Japan.
Clin Lung Cancer. 2025 May;26(3):e232-e235. doi: 10.1016/j.cllc.2024.12.004. Epub 2024 Dec 9.
MET gene exon 14 skipping was identified as a potential driver mutation that occurs in approximately 3%-4% of patients with nonsmall cell lung cancer (NSCLC), typically in the absence of other driver mutations. Capmatinib and tepotinib were the first MET- tyrosine kinase inhibitors (MET-TKIs) approved by the FDA and PMDA, specifically for patients with metastatic NSCLC. Several studies have reported acquired resistance after MET-TKI treatment for MET mutation-positive NSCLC. Sequencing of the MET kinase region of resistant cell lines revealed secondary mutations at residues D1228 and Y1230 that were sensitive to type II MET-TKIs, such as cabozantinib. This suggested that sequential administration of other MET-TKIs may overcome the development of secondary mutations after acquired resistance in MET exon 14 mutation-positive NSCLC.
We designed the single arm phase II study CAPTURE Trial to assess the efficacy of cabozantinib in patients with advanced/metastatic NSCLC with activating MET exon 14 alterations who developed acquired resistance to tepotinib or capmatinib, as well as after 2 prior chemotherapy regimens that included platinum and docetaxel. The primary endpoint was objective response rate by independent review committees. The sample size (n = 30) is calculated by assuming a threshold response rate of 5% and an expected response rate of 25%. Recruitment began in August 2024.
This ongoing study aimed to evaluate the safety and efficacy of cabozantinib after acquired resistance to tepotinib or capmatinib.
MET基因外显子14跳跃被确定为一种潜在的驱动基因突变，约3%-4%的非小细胞肺癌（NSCLC）患者会出现这种突变，通常不存在其他驱动基因突变。卡马替尼和替泊替尼是首批获美国食品药品监督管理局（FDA）和日本药品和医疗器械管理局（PMDA）批准的MET-酪氨酸激酶抑制剂（MET-TKIs），专门用于转移性NSCLC患者。多项研究报告了MET-TKI治疗MET突变阳性NSCLC后出现获得性耐药。对耐药细胞系的MET激酶区域进行测序发现，在D1228和Y1230残基处存在对II型MET-TKIs（如卡博替尼）敏感的二次突变。这表明序贯使用其他MET-TKIs可能克服MET外显子14突变阳性NSCLC获得性耐药后二次突变的发生。
我们设计了单臂II期研究CAPTURE试验，以评估卡博替尼对出现对替泊替尼或卡马替尼获得性耐药以及在接受过包括铂类和多西他赛的2种先前化疗方案后的具有激活型MET外显子14改变的晚期/转移性NSCLC患者的疗效。主要终点是独立审查委员会评估的客观缓解率。样本量（n = 30）通过假设阈值缓解率为5%和预期缓解率为25%来计算。招募工作于2024年8月开始。
这项正在进行的研究旨在评估卡博替尼在对替泊替尼或卡马替尼获得性耐药后的安全性和疗效。
