METex14 skipping mutations occur in about 3–4% of lung adenocarcinoma patients and 1–2% of patients with other lung cancer histology. The MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) are established oncogenic drivers of NSCLC. A mutation that results in loss of exon 14 in the MET gene leads to dysregulation and inappropriate signaling that is associated with increased responsiveness to MET TKIs. Results from GEOMETRY mono-1 and VISION Phase I/II clinical trials demonstrated significant clinical activity in patients treated with the MET Exon 14 skipping mutation inhibitors capmatinib and tepotinib with tolerable toxicity profile. In the GEOMETRY mono-1 trial, capmatinib was especially active in treatment-naïve patients supporting the upfront testing of this oncogenic driver. Tepotinib demonstrated superior activity in the pretreated patients in the VISION trial. Savolitinib is another MET TKI that has shown efficacy in the first- and second-line settings, including patients with aggressive pulmonary sarcomatoid carcinoma. These studies have demonstrated that these TKIs can cross the blood brain barrier and demonstrated some activity toward CNS metastases. MET Exon 14 skipping mutation is detected by NGS-based testing of liquid or tissue biopsies, with preference for RNA-based NGS. The activity of capmatinib and tepotinib is limited by the development of acquired resistance. Current research is focused on strategies to overcome resistance and improve the effectiveness of these agents. Our aim is to review the current status of MET Exon 14 skipping mutation as it pertains NSCLC.

中文翻译：

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METex14跳过突变非小细胞肺癌的治疗策略

METex14 跳跃突变发生在约 3-4% 的肺腺癌患者和 1-2% 的其他肺癌组织学患者中。MET受体酪氨酸激酶及其配体肝细胞生长因子（HGF）是非小细胞肺癌的既定致癌驱动因素。导致 MET 基因中外显子 14 缺失的突变会导致失调和不适当的信号传导，这与对 MET TKI 的反应性增加有关。GEOMETRY mono-1 和 VISION I/II 期临床试验的结果表明，在接受 MET 外显子 14 跳跃突变抑制剂 capmatinib 和 tepotinib 治疗的患者中具有显着的临床活性，具有可耐受的毒性特征。在 GEOMETRY mono-1 试验中，卡马替尼在支持对这种致癌驱动因素进行前期测试的初治患者中特别活跃。在 VISION 试验中，Tepotinib 在预先治疗的患者中表现出优异的活性。Savolitinib 是另一种 MET TKI，已在一线和二线环境中显示出疗效，包括侵袭性肺肉瘤样癌患者。这些研究表明，这些 TKI 可以穿过血脑屏障，并对 CNS 转移具有一定的活性。MET 外显子 14 跳跃突变通过基于 NGS 的液体或组织活检检测来检测，优选基于 RNA 的 NGS。Capmatinib 和 tepotinib 的活性受到获得性耐药的发展的限制。目前的研究集中在克服耐药性和提高这些药物有效性的策略上。我们的目的是回顾与 NSCLC 相关的 MET 外显子 14 跳跃突变的现状。