Santarpia Mariacarmela, Massafra Marco, Gebbia Vittorio, D'Aquino Antonio, Garipoli Claudia, Altavilla Giuseppe, Rosell Rafael
Medical Oncology Unit, Department of Human Patology "G. Barresi", University of Messina, Messina, Italy.
Medical Oncology and Supportive Care Unit, La Maddalena Cancer Center, Palermo, Italy.
Transl Lung Cancer Res. 2021 Mar;10(3):1536-1556. doi: 10.21037/tlcr-20-1113.
Treatment of advanced non-small cell lung cancer (NSCLC) has radically improved in the last years due to development and clinical approval of highly effective agents including immune checkpoint inhibitors (ICIs) and oncogene-directed therapies. Molecular profiling of lung cancer samples for activated oncogenes, including epidermal growth factor receptor (), anaplastic lymphoma kinase (), c-ros oncogene 1 () and , is routinely performed to select the most appropriate up-front treatment. However, the identification of new therapeutic targets remains a high priority. Recently, exon 14 skipping mutations have emerged as novel actionable oncogenic alterations in NSCLC, sensitive to MET inhibition. In this review we discuss: (I) gene and MET receptor structure and signaling pathway; (II) exon 14 alterations; (III) current data on MET inhibitors, mainly focusing on selective MET tyrosine kinase inhibitors (TKIs), in the treatment of NSCLC with exon 14 skipping mutations. We identified the references for this review through a literature search of papers about MET, exon 14 skipping mutations, and MET inhibitors, published up to September 2020, by using PubMed, Scopus and Web of Science databases. We also searched on websites of main international cancer congresses (ASCO, ESMO, IASLC) for ongoing studies presented as abstracts. exon 14 skipping mutations have been associated with clinical activity of selective MET inhibitors, including capmatinib, that has recently received approval by FDA for clinical use in this subgroup of NSCLC patients. A large number of trials are testing MET inhibitors, also in combinatorial therapeutic strategies, in exon 14-altered NSCLC. Results from these trials are eagerly awaited to definitively establish the role and setting for use of these agents in NSCLC patients.
在过去几年中，由于包括免疫检查点抑制剂（ICIs）和致癌基因导向疗法在内的高效药物的研发和临床批准，晚期非小细胞肺癌（NSCLC）的治疗有了根本性的改善。对肺癌样本进行激活致癌基因的分子分析，包括表皮生长因子受体（EGFR）、间变性淋巴瘤激酶（ALK）、c-ros癌基因1（ROS1）等，已成为常规操作，以选择最合适的一线治疗方案。然而，确定新的治疗靶点仍然是重中之重。最近，第14外显子跳跃突变已成为NSCLC中对MET抑制敏感的新型可操作致癌改变。在本综述中，我们将讨论：（I）MET基因和MET受体结构及信号通路；（II）MET第14外显子改变；（III）MET抑制剂的当前数据，主要侧重于选择性MET酪氨酸激酶抑制剂（TKIs）在治疗具有第14外显子跳跃突变的NSCLC中的应用。我们通过使用PubMed、Scopus和Web of Science数据库，对截至2020年9月发表的有关MET、MET第14外显子跳跃突变和MET抑制剂的论文进行文献检索，确定了本综述的参考文献。我们还在主要国际癌症大会（美国临床肿瘤学会、欧洲肿瘤内科学会、国际肺癌研究协会）的网站上搜索了以摘要形式发表的正在进行的研究。MET第14外显子跳跃突变与选择性MET抑制剂（包括卡马替尼）的临床活性相关，卡马替尼最近已获得美国食品药品监督管理局批准，可用于该亚组NSCLC患者的临床治疗。大量试验正在测试MET抑制剂，也包括联合治疗策略，用于治疗第14外显子改变的NSCLC。人们急切期待这些试验的结果，以最终确定这些药物在NSCLC患者中的作用和使用方式。
