美国纪念斯隆·凯特琳癌症中心Alexander Drilon团队提出了克唑替尼在MET外显子14改变的肺癌中的抗肿瘤活性。该研究2020年1月13日在线发表于国际学术期刊《自然—医学》。

MET第14外显子的改变是非小细胞肺癌（NSCLC）的致癌驱动因素。这些改变与MET活性增加和对MET抑制的临床前敏感性有关。克唑替尼是一种多激酶抑制剂，对MET3具有强活性。在69名患有MET外显子14改变的晚期NSCLC患者中评估了克唑替尼的抗肿瘤活性和安全性。在65例可评估反应的患者中，客观缓解率为32%（95%置信区间（CI）为21-45）。观察到客观反应，独立于表征这些癌症的分子异质性，并且未因剪接位点区域和MET外显子14改变的突变类型，并发MET拷贝数增加或循环肿瘤DNA中MET外显子14突变的检测而变化。中位缓解时间为9.1个月（95%CI，6.4-12.7）。中位无进展生存期为7.3个月（95%CI，5.4-9.1）。MET外显子14的改变定义了NSCLC的分子亚型，克唑替尼对MET具有抑制作用。

这些结果解决了具有MET外显子14改变的肺癌患者对靶向治疗的需求未得到满足的问题，并增加了基因组驱动的NSCLC致癌亚型治疗的途径。

附：英文原文

Title: Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration

Author: Alexander Drilon, Jeffrey W. Clark, Jared Weiss, Sai-Hong Ignatius Ou, D. Ross Camidge, Benjamin J. Solomon, Gregory A. Otterson, Liza C. Villaruz, Gregory J. Riely, Rebecca S. Heist, Mark M. Awad, Geoffrey I. Shapiro, Miyako Satouchi, Toyoaki Hida, Hidetoshi Hayashi, Danielle A. Murphy, Sherry C. Wang, Sherry Li, Tiziana Usari, Keith D. Wilner, Paul K. Paik

Issue&Volume: 2020/01/13

Abstract: MET exon 14 alterations are oncogenic drivers of non-small-cell lung cancers (NSCLCs)1. These alterations are associated with increased MET activity and preclinical sensitivity to MET inhibition2. Crizotinib is a multikinase inhibitor with potent activity against MET3. The antitumor activity and safety of crizotinib were assessed in 69 patients with advanced NSCLCs harboring MET exon 14 alterations. Objective response rate was 32% (95% confidence interval (CI), 2145) among 65 response-evaluable patients. Objective responses were observed independent of the molecular heterogeneity that characterizes these cancers and did not vary by splice-site region and mutation type of the MET exon 14 alteration, concurrent increased MET copy number or the detection of a MET exon 14 alteration in circulating tumor DNA. The median duration of response was 9.1 months (95% CI, 6.412.7). The median progression-free survival was 7.3 months (95% CI, 5.49.1). MET exon 14 alteration defines a molecular subgroup of NSCLCs for which MET inhibition with crizotinib is active. These results address an unmet need for targeted therapy in people with lung cancers with MET exon 14 alterations and adds to an expanding list of genomically driven therapies for oncogenic subsets of NSCLC. Results from an expansion cohort of the PROFILE 1001 trial describe the anti-tumor activity of crizotinib in people with non-small-cell lung cancer harboring a MET exon 14 alteration.

DOI: 10.1038/s41591-019-0716-8

Source:https://www.nature.com/articles/s41591-019-0716-8