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), 21–45) 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, 6.4–12.7). The median progression-free survival was 7.3 months (95% CI, 5.4–9.1). 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.

MET外显子 14 改变是非小细胞肺癌 (NSCLC) 的致癌驱动因素¹。这些改变与增加的 MET 活性和对 MET 抑制的临床前敏感性有关²。克唑替尼是一种多激酶抑制剂，对 MET ³具有强效活性。在 69 名携带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 名可评估反应的患者中，客观反应率为 32%（95% 置信区间 (CI)，21-45）。观察到的客观反应独立于表征这些癌症的分子异质性，并且不因MET的剪接位点区域和突变类型而变化外显子 14 改变、同时增加的MET拷贝数或检测到循环肿瘤 DNA 中的MET外显子 14 改变。中位缓解持续时间为 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 改变定义了一个 NSCLC 的分子亚组，其中克唑替尼的 MET 抑制是有效的。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未满足需求，并增加了针对 NSCLC 致癌亚群的基因组驱动疗法的扩展列表。