University of Colorado Cancer Center, Aurora, Colorado.
Ohio State University, Columbus, Ohio.
J Thorac Oncol. 2021 Jun;16(6):1017-1029. doi: 10.1016/j.jtho.2021.02.010. Epub 2021 Mar 4.
MET amplification is a rare, potentially actionable, primary oncogenic driver in patients with NSCLC.
The influence of MET amplification on the clinical activity of the ALK, ROS1, and MET inhibitor, crizotinib (250 mg twice daily), was examined in patients with NSCLC (NCT00585195) who were enrolled into high (≥4 MET-to-CEP7 ratio), medium (>2.2 to <4 MET-to-CEP7 ratio), or low (≥1.8 to ≤2.2 MET-to-CEP7 ratio) amplification categories. Retrospective next-generation sequencing profiling was performed on archival tumor tissue. End points included objective response rate (ORR), duration of response, and progression-free survival.
A total of 38 patients with a MET-to-CEP7 ratio greater than or equal to 1.8 by local fluorescence in situ hybridization testing received crizotinib. All patients were response-assessable, among whom 21, 14, and 3 had high, medium, and low MET amplification, respectively. ORRs of 8 of 21 (38.1%), 2 of 14 (14.3%), and 1 of 3 (33.3%), median duration of response of 5.2, 3.8, and 12.2 months, and median progression-free survival values of 6.7, 1.9, and 1.8 months were observed for those with high, medium, and low MET amplification, respectively. MET amplification gene copy number greater than or equal to 6 was detected by next-generation sequencing in 15 of 19 (78.9%) analyzable patients. Of these 15 patients, objective responses were observed in six (40%), two of whom had concurrent MET exon 14 alterations. No responses were observed among five patients with concurrent KRAS, BRAF, or EGFR mutations.
Patients with high-level, MET-amplified NSCLC responded to crizotinib with the highest ORR. Use of combined diagnostics for MET and other oncogenes may potentially identify patients most likely to respond to crizotinib.
MET 扩增是 NSCLC 患者中一种罕见的、潜在可治疗的主要致癌驱动因素。
在接受 NSCLC 治疗的患者中（NCT00585195），检查 MET 扩增对 ALK、ROS1 和 MET 抑制剂克唑替尼（250mg，每日两次）的临床活性的影响，这些患者被纳入高（≥4 MET-CEP7 比值）、中（>2.2 至 <4 MET-CEP7 比值）或低（≥1.8 至≤2.2 MET-CEP7 比值）扩增类别。对存档肿瘤组织进行回顾性下一代测序分析。终点包括客观缓解率（ORR）、缓解持续时间和无进展生存期。
共有 38 名 MET-CEP7 比值≥1.8 的患者接受了克唑替尼治疗。所有患者均有反应评估，其中 21 名、14 名和 3 名患者的 MET 扩增分别为高、中、低。21 名患者中有 8 名（38.1%）、14 名患者中有 2 名（14.3%）、3 名患者中有 1 名（33.3%）观察到 ORR，高、中、低 MET 扩增患者的中位缓解持续时间分别为 5.2、3.8 和 12.2 个月，中位无进展生存时间分别为 6.7、1.9 和 1.8 个月。在 19 名可分析患者中，有 15 名（78.9%）通过下一代测序检测到 MET 扩增基因拷贝数≥6。在这 15 名患者中，有 6 名（40%）观察到客观缓解，其中 2 名患者同时存在 MET 外显子 14 改变。在 5 名同时存在 KRAS、BRAF 或 EGFR 突变的患者中，没有观察到缓解。
高水平 MET 扩增的 NSCLC 患者对克唑替尼的 ORR 最高。联合使用 MET 和其他致癌基因的联合诊断可能有助于识别最有可能对克唑替尼有反应的患者。
