Table_1_Non-small cell lung cancer with MET amplification: review of epidemiology, associated disease characteristics, testing procedures, burden, and treatments.docx

IntroductionMesenchymal-epidermal transition factor gene amplification (METamp) is being investigated as a therapeutic target in advanced non-small cell lung cancer (NSCLC). We reviewed the epidemiology and disease characteristics associated with primary and secondary METamp, as well as the testing procedures used to identify METamp, in advanced NSCLC. Economic and humanistic burdens, and the practice patterns and treatments under investigation for METamp were also examined.
MethodsEmbase and Medline (via ProQuest), ClinicalTrials.gov, and Cochrane Controlled Register of Trials (2015–2022) were systematically searched. Conference abstracts were searched via Embase and conference proceedings websites (2020–2022). The review focused on evidence from the United States; global evidence was included for identified evidence gaps.
ResultsThe median rate of primary METamp in NSCLC across the references was 4.8% (n=4 studies) and of secondary METamp (epidermal growth factor receptor [EGFR]-mutant NSCLC) was 15% (n=10). Next-generation sequencing (NGS; n=12) and/or fluorescence in situ hybridization (FISH; n=11) were most frequently used in real-world studies and FISH testing most frequently used in clinical trials (n=9/10). METamp definitions varied among clinical trials using ISH/FISH testing (MET to chromosome 7 centromere ratio of ≥1.8 to ≥3.0; or gene copy number [GCN] ≥5 to ≥10) and among trials using NGS (tissue testing: GCN ≥6; liquid biopsy: MET copy number ≥2.1 to >5). Limited to no data were identified on the economic and humanistic burdens, and real-world treatment of METamp NSCLC. Promising preliminary results from trials enrolling patients with EGFR-mutated, METamp advanced NSCLC progressing on an EGFR-tyrosine kinase inhibitor (TKI) were observed with MET-TKIs (i.e., tepotinib, savolitinib, and capmatinib) in combination with EGFR-TKIs (i.e., gefitinib and osimertinib). For metastatic NSCLC and high-level METamp, monotherapy with capmatinib, crizotinib, and tepotinib are recommended in the 2022 published NSCLC NCCN Guidelines.
ConclusionPrimary METamp occurs in approximately 5% of NSCLC cases, and secondary METamp in approximately 15% of cases previously treated with an EGFR inhibitor. Variability in testing methods (including ISH/FISH and NGS) and definitions were observed. Several treatments are promising in treating METamp NSCLC. Additional studies evaluating the clinical, economic, and humanistic burdens are needed.

引言：间质-上皮转化因子基因扩增（Mesenchymal-epidermal transition factor gene amplification, METamp）目前正被作为晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）的治疗靶点开展研究。本研究针对晚期非小细胞肺癌中与原发性及继发性METamp相关的流行病学特征、疾病特点，以及用于识别METamp的检测流程展开综述，同时还对METamp相关的经济负担、人文负担、临床诊疗模式及在研治疗方案进行了分析评估。

方法：本研究系统检索了Embase、Medline（通过ProQuest平台）、ClinicalTrials.gov以及Cochrane对照试验注册库（2015–2022年）的文献；同时通过Embase及会议论文集网站（2020–2022年）检索了会议摘要。本综述聚焦美国地区的相关证据，针对已发现的证据空白，则纳入全球范围内的相关研究证据。

结果：纳入本次综述的文献显示，非小细胞肺癌患者中原发性METamp的中位发生率为4.8%（共纳入4项研究），继发性METamp（伴表皮生长因子受体[EGFR]突变的非小细胞肺癌）的中位发生率为15%（共纳入10项研究）。真实世界研究中最常采用的检测手段为下一代测序（Next-generation sequencing, NGS）和/或荧光原位杂交（Fluorescence in situ hybridization, FISH），共12项和11项研究分别采用了这两种检测方式；而临床试验中最常使用FISH检测，10项试验中有9项采用该方法。不同临床试验中METamp的判定标准存在差异：采用原位杂交/荧光原位杂交（ISH/FISH）检测的试验，其判定阈值为MET基因与7号染色体着丝粒的比值≥1.8至≥3.0，或基因拷贝数（Gene copy number, GCN）≥5至≥10；采用NGS检测的试验，其判定阈值为组织样本检测时GCN≥6，液体活检时MET拷贝数≥2.1至>5。目前关于METamp阳性非小细胞肺癌的经济负担、人文负担及真实世界诊疗方案的相关数据极为有限，甚至几乎空白。针对在接受表皮生长因子受体酪氨酸激酶抑制剂（EGFR-tyrosine kinase inhibitor, TKI）治疗后出现疾病进展的EGFR突变型、METamp阳性晚期非小细胞肺癌患者，采用MET靶向酪氨酸激酶抑制剂（MET-TKIs，如特泊替尼、赛沃替尼、卡马替尼）联合EGFR-TKI（如吉非替尼、奥希替尼）的治疗方案已展现出具有前景的初步研究结果。在2022年发布的非小细胞肺癌美国国家综合癌症网络（National Comprehensive Cancer Network, NCCN）指南中，针对转移性非小细胞肺癌及高拷贝数METamp患者，推荐采用卡马替尼、克唑替尼或特泊替尼进行单药治疗。

结论：原发性METamp约占非小细胞肺癌病例的5%，继发性METamp则约占既往接受过EGFR抑制剂治疗的非小细胞肺癌病例的15%。现有研究显示METamp的检测方法（包括ISH/FISH及NGS）与判定标准均存在差异。目前已有多种治疗方案在METamp阳性非小细胞肺癌的治疗中展现出应用前景，未来仍需开展更多研究以评估该类疾病的临床、经济及人文负担。