Current Situation Investigation of Clinical Diagnosis and Treatment of Non-Small Cell Lung Cancer With MET Alterations in China
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摘要:目的
非小细胞肺癌（non-small cell lung cancer，NSCLC）中间充质上皮转化因子（mesenchymal epithelial transition factor，MET）异常主要包括MET基因第14号外显子（MET exon 14）跳跃突变（简称METex14跳突）、MET基因扩增及MET蛋白过表达等。METex14跳突是NSCLC的原发致癌驱动变异，在NSCLC患者中的发生率约为0.9%~4%，目前国内外已有多个针对METex14跳突的靶向药物获批上市。NSCLC中原发MET基因扩增发生率约为1%~5%，与不良预后相关。MET基因扩增更常继发于其他驱动基因阳性NSCLC患者靶向治疗后，是表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor - tyrosine kinase inhibitor，EGFR-TKI）耐药的重要机制之一。本调研旨在了解国内MET异常NSCLC患者的诊疗现状、受访医师对MET抑制剂的认知、对于MET异常NSCLC患者治疗决策的考量，同时探求临床实践中未被满足的需求。
方法限定时间内诊治过MET异常的医师通过在线问卷形式参与调研，并对结果进行汇总和描述性分析。
结果调研共回收140份有效问卷。对于METex14跳突NSCLC，无论初治还是经治，超过50%的受访医师首选MET-TKI单药治疗。≥3级不良事件发生率是最为关注的安全性指标，最关注的不良反应有肺炎、肝毒性和胃肠道不良反应等，对于MET-TKI导致的外周水肿关注度不高。对于EGFR-TKI耐药后MET扩增NSCLC，受访医师首选MET-TKI和EGFR-TKI双靶联合的治疗方案。大型随机对照研究更充分证据、检测有待规范和临床共识是EGFR-TKI耐药后MET扩增NSCLC主要的未被满足的需求。
结论MET-TKI在METex14跳突NSCLC的首选比例仍有待提升，对于MET-TKI导致的外周水肿的关注度需提高以帮助更科学地进行管理。针对不同类型的MET变异的检测还需进一步标准化和规范化。
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关键词:
- 非小细胞肺癌 /
- METex14跳跃突变 /
- MET基因扩增 /
- 现状调研
Abstract:ObjectiveMesenchymal epithelial transition (MET) factor alteration in non-small cell lung cancer (NSCLC) mainly includes MET exon 14 skipping alteration (METex14 skipping), MET gene amplification, and MET protein overexpression, etc. METex14 skipping is a driver gene mutation in advanced NSCLC, and the incidence of METex14 skipping in NSCLC patients was 0.9%~4%. Currently, several drugs targeting METex14 skipping have been approved in China and other countries. The incidence of de novo MET gene amplification in NSCLC patients was 1%~5%, which was associated with poor prognosis. MET gene amplification is more frequently occurring after targeted therapy in NSCLC patients with other positive driver genes and is one of the important mechanisms of EGFR-TKI resistance. The purpose of this study is to understand the status of diagnosis and treatment of NSCLC patients with MET alterations in China, including awareness of physicians on MET inhibitors, considerations for treatment decisions of NSCLC patients with MET alterations, and to explore the unmet needs in clinical practice.
MethodPhysicians who had treated MET alteration patients within a defined period participated in the survey through the online questionnaire, and the results were summarized and descriptively analyzed.
ResultsA total of 140 valid questionnaires were collected. For METex14 skipping NSCLC, MET-TKI monotherapy was preferred by more than 50% of the physicians interviewed, regardless of whether patients were treatment naïve or pretreated. The incidence of grade ≥3 adverse events (AE) was the most concerned safety indicator, and the most concerned AEs included pneumonia, hepatotoxicity, and gastrointestinal AEs, etc. Peripheral edema caused by MET-TKI was of low concern. For MET-amplified EGFR mutant (EGFRm) NSCLC after EGFR-TKI resistance, the interviewed physicians preferred MET-TKI and EGFR-TKI dual-targeted combination therapy. More sufficient evidence from large-scale randomized controlled studies, standardized testing, and clinical consensus were the major unmet needs for MET-amplified EGFRm NSCLC after EGFR-TKI resistance.
ConclusionsThe preferred proportion of MET-TKI therapy in METex14 skipping NSCLC remains to be improved, and more attention should be paid to MET-TKI-induced peripheral edema to help better management. Testing for different types of MET alteration requires further standardization and normalization.
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间质上皮细胞转化因子（mesenchymal epithelial transition factor，MET）是一种原癌基因，位于人类7号染色体长臂，含有21个外显子，编码c-MET蛋白[1]。MET变异的主要形式包括：MET第14号外显子（MET exon 14，METex14）跳跃突变、MET基因扩增和MET蛋白过表达等。METex14跳突和MET基因扩增均为原发性肿瘤驱动变异。METex14跳突在非小细胞肺癌（non-small cell lung cancer，NSCLC）中的发生率约为0.9%~4%，MET基因扩增在NSCLC中的发生率约为1%~5%[2]。此外，MET基因扩增更常继发于其他驱动基因阳性NSCLC患者靶向治疗后，与表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitor，EGFR‑TKI）的获得性耐药相关[3]。
针对METex14跳突NSCLC，多个高选择性MET酪氨酸激酶抑制剂（MET tyrosine kinase inhibitor，MET-TKI）的临床研究数据显示出良好的疗效[4-8]，组织检测METex14跳突NSCLC初治人群的ORR为58.6%~77.1%，中位无进展生存期（median progression free survival，mPFS）为11.7~15.9个月，中位总生存期（median overall survival，mOS）为20.3~29.7个月。国内外已有多个MET-TKI获得批准上市，改变了此类患者的诊疗格局。但由于高选择性MET抑制剂可及性等原因，2023中国临床肿瘤学会（Chinese Society of Clinical Oncology，CSCO）非小细胞肺癌指南推荐此类初治人群按照驱动基因阴性患者进行治疗[9]。对于EGFR-TKI耐药后MET扩增患者，MET抑制剂也开展了多项临床研究且初步取得了良好的疗效[10-14]。由于MET变异相对少见，且国内外诊疗可能存在差异，因此加强诊疗调研尤为重要。我们进行了全国性调研，旨在了解MET异常NSCLC患者的诊疗现状、受访医师对于MET异常NSCLC诊疗的认知和需求，包括治疗选择和考量因素、安全性评价、尚需要深入研究的方向等方面。
1. 资料和方法
1.1 研究对象
本研究于2023年6月至7月间开展，形式为在线问卷调研。对符合招募标准的医师随机分批次发放问卷。受访者招募标准为：（1）工作医院级别为三级医院；（2）工作科室为肿瘤科、呼吸内科、胸外科、放疗科；（3）医师职称为主治及以上；（4）参与调查前半年内诊治过METex14跳突且诊治过EGFR-TKI耐药后MET扩增晚期NSCLC患者。
1.2 研究方法
研究者自行编制调研问卷，经预调研和专家咨询后修改完善问卷内容，调研内容主要包括医师基本信息、医师对MET抑制剂的认知、医师对于METex14跳突/EGFR-TKI耐药后MET扩增NSCLC患者治疗决策的考量、医师对治疗领域未被满足需求的观念等。
1.3 统计方法
调研结束后，对问卷进行整理、编号，实行双人双录入，采用 SPSS 21.0 软件进行描述性分析。计数资料以使用频数和百分比等指标来描述。
2. 结 果
2.1 受访医师基本情况
本次调研共收集有效问卷140份，来自15个省份的65家三甲医院。其中肿瘤科医师占比为42.9%，呼吸内科医师占比35.7%，胸外科医师占比10.7%，放疗科医师占比10.7%；主任医师占比26.4%，副主任医师占比51.5%，主治医师占比22.1%；32.1%的医师来自一线城市，48.6%的医师来自新一线城市，19.3%的医师来自二线城市[15]（表1）。
表 1 受访医师基本情况(n=140)Table 1. Basic information of interviewed physicians (n=140)Items Number Percentage Department Oncology 60 42.9% Respiratory medicine 50 35.7% Thoracic surgery 15 10.7% Radiotherapy 15 10.7% Professional title Chief physician 37 26.4% Associate chief physician 72 51.5% Attending doctor 31 22.1% City tier First-tier city 45 32.1% New first-tier city 68 48.6% Second-tier city 27 19.3% 2.2 受访医师对METex14跳突NSCLC的诊疗观念调研结果
2.2.1 受访医师对METex14跳突NSCLC患者的治疗方案选择、决策考量因素和治疗满意度
在治疗方案选择上，无论对于初治还是经治METex14跳突NSCLC，受访医师给出的首选治疗方案均为MET-TKI单药治疗（占比分别为初治57.1% 和经治55.0%），其次是免疫+化疗（分别为17.1%和10.0%）或免疫+化疗+抗血管生成治疗（14.3%和18.6%）。选择其余治疗模式如化疗联合抗血管生成治疗的比例在初治和经治患者中的比例均较低（图1A）。
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图 1 METex14跳跃突变初治/经治NSCLC患者治疗方案选择和决策因素注：A. METex14跳跃突变初治/经治NSCLC患者治疗方案选择，其中MET-TKI联合治疗包括联合化疗、抗血管生成治疗、免疫治疗；其他包括单纯化疗或入组双抗/抗体药物偶联物（antibody-drug conjugate，ADC）临床研究；B、C. METex14跳突NSCLC初治和经治患者选择MET-TKI单药治疗作为首选方案的主要原因（多选排序），其他包括亚洲/中国数据优异、中位缓解持续时间长、可医保报销、液体活检指导临床实践等；D. 受访医师对于NSCLC METex14跳突患者选择驱动基因阴性治疗方案的主要考量因素（多选）。Figure 1. Treatment options and decision factors of interviewed physicians for treatment-naïve/pretreated METex14 skipping NSCLC patientsNote: A. Preferred treatment regimen of interviewed physicians for treatment-naïve/pretreated METex14 skipping NSCLC patients. MET-TKI combination therapy includes MET-TKI combined with chemotherapy, anti-angiogenic therapy, or immunotherapy; others include chemotherapy alone or enrolled in clinical trials, e.g., MET bispecific antibody / antibody-drug conjugate (ADC); B, C. Main reasons for choosing MET-TKI monotherapy as preferred regimen (multi-choice, ranking). Others include excellent data in Asian/Chinese subgroups, long median duration of response, health insurance reimbursement and liquid biopsy testing approved etc.; D. Primary considerations of interviewed physicians in choosing non-targeted treatment regimens for METex14 skipping NSCLC patients (multiple choices).对于METex14跳突初治NSCLC患者，首选MET-TKI单药治疗的原因主要是：客观缓解率（overall response rate，ORR）高、mPFS长、mOS长（图1B）。对于METex14跳突经治NSCLC患者，mPFS长是相对ORR高更主要的考量因素（图1C）。无论初治还是经治，ORR高是受访医师选择MET-TKI单药治疗模式的第一因素。对于经治患者，受访医师较初治患者而言更加注重疾病控制率（disease control rate，DCR）。对于初治或经治METex14跳突患者首选驱动基因阴性治疗方案的受访医师，主要的考量因素为程序性死亡配体1（programmed death ligand 1，PD-L1）状态（85.5%）、经济因素（73.9%）、肿瘤负荷（65.2%）（图1D）。
本研究还调研了受访医师对MET-TKI的治疗满意度：1~10分进行打分，1分表示完全不认可，10分表示完全认可，8分以上视为认可。受访医师对于“高选择性MET-TKI作为METex14跳突NSCLC一线治疗首选”给予8分及以上的比例为77.2%，整体对ORR、mPFS、mOS的认可度均值分别为7.7、7.7和7.5。对ORR、PFS、OS的疗效期望值中位数分别为60%、12个月和24个月。
2.2.2 受访医师对MET-TKI的安全性评价
关于药物的安全性，76.4%的受访医师最关注的指标为三级以上不良事件（adverse event，AE）发生率。对于MET-TKI的安全性评价，23.6%的受访医师认为基本没有顾虑，73.6%的受访医师表示有顾虑和担忧，但不良反应相对易处理和恢复。关于MET-TKI相关的AE，受访医师最关注肺炎（31.4%）、其次是肝毒性（27.1%），（表2）。
表 2 受访医师对MET-TKI的安全性关注情况（n=140）Table 2. Interviewed physicians' safety concerns for MET-TKIs (n=140)Items Number Percentage Drug safety indicators Grade ≥3 AEs 107 76.4% AEs leading to dose reduction or
treatment interruption18 12.9% AEs leading to treatment
discontinuation11 7.9% Any grade AE 4 2.9% Safety assessment With concerns, but AEs are relatively
easy to manage and recover103 73.6% Without concerns, AEs can be
well-managed33 23.6% With big concerns 4 2.9% Most concerned AE Pneumonia/pneumonitis 44 31.4% Hepatotoxicity 38 27.1% Gastrointestinal adverse reactions 35 25.0% Peripheral edema 23 16.4% 2.2.3 METex14跳突NSCLC患者未被满足需求和未来期待的方向
对于METex14跳突NSCLC患者，经MET-TKI治疗后进展/耐药的后续治疗方案，选择占比最高的是化疗+抗血管生成治疗（45.7%）、其次为MET-TKI联合化疗（20.7%）、MET-TKI联合抗血管生成治疗（12.9%）。受访医师认为晚期NSCLC METex14跳跃突变患者未被满足的需求（多选）主要是：MET-TKI治疗费用过高（64.3%）、检测价格过高（47.1%）、耐药后的治疗方案（46.4%）。
受访医师期待深入研究的方向有：NSCLC其他MET异常的探索（66.4%）、METex14跳突联合治疗方式的探索（62.9%）、MET-TKI耐药之后的探索（51.4%）（图2）。
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图 2 受访医师期待深入研究的方向（n=140）Figure 2. Direction of in-depth study expected by the interviewed physicians (n=140)2.3 受访医师对EGFR-TKI耐药后MET扩增NSCLC的诊疗观念调研结果
2.3.1 受访医师对EGFR-TKI耐药后MET扩增NSCLC患者的治疗方案选择和治疗满意度
对于EGFR-TKI耐药后MET扩增NSCLC患者，受访医师选择的治疗方案主要为赛沃替尼+EGFR-TKI、免疫治疗+化疗±抗血管生成治疗和特泊替尼+EGFR-TKI（图3A）。影响受访医师治疗决策主要的指标为OS、PFS、ORR（图3B）；受访医师对EGFR-TKI耐药后MET扩增患者采取MET-TKI+EGFR-TKI模式作为首选方案的主要原因依次为mOS长、mPFS长、ORR高（图3C）。受访医师认为双靶联合方案存在的问题主要为AE（85.7%）和经济原因（57.1%），（图3D）。
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图 3 EGFR-TKI耐药后MET扩增NSCLC患者治疗方案选择和决策因素注：A. EGFR-TKI耐药后MET扩增患者的治疗方案选择（多选排序）；B. EGFR-TKI耐药后MET扩增患者治疗方案选择原因（多选排序）；C. 受访医师认可双靶方案作为首选用于EGFR-TKI耐药后MET扩增NSCLC患者的原因（多选排序）；D. 受访医师认为双靶联合方案存在的问题。Figure 3. Treatment options and decision factors of interviewed physicians for patients with MET-amplified EGFRm NSCLC after EGFR-TKI resistanceNote: A. Regimen selection of interviewed physicians for patients with MET-amplified EGFRm NSCLC after EGFR-TKI resistance (multi-choice, ranking). B. Reasons for treatment regimen selection (multi-choice, ranking); C. Main reasons for choosing MET-TKI+EGFR-TKI dual targeted regimen as preferred regimen (multi-choice, ranking); D. Concerns of the dual targeted combination regimen considered by the interviewed physicians.本研究还调研了受访医师对MET-TKI联合EGFR-TKI双靶联合方案的治疗满意度，对双靶联合方案给予8分及以上的比例为75.8%。对双靶联合方案的ORR、mPFS、mOS认可度均值分别为7.4、7.3和7.2。而受访医师对此类患者治疗方案ORR、PFS、OS期待的中位数值分别为65%、13个月和24个月。
2.3.2 受访医师对MET-TKI联合EGFR-TKI方案的安全性评价
对EGFR-TKI耐药后MET扩增NSCLC患者治疗方案的安全性方面，受访医师最为关注的指标为仍是三级以上治疗相关AE发生率（83.6%）。对于双靶联合方案的安全性，20.7%的受访医师认为基本没有顾虑，82.1%的受访医师表示有顾虑和担忧，但不良反应相对易处理和恢复。对于双靶联合方案的AE，受访医师最为关注间质性肺病、胃肠道不良反应和EGFR-TKI相关的AE，见表3。
表 3 受访医师对MET-TKI联合EGFR-TKI方案的安全性关注情况（n=140）Table 3. Interviewed physicians' safety concerns for MET-TKI+EGFR-TKI therapy (n=140)Items Number Percentage Drug safety indicators Grade ≥3 AEs 117 83.6% AEs leading to dose reduction or treatment interruption 15 10.7% AEs leading to treatment discontinuation 3 2.1% Any grade AE 5 3.6% Safety assessment With concerns, but AEs are relatively easy to manage and recover 115 82.1% Without concerns, AEs can be well managed 20 14.3% With big concerns 5 3.6% Most concerned AE Interstitial pneumonia 55 39.3% Gastrointestinal adverse reactions 31 22.1% EGFR-TKI related AEs 23 16.4% Hepatotoxicity 12 8.6% Cardiac toxicity 10 7.1% Peripheral edema 9 6.4% 2.3.3 EGFR-TKI耐药后MET扩增人群主要的未被满足需求
对于EGFR-TKI耐药后MET扩增人群，受访医师认为主要的未被满足的需求包括大型随机对照试验（randomized controlled trial，RCT）更充分的证据（77.9%）和检测有待规范和临床共识（65.7%）（图4）。
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图 4 受访医师认为EGFR-TKI耐药后MET扩增NSCLC患者未被满足的需求（n=140）Figure 4. Unmet needs of patients with MET-amplified EGFRm NSCLC after EGFR-TKI resistance considered by interviewed physicians (n=140)此外本研究还调研了医师对于MET过表达作为潜在驱动基因的可行性：多数受访医师认为可行（87.2%），认为可行的主要原因是有临床数据支撑（81.1%）、临床意义较为明确（54.9%）、覆盖更广泛的人群（40.2%）、检测便捷（22.1%）。
3. 讨 论
METex14跳突作为NSCLC重要的治疗靶点，MET-TKI已确立对于METex14跳突NSCLC患者的标准治疗地位[16]。目前国内外的主要诊疗指南[9，16-17]，均已将METex14跳突列入了晚期NSCLC一级或二级推荐检测项目。2023版CSCO指南推荐对不可手术Ⅲ期及Ⅳ期NSCLC的非鳞癌组织标本进行METex14跳跃突变检测，并推荐Ⅳ期METex14跳跃突变NSCLC患者接受MET-TKI的治疗[9]。代表性的Ⅱ期VISION研究中组织检测确认METex14的NSCLC初治患者（n=111）特泊替尼治疗的ORR为58.6%，mPFS为15.9个月，mOS为29.7个月，经治人群同样获益。国内外已有多个针对此靶点的MET-TKI获批适应证，均显示出良好的抗肿瘤疗效和可耐受的安全性[4-8]。本调研进行时国内已有两种MET-TKI获批，但本次调研结果显示，MET-TKI在受访医师中的首选比例不足60%，仍有待进一步提升。部分受访医师仍选择化疗联合免疫治疗的方案作为METex14跳跃突变NSCLC患者的治疗选择。对于初治患者而言或许部分由于首个获批药物赛沃替尼的适应证是针对化疗不耐受或化疗失败的METex14跳跃突变NSCLC患者，也因此CSCO指南中对初治人群没有给予推荐。除了前述的可及性原因，部分原因可能是由于目前MET-TKI的获批研究均为单臂研究，未与现有标准治疗进行头对头比较，无法直接比较两种方案的疗效差异。其次，相关研究显示约61%的METex14跳突NSCLC患者PD-L1高表达（≥50%）[18]，这可能导致部分临床医师倾向于对METex14跳跃突变NSCLC使用免疫治疗。
目前免疫检查点抑制剂（immune checkpoint inhibitors，ICI）联合化疗治疗METex14跳突的NSCLC的疗效数据有限，2023年中国肺癌高峰论坛发布的《非小细胞肺癌少见/罕见靶点：共识与争鸣》[19]中提到“除BRAF突变或KRAS和TP53共突变的NSCLC之外，其他驱动基因阳性NSCLC难于从一线免疫治疗中获益。”真实世界背景下开展的TOGETHER研究间接对比了不同一线治疗方案在METex14跳突NSCLC中的疗效[20]：与化疗联合免疫治疗方案相比，特泊替尼的一线治疗的PFS和OS有更长的趋势。另一项卡马替尼的真实世界RECAP研究同样显示[21]，相较于化疗联合免疫治疗方案，MET-TKI一线治疗可为METex14跳跃突变NSCLC患者带来更高的获益。此外，考虑到METex14跳跃突变NSCLC患者多为更高龄的患者[22]，有较少的机会接受多线治疗，将最有效治疗手段前移尤为重要。截止2023年底，国内已经获批4种高选择性MET-TKI，其中有3种均可用于一线治疗，可及性问题将得到很大改善。因此，有必要进一步提高临床医师一线使用MET-TKI治疗METex14跳跃突变NSCLC的比例，加强MET-TKI在临床医师中的认知观念。
MET基因扩增常继发于其他驱动基因阳性NSCLC患者靶向治疗后，是EGFR-TKI耐药的重要机制之一。目前CSCO指南推荐EGFR-TKI治疗失败的T790M阴性NSCLC患者标准治疗方案为含铂双药化疗±贝伐珠单抗，但此种模式的疗效有限。多项共识和研究均提示再次活检以明确耐药机制[23-25]，基于耐药机制的治疗方案可能有效改善EGFR-TKI耐药患者的预后[26]。对于检测到MET继发扩增的患者，临床研究数据表明，EGFR-TKI联合MET抑制剂可能是继发MET基因扩增导致的EGFR-TKI耐药患者的潜在治疗策略[10-14]。INSIGHT研究[10]结果表明特泊替尼联合吉非替尼的双靶联合方案与化疗相比，可改善一/二代EGFR-TKI耐药后T790M阴性NSCLC患者的PFS[16.6个月vs. 4.2个月；风险比（hazard ratio，HR）=0.13]和OS（37.3个月vs. 13.1个月；HR=0.10）。TATTON研究[11]数据表明，一/二代EGFR-TKI耐药后MET扩增患者接受赛沃替尼联合奥希替尼治疗的ORR为62%~67%，三代EGFR-TKI耐药后此方案治疗的ORR为33%。而INSIGHT2研究[12]在一线奥希替尼耐药后MET扩增患者中也观察到了疗效（n=98）：ORR为50.0%，中位缓解持续时间（median duration of response，mDOR）为8.5个月，mPFS为5.6个月，mOS为17.8个月；其中在亚洲人群中看到更好的获益趋势（n=52）：ORR为59.6%，mDOR为7.3个月，mPFS为6.9个月，mOS为19.8个月。然而针对这部分人群，从本次调研结果可观察到，现有治疗方案（包括已发表的临床实验数据）均未达到受访医师对疗效的期待值，提示仍需更多的探索以寻找更优的方案。目前双靶联合方案尚未获批适应证，化疗+免疫治疗+抗血管生成药物已在国内获批用于EGFR-TKI耐药后的治疗，但从调研结果看到：相较而言，MET-TKI联合EGFR-TKI的双靶方案在受访医师中认可度和治疗选择率均更高，提示未被满足的治疗需求以及受访医师对肺癌需精准治疗即“有靶打靶”的治疗观念。调研显示受访医师认为对于MET扩增的检测也有待更进一步规范。目前临床研究主要采用MET GCN≥5或MET/CEP7≥2作为入组标准[10-13]，SAVANNAH研究初步结果显示[13]，奥希替尼耐药后MET高扩增（FISH GCN≥10）的患者奥希替尼联合赛沃替尼治疗显示出更好的临床疗效。目前有更多的双靶联合研究在进行中，如SAFFERON、SACHI等；相关的双抗和ADC药物在这一部分人群的研究也在进行中，后续根据临床研究的结果，具有疗效预测价值的MET基因扩增阈值可能会有调整。
关于MET-TKI的安全性，本次调研结果显示，受访医师对MET-TKI单药使用的安全性管理较有信心，高达97.1%的受访医师认为MET-TKI安全可控。MET-TKI的常见不良反应包括外周水肿、低白蛋白血症、肌酐升高、胃肠道紊乱、肝不良反应等[27]，其中外周水肿是MET-TKI共同的常见不良反应。目前上市的MET-TKI外周水肿发生率均超过50%[4-8]，虽主要为1~2级，但如若管理不善可能影响治疗依从性。本次调研中，受访医师对MET-TKI导致的外周水肿的关注度较低（16.4%）。由于外周水肿的治疗需进行早期干预，因此临床医师有必要重视MET-TKI使用过程中出现的水肿，进行提前干预。调研还显示，受访医师对肝毒性的关注度较高，可能由于肝毒性是最早在国内上市的MET-TKI赛沃替尼的主要AE和其导致停药的主要AE之一。因此临床在应用赛沃替尼时，还应特别注意肝功能监测[28]。
对于MET-TKI联合EGFR-TKI的双靶联合方案的安全性，整体上受访医师对EGFR-TKI相关的AE的关注度更高，同时也是受访医师顾虑双靶联合方案的主要原因，其他MET-TKI相关AE的关注度与MET-TKI单药基本一致。对于双靶联合方案导致的外周水肿，受访医师的关注度较单药治疗更低（6.4%），这一点需提高重视程度以便科学管理。
MET变异NSCLC的诊治目前还存在许多需要优化和解决的课题。如在调研结果中看到，对于METex14跳突NSCLC患者，对经MET-TKI治疗后进展/耐药的后续治疗方案受访医师的选择呈现多样化，而国内外指南也并没有较为一致的观点。因此受访医师认为MET-TKI耐药后的治疗方案也是主要的临床需求之一，随着未来更多患者使用MET-TKI治疗这一需求会更加凸显。因此有必要进一步明确METex14跳突NSCLC对MET-TKI的原发性和获得性耐药机制，开展更多的研究和探索，以更好地应对MET-TKI治疗过程中可能产生的耐药。除METex14跳跃突变和MET基因扩增外，其他MET异常尤其是MET过表达，其临床价值、与MET扩增的相关性、获益人群的阈值及相应治疗策略也有必要进行进一步的探索。此外，针对不同类型的MET变异的检测，除检测标准仍有待进一步规范外，还需进一步推动技术手段的整合和统一，使更多MET变异NSCLC患者能从MET-TKI治疗中获益。
本研究存在一定局限性。首先，本研究未对MET变异NSCLC患者的检测情况进行调研；其次，受访医师仅限三甲医院的医师，未对二级和一级医院进行调研，这一点也部分由于MET异常比例相对偏低产生的限制和影响。因此，本研究的结论只能部分揭示目前临床医师对MET变异NSCLC的认知与诊治现状。
本研究通过问卷调研，发现受访医师对于MET变异NSCLC的认知与诊疗现状中的一些问题。MET-TKI在METex14跳跃突变NSCLC的一线治疗中的使用率仍较低，对于MET-TKI导致的外周水肿的关注度需提高以帮助更科学地管理水肿。此外，具有疗效预测价值的MET基因扩增阈值和MET蛋白过表达的潜在指导价值有待进一步明确，针对不同类型的MET变异的检测还需进一步标准化和规范化。
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图 1 METex14跳跃突变初治/经治NSCLC患者治疗方案选择和决策因素
注：A. METex14跳跃突变初治/经治NSCLC患者治疗方案选择，其中MET-TKI联合治疗包括联合化疗、抗血管生成治疗、免疫治疗；其他包括单纯化疗或入组双抗/抗体药物偶联物（antibody-drug conjugate，ADC）临床研究；B、C. METex14跳突NSCLC初治和经治患者选择MET-TKI单药治疗作为首选方案的主要原因（多选排序），其他包括亚洲/中国数据优异、中位缓解持续时间长、可医保报销、液体活检指导临床实践等；D. 受访医师对于NSCLC METex14跳突患者选择驱动基因阴性治疗方案的主要考量因素（多选）。
Figure 1. Treatment options and decision factors of interviewed physicians for treatment-naïve/pretreated METex14 skipping NSCLC patients
Note: A. Preferred treatment regimen of interviewed physicians for treatment-naïve/pretreated METex14 skipping NSCLC patients. MET-TKI combination therapy includes MET-TKI combined with chemotherapy, anti-angiogenic therapy, or immunotherapy; others include chemotherapy alone or enrolled in clinical trials, e.g., MET bispecific antibody / antibody-drug conjugate (ADC); B, C. Main reasons for choosing MET-TKI monotherapy as preferred regimen (multi-choice, ranking). Others include excellent data in Asian/Chinese subgroups, long median duration of response, health insurance reimbursement and liquid biopsy testing approved etc.; D. Primary considerations of interviewed physicians in choosing non-targeted treatment regimens for METex14 skipping NSCLC patients (multiple choices).
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图 2 受访医师期待深入研究的方向（n=140）
Figure 2. Direction of in-depth study expected by the interviewed physicians (n=140)
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图 3 EGFR-TKI耐药后MET扩增NSCLC患者治疗方案选择和决策因素
注：A. EGFR-TKI耐药后MET扩增患者的治疗方案选择（多选排序）；B. EGFR-TKI耐药后MET扩增患者治疗方案选择原因（多选排序）；C. 受访医师认可双靶方案作为首选用于EGFR-TKI耐药后MET扩增NSCLC患者的原因（多选排序）；D. 受访医师认为双靶联合方案存在的问题。
Figure 3. Treatment options and decision factors of interviewed physicians for patients with MET-amplified EGFRm NSCLC after EGFR-TKI resistance
Note: A. Regimen selection of interviewed physicians for patients with MET-amplified EGFRm NSCLC after EGFR-TKI resistance (multi-choice, ranking). B. Reasons for treatment regimen selection (multi-choice, ranking); C. Main reasons for choosing MET-TKI+EGFR-TKI dual targeted regimen as preferred regimen (multi-choice, ranking); D. Concerns of the dual targeted combination regimen considered by the interviewed physicians.
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图 4 受访医师认为EGFR-TKI耐药后MET扩增NSCLC患者未被满足的需求（n=140）
Figure 4. Unmet needs of patients with MET-amplified EGFRm NSCLC after EGFR-TKI resistance considered by interviewed physicians (n=140)
表 1 受访医师基本情况(n=140)
Table 1 Basic information of interviewed physicians (n=140)
Items Number Percentage Department Oncology 60 42.9% Respiratory medicine 50 35.7% Thoracic surgery 15 10.7% Radiotherapy 15 10.7% Professional title Chief physician 37 26.4% Associate chief physician 72 51.5% Attending doctor 31 22.1% City tier First-tier city 45 32.1% New first-tier city 68 48.6% Second-tier city 27 19.3% 
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表 2 受访医师对MET-TKI的安全性关注情况（n=140）
Table 2 Interviewed physicians' safety concerns for MET-TKIs (n=140)
Items Number Percentage Drug safety indicators Grade ≥3 AEs 107 76.4% AEs leading to dose reduction or
treatment interruption18 12.9% AEs leading to treatment
discontinuation11 7.9% Any grade AE 4 2.9% Safety assessment With concerns, but AEs are relatively
easy to manage and recover103 73.6% Without concerns, AEs can be
well-managed33 23.6% With big concerns 4 2.9% Most concerned AE Pneumonia/pneumonitis 44 31.4% Hepatotoxicity 38 27.1% Gastrointestinal adverse reactions 35 25.0% Peripheral edema 23 16.4%
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表 3 受访医师对MET-TKI联合EGFR-TKI方案的安全性关注情况（n=140）
Table 3 Interviewed physicians' safety concerns for MET-TKI+EGFR-TKI therapy (n=140)
Items Number Percentage Drug safety indicators Grade ≥3 AEs 117 83.6% AEs leading to dose reduction or treatment interruption 15 10.7% AEs leading to treatment discontinuation 3 2.1% Any grade AE 5 3.6% Safety assessment With concerns, but AEs are relatively easy to manage and recover 115 82.1% Without concerns, AEs can be well managed 20 14.3% With big concerns 5 3.6% Most concerned AE Interstitial pneumonia 55 39.3% Gastrointestinal adverse reactions 31 22.1% EGFR-TKI related AEs 23 16.4% Hepatotoxicity 12 8.6% Cardiac toxicity 10 7.1% Peripheral edema 9 6.4%
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