PDF(Pubmed)
Abstract：
UNASSIGNED: Acquired MET gene amplification, MET exon 14 skip mutations, or MET fusions can emerge as resistance mechanisms to tyrosine kinase inhibitors (TKIs) in patients with lung cancer. The efficacy and safety of combining MET TKIs (such as crizotinib, capmatinib, or tepotinib) with parent TKIs to target acquired MET resistance are not well characterized.
UNASSIGNED: Multi-institutional retrospective chart review identified 83 patients with metastatic oncogene-driven NSCLC that were separated into the following two pairwise matched cohorts: (1) MET cohort (n = 41)-patients with acquired MET resistance continuing their parent TKI with a MET TKI added or (2) Chemotherapy cohort (n = 42)-patients without any actionable resistance continuing their parent TKI with a platinum-pemetrexed added. Clinicopathologic features, radiographic response (by means of Response Evaluation Criteria in Solid Tumors version 1.1), survival outcomes, adverse events (AEs) (by means of Common Terminology Criteria for Adverse Events version 5.0), and genomic data were collected. Survival outcomes were assessed using Kaplan-Meier methods. Multivariate modeling adjusted for lines of therapy, brain metastases, TP53 mutations, and oligometastatic disease.
UNASSIGNED: Within the MET cohort, median age was 56 years (range: 36-83 y). Most patients were never smokers (28 of 41, 68.3%). Baseline brain metastases were common (21 of 41, 51%). The most common oncogenes in the MET cohort were EGFR (30 of 41, 73.2%), ALK (seven of 41, 17.1%), and ROS1 (two of 41, 4.9%). Co-occurring TP53 mutations (32 of 41, 78%) were frequent. Acquired MET alterations included MET gene amplification (37 of 41, 90%), MET exon 14 mutations (two of 41, 5%), and MET gene fusions (two of 41, 5%). After multivariate adjustment, the objective response rate (ORR) was higher in the MET cohort versus the chemotherapy cohort (ORR: 69.2% versus 20%, p < 0.001). Within the MET cohort, MET gene copy number (≥10 versus 6-10) did not affect radiographic response (54.5% versus 68.4%, p = 0.698). There was no difference in ORR on the basis of MET TKI used (F [2, 36] = 0.021, p = 0.978). There was no difference in progression-free survival (5 versus 6 mo; hazard ratio = 0.64; 95% confidence interval: 0.34-1.23, p = 0.18) or overall survival (13 versus 11 mo; hazard ratio = 0.75; 95% confidence interval: 0.42-1.35, p = 0.34) between the MET and chemotherapy cohorts. In the MET cohort, dose reductions for MET TKI-related toxicities were common (17 of 41, 41.4%) but less frequent for parent TKIs (two of 41, 5%). Grade 3 AEs were not significant between crizotinib, capmatinib, and tepotinib (p = 0.3). The discontinuation rate of MET TKIs was 17% with no significant differences between MET TKIs (p = 0.315). Among pre- and post-treatment biopsies (n = 17) in the MET cohort, the most common next-generation sequencing findings were loss of MET gene amplification (15 of 17, 88.2%), MET on-target mutations (seven of 17, 41.2%), new Ras-Raf-MAPK alterations (three of 17, 17.6%), and EGFR gene amplification (two of 17, 11.7%).
UNASSIGNED: The efficacy and safety of combining MET TKIs (crizotinib, capmatinib, or tepotinib) with parent TKIs for acquired MET resistance are efficacious. Radiographic response and AEs did not differ significantly on the basis of the underlying MET TKI used. Loss of MET gene amplification, development of MET on-target mutations, Ras-Raf-MAPK alterations, and EGFR gene amplification were molecular patterns found on progression with dual parent and MET TKI combinations.
UNASSIGNED: Multi-institutional retrospective chart review identified 83 patients with metastatic oncogene-driven NSCLC that were separated into the following two pairwise matched cohorts: (1) MET cohort (n = 41)-patients with acquired MET resistance continuing their parent TKI with a MET TKI added or (2) Chemotherapy cohort (n = 42)-patients without any actionable resistance continuing their parent TKI with a platinum-pemetrexed added. Clinicopathologic features, radiographic response (by means of Response Evaluation Criteria in Solid Tumors version 1.1), survival outcomes, adverse events (AEs) (by means of Common Terminology Criteria for Adverse Events version 5.0), and genomic data were collected. Survival outcomes were assessed using Kaplan-Meier methods. Multivariate modeling adjusted for lines of therapy, brain metastases, TP53 mutations, and oligometastatic disease.
UNASSIGNED: Within the MET cohort, median age was 56 years (range: 36-83 y). Most patients were never smokers (28 of 41, 68.3%). Baseline brain metastases were common (21 of 41, 51%). The most common oncogenes in the MET cohort were EGFR (30 of 41, 73.2%), ALK (seven of 41, 17.1%), and ROS1 (two of 41, 4.9%). Co-occurring TP53 mutations (32 of 41, 78%) were frequent. Acquired MET alterations included MET gene amplification (37 of 41, 90%), MET exon 14 mutations (two of 41, 5%), and MET gene fusions (two of 41, 5%). After multivariate adjustment, the objective response rate (ORR) was higher in the MET cohort versus the chemotherapy cohort (ORR: 69.2% versus 20%, p < 0.001). Within the MET cohort, MET gene copy number (≥10 versus 6-10) did not affect radiographic response (54.5% versus 68.4%, p = 0.698). There was no difference in ORR on the basis of MET TKI used (F [2, 36] = 0.021, p = 0.978). There was no difference in progression-free survival (5 versus 6 mo; hazard ratio = 0.64; 95% confidence interval: 0.34-1.23, p = 0.18) or overall survival (13 versus 11 mo; hazard ratio = 0.75; 95% confidence interval: 0.42-1.35, p = 0.34) between the MET and chemotherapy cohorts. In the MET cohort, dose reductions for MET TKI-related toxicities were common (17 of 41, 41.4%) but less frequent for parent TKIs (two of 41, 5%). Grade 3 AEs were not significant between crizotinib, capmatinib, and tepotinib (p = 0.3). The discontinuation rate of MET TKIs was 17% with no significant differences between MET TKIs (p = 0.315). Among pre- and post-treatment biopsies (n = 17) in the MET cohort, the most common next-generation sequencing findings were loss of MET gene amplification (15 of 17, 88.2%), MET on-target mutations (seven of 17, 41.2%), new Ras-Raf-MAPK alterations (three of 17, 17.6%), and EGFR gene amplification (two of 17, 11.7%).
UNASSIGNED: The efficacy and safety of combining MET TKIs (crizotinib, capmatinib, or tepotinib) with parent TKIs for acquired MET resistance are efficacious. Radiographic response and AEs did not differ significantly on the basis of the underlying MET TKI used. Loss of MET gene amplification, development of MET on-target mutations, Ras-Raf-MAPK alterations, and EGFR gene amplification were molecular patterns found on progression with dual parent and MET TKI combinations.
摘要：
■获得MET基因扩增，MET第14外显子跳跃突变，或MET融合可以作为肺癌患者对酪氨酸激酶抑制剂（TKIs）的耐药机制出现。联合使用METTKIs(如克唑替尼，卡马替尼,或替泊替尼）与针对获得性MET抗性的亲本TKIs没有很好地表征。
■多机构回顾性图表回顾确定了83例转移性癌基因驱动的NSCLC患者，将其分为以下两个配对队列：（1）MET队列（n=41）-获得MET耐药的患者继续其父母TKI并添加了METTKI或（2）化疗队列（n=42）-无任何可行的TpreKI并继续其父母铂耐药。临床病理特征,放射学反应（通过实体瘤1.1版的反应评估标准），生存结果，不良事件(AE)(通过不良事件通用术语标准5.0版)，并收集基因组数据。使用Kaplan-Meier方法评估生存结果。根据治疗路线调整的多变量建模，脑转移瘤,TP53突变,和寡转移疾病。
■在MET队列中，中位年龄为56岁(范围:36-83岁).大多数患者从不吸烟者（41人中有28人，占68.3%）。基线脑转移是常见的（21/41，51％）。MET队列中最常见的癌基因是EGFR（41个中的30个，73.2%），ALK（41个中的7个，17.1%），和ROS1（41个中的两个，4.9%）。常见的TP53突变（41个中的32个，占78％）。获得的MET改变包括MET基因扩增（41个中的37个，90％），MET外显子14突变（41个中的两个，5%），和MET基因融合(41个中的两个，5%)。经过多变量调整后，MET队列的客观缓解率（ORR）高于化疗队列（ORR：69.2％对20％，p<0.001)。在MET队列中，MET基因拷贝数（≥10对6-10）不影响放射学反应（54.5％对68.4％，p=0.698)。基于使用的METTKI,ORR没有差异(F[2,36]=0.021,p=0.978)。MET和化疗组之间的无进展生存期（5对6个月；风险比=0.64;95％置信区间：0.34-1.23，p=0.18）或总生存期（13对11个月；风险比=0.75;95％置信区间：0.42-1.35，p=0.34）没有差异。在MET队列中，METTKI相关毒性的剂量减少是常见的(41个中的17个,41.4%),但对于父母TKIs的频率较低(41个中的2个,5%).3级AE在克唑替尼之间不显著，卡马替尼,和替泊替尼（p=0.3）。METTKIs的停药率为17％，METTKIs之间没有显着差异（p=0.315）。在MET队列的治疗前和治疗后活检(n=17)中，最常见的下一代测序结果是MET基因扩增丢失（17人中有15人，占88.2%），MET靶突变（17个中的7个，41.2%），新的Ras-Raf-MAPK改变（17个中的三个，17.6％），和EGFR基因扩增（17个中的两个，11.7%）。
■联合使用METTKIs（克唑替尼，卡马替尼,或替泊替尼）与亲本TKIs对获得性MET抗性是有效的。根据所使用的基础METTKI，放射学反应和AE没有显着差异。MET基因扩增丢失，MET靶向突变的发展，Ras-Raf-MAPK改变,和EGFR基因扩增是在双亲和METTKI组合的进展中发现的分子模式。
■多机构回顾性图表回顾确定了83例转移性癌基因驱动的NSCLC患者，将其分为以下两个配对队列：（1）MET队列（n=41）-获得MET耐药的患者继续其父母TKI并添加了METTKI或（2）化疗队列（n=42）-无任何可行的TpreKI并继续其父母铂耐药。临床病理特征,放射学反应（通过实体瘤1.1版的反应评估标准），生存结果，不良事件(AE)(通过不良事件通用术语标准5.0版)，并收集基因组数据。使用Kaplan-Meier方法评估生存结果。根据治疗路线调整的多变量建模，脑转移瘤,TP53突变,和寡转移疾病。
■在MET队列中，中位年龄为56岁(范围:36-83岁).大多数患者从不吸烟者（41人中有28人，占68.3%）。基线脑转移是常见的（21/41，51％）。MET队列中最常见的癌基因是EGFR（41个中的30个，73.2%），ALK（41个中的7个，17.1%），和ROS1（41个中的两个，4.9%）。常见的TP53突变（41个中的32个，占78％）。获得的MET改变包括MET基因扩增（41个中的37个，90％），MET外显子14突变（41个中的两个，5%），和MET基因融合(41个中的两个，5%)。经过多变量调整后，MET队列的客观缓解率（ORR）高于化疗队列（ORR：69.2％对20％，p<0.001)。在MET队列中，MET基因拷贝数（≥10对6-10）不影响放射学反应（54.5％对68.4％，p=0.698)。基于使用的METTKI,ORR没有差异(F[2,36]=0.021,p=0.978)。MET和化疗组之间的无进展生存期（5对6个月；风险比=0.64;95％置信区间：0.34-1.23，p=0.18）或总生存期（13对11个月；风险比=0.75;95％置信区间：0.42-1.35，p=0.34）没有差异。在MET队列中，METTKI相关毒性的剂量减少是常见的(41个中的17个,41.4%),但对于父母TKIs的频率较低(41个中的2个,5%).3级AE在克唑替尼之间不显著，卡马替尼,和替泊替尼（p=0.3）。METTKIs的停药率为17％，METTKIs之间没有显着差异（p=0.315）。在MET队列的治疗前和治疗后活检(n=17)中，最常见的下一代测序结果是MET基因扩增丢失（17人中有15人，占88.2%），MET靶突变（17个中的7个，41.2%），新的Ras-Raf-MAPK改变（17个中的三个，17.6％），和EGFR基因扩增（17个中的两个，11.7%）。
■联合使用METTKIs（克唑替尼，卡马替尼,或替泊替尼）与亲本TKIs对获得性MET抗性是有效的。根据所使用的基础METTKI，放射学反应和AE没有显着差异。MET基因扩增丢失，MET靶向突变的发展，Ras-Raf-MAPK改变,和EGFR基因扩增是在双亲和METTKI组合的进展中发现的分子模式。
