MET抑制剂新进展课件.pptx

1、MET抑制剂新进展目目 录录 一 MET抑制剂的概述 二 9509:GEOMETRY 三 9510：Sym015目目 录录 一 MET抑制剂的概述 二 9509:GEOMETRY 三 9510：Sym015MET基因信号传导通路Comoglio PM,et al.Nat Rev Cancer.2018 Jun;18(6):341-358.Ghiso E,Giordano S.Curr Opin Pharmacol.2013 Aug;13(4):511-8.首要环节：首要环节：H G F 与MET基因(SEMA区)特异性结合激酶激活：激酶激活：酪氨酸残基自身磷酸化，激活酪氨酸激酶下游多种信号通路

2、被激下游多种信号通路被激活活：RAS-RAF-MAPK信号通路：参与细胞生长增殖PI3K-AKT信号通路：参与细胞生存PI3K-FAK信号通路：促进细胞迁移，具有侵袭特性非非H G F 依依赖性赖性激激活：活：MET基因扩增 MET基因转录上调 MET基因活性突变 MET-exon14 跳跃HGF(肝肝细胞细胞生生长因长因子子)依赖性激活：依赖性激活：H G F 自分泌增加 H G F 旁分泌增加NSCLC中的MET基因异常的分类1.Vuong HG,et al.Lung Cancer.2018 Sep;123:76-82.2.Papadimitrakopoulou V,et al.2018

3、E S M O Abstract LBA51.3.Ramalingam SS,et al.2018 E S M O Abstract LBA50.MET过表达MET 14外显子跳跃突变MET扩增MET基因作为原发驱动基因基因作为原发驱动基因1MET蛋白蛋白 过表达过表达1E G F R-TKIEGFR突变EGFR突变MET扩增MET基因作为继发基因作为继发/共同驱动基因共同驱动基因2,3NSCLC中的MET基因异常的发生率Salgia R.Mol Cancer Ther.2017 Apr;16(4):555-565.MET基基因异常因异常功能结果功能结果生物标志物生物标志物肺癌患者发生率肺癌患

4、者发生率基因过表达减少或去除配体激活的需要，导致受体信号传导属性的维持或改变IHC MET/p-MET表达N S C L C IHC 2+:37%-61%腺癌：35-72%IHC 2+：67%鳞癌：38%SCLC p-MET：67%H G F 过表达配体诱导的激活可导致信号传导的维持或改变循环血浆H G FS C L C 中升高基因突变基因突变MET基基因突因突变变可导可导致致降解降解减减少，少，结果引起过表达以及信结果引起过表达以及信号号传导传导的的维持维持或或改变改变MET 14跳跳跃突变跃突变腺癌腺癌：3%-4%鳞癌鳞癌：2%其他肺癌类型其他肺癌类型：1-8%基因扩增基因扩增导致过表达，

5、并减少或导致过表达，并减少或去去除配除配体体激活激活的的需要，需要，导致导致MET受受体体信号信号传传导属导属性性的维的维持持或改变或改变MET G C N MET/CEP7比比率率新诊断腺癌新诊断腺癌：2%-5%E G F R TKI耐耐药药的腺的腺癌癌：5%22%基因重排减少或去除配体激活的需要，导致MET受体信号传导属性的 维持或改变MET重排在腺癌患者中已发现下游MET信号传导改变减少RTK周转，使MET的致癌激活永久化CBL突变或LOH已在N S C L C 患者中检出-常见于老年(70岁)、有吸烟史、晚期疾病的患者，预后不佳2 与其他基因变异相互排斥，如E G F R、ALK、RO

6、S1.同时合并同时合并MET扩增扩增：15%20%3 41.Awad MM,et al.2017 ASCO Abstract 8511.2.Vuong HG,et al.Lung Cancer.2018 Sep;123:76-82.3.Schrock AB,et al.J Thorac Oncol.2016 Sep;11(9):1493-502.4.Drilon A,et al.J Thorac Oncol.2017 Jan;12(1):15-26.5.Li Y,et al.Lung Cancer.2018 Aug;122:113-119.正常M ET信号通路MET 外显子外显子14跳跃跳跃外

7、显子14跳跃受体内化受体降解C-C BI连接位点丢失 泛素化减少受体降解受影响MET信号增加受体激活外显子14跳跃1.Tong JH,et al.Clin Cancer Res.2016 Jun 15;22(12):3048-56.2.Cappuzzo F,et al.J Clin Oncol.2009 Apr 1;27(10):1667-74.3.Park S,et al.Histol Histopathol.2012 Feb;27(2):197-207.4.Awad MM,et al.2017 ASCO Abstract 8511.0.00.20.40.60.81.0OS012243648

8、60时间(月)HR=3.0P=0.06未接受未接受MET TKI治疗的治疗的IV期患者生存情况期患者生存情况N中 位 O S (95%CI)未合并MET扩增2010.5 月(5.3-NR)合并MET扩增65.2 月(2.3-NR)IV期患者总生存期患者总生存0.00.20.40.60.81.0OS01248602436时间(月)0.00.20.40.60.81.0OS01248602436时间(月)未接受MET TKI N=34接受MET TKI N=27中 位 O S (95%CI)8.1 月(5.3-NR)中 位 O S (95%CI)24.6 月(12.1-NR)不同EGFR-TKI用于

9、一线治疗与二线治疗时的MET扩增发生率不同1.Ramalingam SS,et al.2018 E S M O Abstract LBA50.2.Papadimitrakopoulou V,et al.2018 E S M O Abstract LBA51.3.Sequist LV,et al.Sci Transl Med.2011 Mar 23;3(75):75ra26.4.Engelman JA,et al.Science.2007 May 18;316(5827):1039-43.5.Yu HA,et al.Clin Cancer Res.2013 Apr 15;19(8):2240-7

10、.6.Piotrowska Z,et al.Cancer Discov.2018 Dec;8(12):1529-1539.7.Oxnard G,et al.JAMA Oncol.2018 Nov 1;4(11):1527-1534.HER2 扩增扩增：2%HER2 突变：1%MET 扩增扩增：15%二次二次E G F R 突变突变:#C797X:7%;L718Q+C797S:1%;L718Q+ex20ins:1%;S768I:1%增殖存活细胞凋亡PIK3CA 突变突变:3%BRAF 突突 变变(V600E):3%KRAS 突突 变变(G12D/C,A146T):3%细胞循环基因改变细胞循环基因

11、改变C C N D 扩增扩增:3%C C N E 1 扩增扩增:2%CDK4/6 扩增扩增:5%一、二代EGFR-TKI奥希替尼5%22%15%19%二线 奥希替尼MET 扩增比例扩增比例初治患者2-4%一线奥希替尼治疗后一线奥希替尼治疗后Dagogo-Jack I,et al.Clin Cancer Res.2020 Feb 21.下一代ALK抑制剂治疗后1 5%的肿 瘤活检样本检出MET扩增 克唑替尼：0%二代二代ALK抑抑制制剂剂：12%三代劳拉替尼三代劳拉替尼：22%M E T扩增患者中，55%(6/11)从未接 受过克唑替尼治疗 一线接受二代ALK抑制剂的患者 较一线接受克唑替尼后下

12、一代 ALK抑制剂治疗的患者更容易出 现MET扩增(9%vs.33%;P=0.019)目目 录录 一 MET抑制剂的概述 二 9509:GEOMETRY 三 9510：Sym015Capmatinib in patients with high-level MET-amplified advanced nonsmall cell lung cancer(NSCLC):Results from the phase 2 GEOMETRY mono-1 studyPresented By Juergen Wolf at TBDB ackgroundPresented By Juergen Wolf

13、at TBDGEOMETRY mono-1:An open-label international multicohort phase 2 studyPresented By Juergen Wolf at TBDBaseline characteristics(Cohorts 1a and 5a)Presented By Juergen Wolf at TBDBaseline characteristics(Cohorts 1a and 5a)Presented By Juergen Wolf at TBDBest overall response(Cohorts 1a and 5a)Pre

14、sented By Juergen Wolf at TBDTumor shrinkage assessed by the BIRCDeep responses observed in the majority of patients across both cohortsPresented By Juergen Wolf at TBDDuration of response assessed by the BIRCMedian D O R:8.31 months in pretreated patients and 7.54 months in treatment-naive patients

15、Presented By Juergen Wolf at TBDProgression-free survival assessed by the BIRCMedian PFS:4.07 months in pretreated patients and 4.17 months in treatment-naive patientsPresented By Juergen Wolf at TBDOverall survivalMedian OS:10.61 months in pretreated patients and 9.56 months in treatment-naive pati

16、entsPresented By Juergen Wolf at TBDCapmatinib was well tolerated and with a favorable safety profile,consistent with previous reports1Presented By Juergen Wolf at TBDC onclusionsPresented By Juergen Wolf at TBD目目 录录 一 MET抑制剂的概述 二 9509:GEOMETRY 三 9510:Sym015Safety and preliminary clinical activity o

17、f the MET antibody mixture Sym015 in advanced non-small cell lung cancer(NSCLC)patients with MET-amplification/exon 14 deletion(METAmp/Ex14)Presented By D.Camidge at TBDBackground for Sym015Presented By D.Camidge at TBDClinical Trial DesignSlide 4Presented By D.Camidge at TBDSym015-01 Phase 2a data

18、indicate favorable safety profilePresented By D.Camidge at TBDTreatment Duration:N S C L C (n=20)Presented By D.Camidge at TBDSlide 7Presented By D.Camidge at TBDN S C L C Case Story#1-MET TKI Nave-MET-AmplificationPresented By D.Camidge at TBDN S C L C Patient Case Story#2-MET TKI Nave-METEx14Presented By D.Camidge at TBDSlide 10NSCLC-BMx Concordance and Temporal dataPresented By D.Camidge at TBDC onclusions:Presented By D.Camidge at TBD谢谢！谢谢！