MET抑制劑新進(jìn)展

1、MET抑制劑新進(jìn)展MET抑制劑新進(jìn)展目錄一 MET抑制劑的概述二 9509:GEOMETRY三 9510：Sym015目錄目錄一 MET抑制劑的概述二 9509:GEOMETRY三 9510：Sym015目錄MET抑制劑新進(jìn)展MET基因信號傳導(dǎo)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.首要環(huán)節(jié)：HGF與MET基因(SEMA區(qū))特異性結(jié)合激酶激活：酪氨酸殘基自身磷酸化，激活酪氨酸激酶下游多種

2、信號通路被激活：RAS-RAF-MAPK信號通路：參與細(xì)胞生長增殖PI3K-AKT信號通路：參與細(xì)胞生存PI3K-FAK信號通路：促進(jìn)細(xì)胞遷移，具有侵襲特性非HGF依賴性激活：MET基因擴(kuò)增MET基因轉(zhuǎn)錄上調(diào)MET基因活性突變MET-exon14 跳躍HGF(肝細(xì)胞生長因子)依賴性激活：HGF自分泌增加HGF旁分泌增加MET基因信號傳導(dǎo)通路Comoglio PM, et al.NSCLC中的MET基因異常的分類Vuong HG, et al. Lung Cancer. 2018 Sep;123:76-82.Papadimitrakopoulou V, et al. 2018 ESMO Abst

3、ract LBA51.Ramalingam SS, et al. 2018 ESMO Abstract LBA50.MET過表達(dá)MET 14外顯子跳躍突變MET擴(kuò)增MET基因作為原發(fā)驅(qū)動基因1MET蛋白 過表達(dá)1EGFR-TKIEGFR突變EGFR突變MET擴(kuò)增MET基因作為繼發(fā)/共同驅(qū)動基因2,3NSCLC中的MET基因異常的分類Vuong HG, et NSCLC中的MET基因異常的發(fā)生率Salgia R. Mol Cancer Ther. 2017 Apr;16(4):555-565.MET基因異常功能結(jié)果生物標(biāo)志物肺癌患者發(fā)生率基因過表達(dá)減少或去除配體激活的需要， 導(dǎo)致受體信號傳導(dǎo)屬性

4、的維持或改變IHC MET/p-MET表達(dá)NSCLC IHC 2+:37%-61%腺癌：35-72%IHC 2+：67%鱗癌：38%SCLC p-MET：67%HGF過表達(dá)配體誘導(dǎo)的激活可導(dǎo)致信號傳導(dǎo)的維持或改變循環(huán)血漿HGFSCLC中升高基因突變MET基因突變可導(dǎo)致降解減少，結(jié)果引起過表達(dá)以及信號傳導(dǎo)的維持或改變MET 14跳躍突變腺癌：3%-4%鱗癌：2%其他肺癌類型：1-8%基因擴(kuò)增導(dǎo)致過表達(dá)，并減少或去除配體激活的需要， 導(dǎo)致MET受體信號傳導(dǎo)屬性的維持或改變MET GCN MET/CEP7比率新診斷腺癌：2%-5%EGFR TKI耐藥的腺癌：5%22%基因重排減少或去除配體激活的需要

5、， 導(dǎo)致MET受體信號傳導(dǎo)屬性的 維持或改變MET重排在腺癌患者中已發(fā)現(xiàn)下游MET信號傳導(dǎo)改變減少RTK周轉(zhuǎn)，使MET的致癌激活永久化CBL突變或LOH已在NSCLC患者中檢出NSCLC中的MET基因異常的發(fā)生率Salgia R. Mo-常見于老年(70歲)、有吸煙史、晚期疾病的患者，預(yù)后不佳2與其他基因變異相互排斥，如EGFR、ALK、ROS1.同時合并MET擴(kuò)增：15%20%341. Awad MM, et al. 2017 ASCO Abstract 8511. 2. Vuong HG, et al. Lung Cancer. 2018 Sep;123:76-82. 3. Schrock

6、 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MET信號通路MET 外顯子14跳躍外顯子14跳躍受體內(nèi)化受體降解C-CBI連接位點(diǎn)丟失 泛素化減少受體降解受影響MET信號增加受體激活外顯子14跳躍-常見于老年(70歲)、有吸煙史、晚期疾病的患者，預(yù)后不佳1. Tong JH, et al. Clin Cancer Res

7、. 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 8511.0.00.20.40.60.81.0OS01224364860時間 (月)HR=3.0P=0.06未接受MET TKI治療的IV期患者生存情況N中 位 OS (95% CI)未合并MET擴(kuò)增2010.5 月

8、 (5.3-NR)合并MET擴(kuò)增65.2 月 (2.3-NR)IV期患者總生存0.00.20.40.60.81.0OS01248602436時間 (月)0.00.20.40.60.81.0OS01248602436時間 (月)未接受MET TKI N=34接受MET TKI N=27中 位 OS (95% CI) 8.1 月 (5.3-NR)中 位 OS (95% CI)24.6 月 (12.1-NR)1. Tong JH, et al. Clin Cancer不同EGFR-TKI用于一線治療與二線治療時的MET擴(kuò)增發(fā)生率不同1. Ramalingam SS, et al. 2018 ESMO

9、 Abstract LBA50. 2. Papadimitrakopoulou V, et al. 2018 ESMO 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. 6. Piotrowska Z, et al. Cancer Discov.

10、2018 Dec;8(12):1529-1539. 7. Oxnard G, et al. JAMA Oncol. 2018 Nov 1;4(11):1527-1534.HER2擴(kuò)增：2%HER2 突變：1%MET擴(kuò)增：15%二次EGFR突變:#C797X:7%; L718Q+C797S:1%; L718Q+ex20ins:1%; S768I:1%增殖存活細(xì)胞凋亡PIK3CA 突變: 3% BRAF 突 變 (V600E): 3%KRAS 突 變 (G12D/C, A146T): 3%細(xì)胞循環(huán)基因改變CCND 擴(kuò)增: 3%CCNE1 擴(kuò)增: 2%CDK4/6 擴(kuò)增: 5%一、二代EGFR-TK

11、I奧希替尼5%22%15%19%二線 奧希替尼MET 擴(kuò)增比例初治患者2-4%一線奧希替尼治療后不同EGFR-TKI用于一線治療與二線治療時的MET擴(kuò)增發(fā)生Dagogo-Jack I, et al. Clin Cancer Res. 2020 Feb 21.下一代ALK抑制劑治療后15%的腫 瘤活檢樣本檢出MET擴(kuò)增克唑替尼：0%二代ALK抑制劑：12%三代勞拉替尼：22%MET擴(kuò)增患者中，55%(6/11)從未接 受過克唑替尼治療一線接受二代ALK抑制劑的患者 較一線接受克唑替尼后下一代 ALK抑制劑治療的患者更容易出 現(xiàn)MET擴(kuò)增 (9% vs. 33%; P=0.019)Dagogo-J

12、ack I, et al. Clin Can目錄一 MET抑制劑的概述二 9509:GEOMETRY三 9510：Sym015目錄Capmatinib 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 TBDCapmatinib in patients with hiBackgroundPresented By Juergen

13、 Wolf at TBDBackgroundPresented By JuergenGEOMETRY mono-1: An open-label international multicohort phase 2 studyPresented By Juergen Wolf at TBDGEOMETRY mono-1: An open-labeBaseline characteristics (Cohorts 1a and 5a)Presented By Juergen Wolf at TBDBaseline characteristics (CohoBaseline characterist

14、ics (Cohorts 1a and 5a)Presented By Juergen Wolf at TBDBaseline characteristics (CohoBest overall response (Cohorts 1a and 5a)Presented By Juergen Wolf at TBDBest overall response (CohortsTumor shrinkage assessed by the BIRCDeep responses observed in the majority of patients across both cohortsPrese

15、nted By Juergen Wolf at TBDTumor shrinkage assessed by thDuration of response assessed by the BIRCMedian DOR: 8.31 months in pretreated patients and 7.54 months in treatment-naive patientsPresented By Juergen Wolf at TBDDuration of response assessed Progression-free survival assessed by the BIRCMedi

16、an PFS: 4.07 months in pretreated patients and 4.17 months in treatment-naive patientsPresented By Juergen Wolf at TBDProgression-free survival asseOverall survivalMedian OS: 10.61 months in pretreated patients and 9.56 months in treatment-naive patientsPresented By Juergen Wolf at TBDOverall surviv

17、alMedian OCapmatinib was well tolerated and with a favorable safety profile, consistent with previous reports1Presented By Juergen Wolf at TBDCapmatinib was well tolerated ConclusionsPresented By Juergen Wolf at TBDConclusionsPresented By Juerge目錄一 MET抑制劑的概述二 9509:GEOMETRY三 9510:Sym015目錄Safety and p

18、reliminary clinical activity of 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 TBDSafety and preliminary clinicaBackground for Sym015Presented By D. Camidge at TBDBackground for Sym015PresentedClinical Trial DesignClinical Trial DesignSlide 4Presented By D. Camidge at TBDSlide 4Presented By D. CamidgeSym015-01 Phase 2a data indicate favorable safety profilePresented By D. Camidge at TBDSym015-01 Phase