胃癌靶向治疗PPT课件

张俊上海交通大学医学院附属瑞金医院外科,胃癌分子靶向治疗的若干热点问题,.,分子靶向治疗困惑的临床,理解分子靶点理解疗效与特异性毒性反应药物机理与临床研究结果的解读分子靶向治疗药物的应用实践做到真正的translationalresearch指导临床研究设计指导临床指南,.,近十年的晚期胃癌临床研究,MAGICinNEJM(Cunningham,2006)TAX325inJCO（EricVanCutsem,2006）REAL-2inNEJM(Cunningham,2008)ML-17032inAnnOncology（Kang,2009）FLAGSinASCOGI（Ajani,2009）ToGAinASCO(EricVanCutsem17:346-358.,.,合理治疗靶点的标准,与肿瘤的恶性表型相关重要脏器与组织中很少表达分子特性与生物学行为相关能在临床较易获得的样本中重复检测与临床预后相关当该靶点被阻断、干扰或抑制时，对高度表达该靶点的患者应有一定的临床反应，对不表达该靶点者，应无或产生较少临床反应,.,胃癌的分子靶点寻找,KRASMT40%)HER-2过表达10-25%,.,单药应用疗效有限（Phase2）,.,靶向化疗：成绩较好（Phase2）,1.Shahetal.JClinOncol,2006;24;6201;2.DLFabioetal.ESMO,2006,Abstract1077PD;3.Pintoetal.AnnOncol2007;4.Lordicketal.AnnOncol2008,.,铂类药物替换,氟尿嘧啶类药物替换,分子靶向药物,添加药物,替换药物,基于优效性检验的胃癌一线化疗方案,晚期胃癌药物治疗的优化策略,序贯治疗,诱导化疗/维持化疗,其他策略,目标：延长生存,.,ToGA（XP/FPH）,AVAGAST（XPBV）,07/23/2007,11,胃癌EGFR表达,包括EGF家族在内的各类生长因子及其受体在胃癌中呈过度表达(GastricCancer2004;7:61-77)免疫组化染色提示胃癌组织中EGFR表达率为59,586%(JCO2006;24:4922-4927;ASCO2007#4526)RT-PCR检测提示胃癌组织中EGFR基因扩增率约62%(WorldJGastroenterol2007;13:3605-3609)EGFR表达升高与以下临床病理因素相关:进展期胃癌淋巴结转移生存期缩短(EJC2001;37:S9-S15),.,EGFreceptorsignalingpathway:Arationaleforpersonalizedtherapy,YardenY,SliwkowskiMX.NatRevMolCellBiol2001;2:127137;ChakravartiA,etal.CancerRes2002;62:43074315;BaselgaJ.EurJCancer2001;37(Suppl.4):S16S22;KawanakaH,etal.LifeSci2001;69:30193033,.,EGFRTKIinGC(Phase2),Doi2036,ProcASCO22,2003;FerryClinCanRes,132:5669,2007,Jarmaat,JCO,24,2008,07/23/2007,14,西妥昔单抗一线治疗胃癌的尝试,.,年龄18岁，KPS评分60分病理学和/或细胞学证实为胃腺癌，预计生存期3月局部晚期或转移性癌，无法手术切除一线治疗患者，接受辅助治疗至少间隔6月以上血常规检查正常：WBC3.0109/L，中性粒细胞1.5109/L，PLT80109/LECOG评分为2无严重心、肺、肝、肾功能障碍，未伴发急性感染,西妥昔单抗+FOLFOX4一线治疗晚期胃癌临床观察,ShiM,ZhangJ,etal,Hepatogastroenterology,2011,.,临床疗效评价,例数百分比（%）,CR00,PD416.0,SD1248.0,PR936.0,ORR=9/25=36.0%DCR=20/24=84.0%,ShiM,ZhangJ,etal,Hepatogastroenterology,2011,.,治疗前后CT,病例1：胃癌肝转移,ShiM,ZhangJ,etal,Hepatogastroenterology,2011,.,治疗前后CT,病例2：胃癌肝多发转移,ShiM,ZhangJ,etal,Hepatogastroenterology,2011,.,治疗前后CT,病例3：胃癌肝多发转移,ShiM,ZhangJ,etal,Hepatogastroenterology,2011,.,PFSd1-14q3w,RANDOM,UntilradiographicallydocumentedPDorunacceptabletoxicityPrimaryendpoint:PFStime(asassessedbyIndependentReviewCommittee),Cisplatin80mg/m2d1Capecitabine1000mg/m2twicedaily;d1-14q3wCetuximab400mg/m2loadingdose,then250mg/m2perweek,EXPANDPhaseIII,23,.,EGFR单克隆抗体的分类,-momab,-ximab,-mumab,-zumab,鼠源,嵌合,全人源化,人源化,24,.,如何改进？,进行亲和力设计，实现最适亲和力,25,.,TITLE,26,.,TITLE,27,.,TITLE,28,.,TITLE,29,.,皮疹与疗效相关？,.,ToGA研究中HER-2检测情况,HER2withIHCAbstract4556,ASCO2009,3807位患者接受筛选1810HER2-阳性(22.1%),.,患者的人口统计学以及基线特征,入组最多的为韩国，日本，中国和俄罗斯F,氟尿嘧啶;C,顺铂an=287;bn=293,.,Primaryendpoint:OS,Time(months),294290,277266,246223,209185,173143,147117,11390,9064,7147,5632,4324,3016,2114,137,126,65,40,10,00,No.atrisk,11.1,13.8,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,Event,FC+T,FC,Events167182,HR0.74,95%CI0.60,0.91,pvalue0.0046,MedianOS13.811.1,T,trastuzumab,.,Secondaryendpoint:PFS,0,2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,Event,294290,258238,201182,14199,9562,6033,4117,287,215,133,93,82,62,61,61,40,20,00,5.5,6.7,No.atrisk,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,Time(months),FC+T,FC,Events226235,HR0.71,95%CI0.59,0.85,pvalue0.0002,MedianPFS6.75.5,.,Secondaryendpoint:tumorresponserate,2.4%,5.4%,32.1%,41.8%,34.5%,47.3%,Intenttotreat,ORR=CR+PRCR,completeresponse;PR,partialresponse,p=0.0599,p=0.0145,F+C+trastuzumab,F+C,p=0.0017,Patients(%),CR,PR,ORR,.,Cross-trialComparationof1stTxofGC,张俊,中国医学论坛报,20090723,.,TheresponserateofHerceptin+CTinHER-2positivepatientswas47.3%,whichmeanstheotherhalfofthepatientswerenoresponsetoHerceptintreatmentTheunderlyingmechanismisstillunclear,Comments(Responserate),.,TITLE,.,标本储藏条件对IHC和FISH结果的影响胃癌的异质性胃癌细胞HER-2染色特征与乳腺癌的差异,Comments(StandardtechniquesforHER-2detection),.,Comments(Predictivemarker),HER-2与胃癌预后不良相关，HER-2作为Herceptin治疗胃癌的疗效预测标志物的价值？HER-2/neu信号通路内的其他接头蛋白或转录因子作为潜在疗效预测标志物的价值？EGFR单抗治疗中KRAS的故事,.,113,OSinIHC2+/FISH+orIHC3+(exploratoryanalysis),1.0,0.8,0.6,0.4,0.2,0.0,36,34,32,30,28,26,24,22,20,18,16,14,12,10,8,6,4,2,0,Time(months),11.8,16.0,FC+T,FC,Events120136,HR0.65,95%CI0.51,0.83,MedianOS16.011.8,Event,0.1,0.3,0.5,0.7,0.9,218198,40,53,124,2011,228218,196170,170141,142112,12296,10075,8453,6539,5128,10,00,No.atrisk,3920,2813,研究设计:开放、单组、II期研究主要终点:ORR次要终点:PFS,中国晚期胃癌患者HER2阳性率,OS,安全性,HER2+晚期胃癌之前未接受治疗,曲妥珠单抗8mg/kg首剂,然后6mg/kg每3周卡培他滨1000mg/m2BIDD1-14每3周奥沙利铂130mg/m2,D1每3周,曲妥珠单抗6mg/kg每3周卡培他滨1000mg/m2BIDD1-14每3周直到进展,6cycles,第一阶段,CGOG1001（ML25578）:曲妥珠单抗联合XELOX方案用于HER2阳性晚期胃癌的一线治疗,HER2+晚期胃癌之前未接受治疗,曲妥珠单抗8mg/kg首剂,然后6mg/kg每3周卡培他滨1000mg/m2BIDD1-14每3周奥沙利铂130mg/m2,D1每3周,曲妥珠单抗6mg/kg每3周卡培他滨1000mg/m2BIDD1-14每3周直到进展,6cycles,第二阶段,如果16例患者中有7例以上患者缓解，研究进入第二阶段,全部N=51,44,mTOR,mTOR是细胞代谢、生长、增殖和血管生成的核心调控者1,2mTOR是肿瘤生长开关1,2胰岛素样生长因子-1（IGF-1）等激活mTOR通路mTOR激活以下基因突变:PTEN,TSC2,NF1和VHL丢失抑制mTOR能抑制肿瘤的生长和增殖2,1.YaoJC,etal.BestPracClinEndocrinolMetab.2007;21:163-172.2.vonWichertG,etal.CancerRes.2000;60:4573-4581.,mTOR:哺乳动物雷帕霉素靶蛋白,GRANITE-1研究,N=656,靶向组(439):BSC+Everolimus,对照组(217):BSC+安慰剂,R,2012ASCOGI,Everolimus用于胃癌的思考,单药用于二线/三线并未显著延长OSmOSHR0.90（N.S.）mPFS1.441.68mos，HR0.66，P0.001疾病控制率22%43%III期研究未能重复II期数据(n=53)OS10.1mos，PFS2.7mos，DCR56%,.,AVAGAST:ARandomizedDouble-BlindPlacebo-ControlledPhaseIIIStudy,Startingdoseofbev/placebo:30minutes,subsequentdoses:15minutes,Capecitabine*/Cisplatin(XP)+Placeboq3w,Capecitabine*/Cisplatin(XP)+Bevacizumabq3w,Locallyadvancedormetastaticgastriccancer,R,*5-FUalsoallowedifcapecontraindicatedCape1000mg/m2oralbid,d114,1-weekrestCisplatin80mg/m2d1Bevacizumab7.5mg/kgd1Maximumof6cyclesofcisplatinCapeandbevacizumab/placebountilPD,Stratificationfactors:1.Geographicregion2.Fluoropirimidinebackbone3.Diseasestatus,.,病例特征(I),*1additionalpatienthadanECOGPSof4,.,病例特征(II),.,总生存,387387,343355,271291,204232,146178,98104,1519,XP+PlaceboXP+Bev,Numberatrisk,5450,00,.,无进展生存,387387,279306,145201,86123,5571,3238,33,1511,00,XP+PlaceboXP+Bev,Numberatrisk,.,最佳总体反应率,.,总生存:亚组分析,Pan-America,*29patientswithlocallyadvanceddiseaseonly,.,不同地理区域的患者特征,*1additionalpatienthadanECOGPSof4,.,不同地理区域患者接受二线治疗情况,.,AVAGAST分析,东西方的胃癌因发病机制、遗传背景、高发部位、人种差异ToGA研究的干扰分子标志物的探索,58,.,ResectableadenocarcinomaofthestomachorTypeIIIOGJPlannedn=1100,Randomised,Pre-operativeECXx3,Surgi