胃癌靶向治疗课件

后面内容直接删除就行资料可以编辑修改使用资料可以编辑修改使用后面内容直接删除就行主要经营：网络软件设计、图文设计制作、发布广告等公司秉着以优质的服务对待每一位客户，做到让客户满意！主要经营：网络软件设计、图文设计制作、发布广告等致力于数据挖掘，合同简历、论文写作、PPT设计、计划书、策划案、学习课件、各类模板等方方面面，打造全网一站式需求致力于数据挖掘，合同简历、论文写作、PPT设计、计划书、策划感谢您的观看和下载Theusercandemonstrateonaprojectororcomputer,orprintthepresentationandmakeitintoafilmtobeusedinawiderfield感谢您的观看和下载Theusercandemonstr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分子靶向治疗——困惑的临床理解分子靶点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(EricVanCutsem&Bang,2009)AVAGASTinASCO(Kang,2010)GRANIT-1((EricVanCutsem,2012）REAL-3(Waddell,2012)……近十年的晚期胃癌临床研究MAGICinNEJM(Cun目前正在研究中的胃癌治疗靶点与靶向药物WongH,YauT.TheOncologist2012;17:346-358.西妥昔单抗帕尼单抗曲妥珠单抗贝伐珠单抗FigitumumabGDC-0449拉帕替尼厄洛替尼吉非替尼索拉非尼舒尼替尼依维莫司细胞生存/增殖GSK089RasRafMEKERKP13KAktmTORSmoGli-1Ptch-1PTENHhIGF-1RPDGFRVEGFRHER-2HER-1VEGFMet目前正在研究中的胃癌治疗靶点与靶向药物WongH,Yau

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合理治疗靶点的标准与肿瘤的恶性表型相关胃癌的分子靶点寻找KRASMT <10%BRAFMT <5%EGFRMT <5%C-met扩增 <10%(IHC>40%)HER-2过表达 10-25%胃癌的分子靶点寻找KRASMT <10%单药应用疗效有限（Phase2）PhaseIIStudyRegimenNResponse(%)TTP/OSBang2007Sunitinib383%NSMuro2008RAD001240%NSGold2008Cetuximab552%1.8mos/4mosHecht2008Lapatinib210%--Lqbal2007477%2mos/5mos单药应用疗效有限（Phase2）PhaseIIRegi靶向＋化疗：成绩较好（Phase2）PhaseIIStudyRegimenNRR(%)TTP/OSLordicketal.20064Cetuximab+FUFOX2856%8.1/28.2mosDiFabioetal.20062Cetuximab+FOLFIRI2752%Pintoetal.20063Cetuximab+FOLFIRI2556%8/16mosJhawer2009Bev+ModifiedDCF3664%12mos/16mosShahetal.20061Bev+Cisplatin+Irinotecan3465%8.3/12.3MosEnzingeretal.2008Bev+Irino/Docet/Cisplatin2268%NS1.Shahetal.JClinOncol,2006;24;6201;2.DLFabioetal.ESMO,2006,Abstract1077PD;3.Pintoetal.AnnOncol2007;4.Lordicketal.AnnOncol2008靶向＋化疗：成绩较好（Phase2）PhaseIISt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：延长生存氟尿嘧啶类分子靶向添加药物替换药物基于优效性检验的晚期胃癌药ToGA（XP/FP±H）AVAGAST（XP±BV）ToGAAVAGAST07/23/2007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59,5％－86%(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)07/23/2007胃癌EGFR表达包括EGF家族在内的EGFreceptorsignalingpathway:

ArationaleforpersonalizedtherapySurvival

(anti-apoptosis)GenetranscriptionCell-cycleprogressionMYCMYCCyclinD1FOSJUNPPCyclinD1AngiogenesisInvasionandmetastasisChemotherapy/

radiotherapyresistanceProliferation/

maturationMAPKMEKRASRAFSOSGRB2PTENAKTSTATP13KpYpYLigand:AREG/EREGTargetforEGFR-ERBITUXEGFR-TKTargetforEGFT-TKinhibitorpYYardenY,SliwkowskiMX.NatRevMolCellBiol2001;2:127–137;ChakravartiA,etal.CancerRes2002;62:4307–4315;

BaselgaJ.EurJCancer2001;37(Suppl.4):S16–S22;KawanakaH,etal.LifeSci2001;69:3019–3033EGFreceptorsignalingpathwayEGFRTKIinGC(Phase2)GastricCaseNumberResponse(%)Dragovich(erlotinib)250Doi(Gefitinib)751GEJunctionFerry(Gefitinib)2711Janmaat(Gefitinib)260Tew(Erlotinib)170Dragovich(Erlotinib)439Doi2036,ProcASCO22,2003;FerryClinCanRes,132:5669,2007,Jarmaat,JCO,24,2008EGFRTKIinGC(Phase2)Gastri07/23/2007西妥昔单抗一线治疗胃癌的尝试方案病例数RR(%)PFS(mo)OS(mo)作者FOLFIRI+Erbitux38448.016.0Pinto,AnnOnc.2007FUFOX+Erbitux46657.69.5Lordick,ASCO2007Iri/5-FU/FA+Erbitux49428.516.6Kanzler,ASCO2009Irino/Oxa+Erbitux31426.29.5Woell,ASCO2009Docetaxel+Erbitux3441Pinto,ASCOGI2008Cispl.+Cape+Erbi47485.2Zhang,ASCOGI2009Cis+5-FU+Erbitux35691114.5Yeh,ASCO2009XELOX+Erbitux44526.611.7Kim,ASCOGI2009FOLFOX-6+Erbitux38505.59.9Han,Br.J.Cancer200907/23/2007西妥昔单抗一线治疗胃癌的尝试方案病例数R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：WBC≥3.0×109/L，中性粒细胞≥1.5×109/L，PLT≥80×109/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年龄≥18岁，KPS评分≥60分西妥昔单抗+FOLFOX4一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临床疗效评价例数治疗前后CT病例1：胃癌肝转移ShiM,ZhangJ,etal,Hepatogastroenterology,2011治疗前后CT病例1：胃癌肝转移ShiM,ZhangJ,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2：胃癌肝多发转移ShiM,Zhang治疗前后CT病例3：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,ZhangPFS&OSmPFS=6.5个月mOS=10.6个月ShiM,ZhangJ,etal,Hepatogastroenterology,2011PFS&OSmPFS=6.5个月mOS=10.6个月Sh胃癌KRAS突变率StudyNo.ofexaminedsamplesNo.(%)ofsampleswithKRASmutationsZhaoetal.,IntJCancer2004;108:167948(8.5%)Leeetal.,Oncogene2003;22:694260earlyGC

259advancedGC1inEGC(1.7%),

8inAGC(3.1%)Kimetal.,HumGenet2003;114:118664(6.1%)KRASrecentlyidentifiedaspredictivemarkerforresponsetoEGFR-inhibitortherapyinmCRC.

IncidenceofKRASmutationsingastriccancer?Currentassumption:KRAS尚不能作为胃癌EGFR靶向抑制治疗的疗效预测标志物胃癌KRAS突变率StudyNo.ofexamineCisplatin 80mg/m2d1Capecitabine 1000mg/m2twicedaily;d1-14q3wRANDOMUntilradiographicallydocumentedPDorunacceptabletoxicityPrimaryendpoint:PFStime

(asassessedbyIndependentReviewCommittee)Cisplatin 80mg/m2d1Capecitabine 1000mg/m2twicedaily;d1-14q3wCetuximab 400mg/m2loadingdose,

then250mg/m2perweekEXPAND

PhaseIIICisplatin 80mg/m2d1RUntEGFR单克隆抗体的分类30%鼠源蛋白嵌合5%鼠源蛋白人源化100%鼠源蛋白全鼠源100%人蛋白全人源化cetuximabnimotuzumabpanitumumab-momab-ximab-mumab-zumab鼠源嵌合全人源化人源化HAMA反应发生率降低EGFR单克隆抗体的分类30%鼠源蛋白嵌合5%鼠源蛋白人如何改进？进行亲和力设计，实现最适亲和力

如何改进？进行亲和力设计，实现最适亲和力[TITLE][TITLE][TITLE][TITLE][TITLE][TITLE][TITLE][TITLE]皮疹与疗效相关？皮疹与疗效相关？ToGA研究中HER-2检测情况HER2withIHC&FISHResults2484个进展期胃癌蜡块544HER2+(21,9%)IHC-FISH一致率87,3％与胃癌临床病理因素的关系LocationCardia32,2%Noncardia19,9%P=0.02typeIntestinal:32,5%Diffuse:6%P=0.001ToGA研究中HER-2检测情况HER2withIHCHER-2在胃癌表达AnnOncol,2008,19:1523外科杂志1996,1:25宫立群 133 中国 18,1％ IHCHER-2在胃癌表达AnnOncol,2008,19:ToGA研究设计HER2-阳性

晚期胃癌患者

(n=584)5-FU或卡培他滨a

+顺铂(n=290)R

a由研究者的判别来选择

GEJ,胃食管连接部5-FU或卡培他滨a

+顺铂+赫赛汀(n=294)分层因素局部晚期或转移性胃体部vs胃食管连接部可测量vs不可测量ECOG评分0-1vs2卡培他滨vs5-FU全球、多中心、随机、开放III期临床研究

1Bangetal;Abstract4556,ASCO20093807位患者接受筛选1810HER2-阳性(22.1%)ToGA研究设计HER2-阳性

晚期胃癌患者

(n=58患者的人口统计学以及基线特征特征F+C

n=290F+C+

赫赛汀

n=294性别,%

男性/女性

75/25

77/23中位年龄(年龄范围)岁59.0(21-82)61.0(23-83)中位体重(体重范围)公斤60.3(28-105)61.5(35-110)地区,n(%)

亚洲

美洲

欧洲

其他

166(56)

26(9)

95(32)

9(3)

158(53)

27(9)

99(33)

14(5)胃癌的类型(中心实验室评估结果)

肠型

弥漫型

混合型

74.2a

8.7a

17.1a

76.8b

8.9b

14.3b曾行胃部切除术21.424.1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患者的人口统计学以及基线特征特征F+C

n=290F+C+Primaryendpoint:OSTime(months)2942902772662462232091851731431471171139090647147563243243016211413712665401000No.

atrisk11.113.80.00.10.20.30.40.50.60.70.80.91.0024681012141618202224262830323436EventFC+TFCEvents167

182HR0.7495%CI0.60,0.91pvalue0.0046Median

OS13.8

11.1T,trastuzumabPrimaryendpoint:OSTime(monSecondaryendpoint:PFS0246810121416182022242628303234Event2942902582382011821419995626033411728721513393826261614020005.56.7No.

atrisk0.00.10.20.30.40.50.60.70.80.91.0Time(months)FC+TFCEvents226

235HR0.7195%CI0.59,0.85pvalue0.0002Median

PFS6.7

5.5Secondaryendpoint:PFS024681Secondaryendpoint:

tumorresponserate2.4%5.4%32.1%41.8%34.5%47.3%IntenttotreatORR=CR+PR

CR,completeresponse;PR,partialresponsep=0.0599p=0.0145F+C+trastuzumabF+Cp=0.0017Patients(%)CRPRORRSecondaryendpoint:

tumorreCross-trialComparationof1stTxofGC张俊,中国医学论坛报,20090723Cross-trialComparationof1stTheresponserateofHerceptin+CTinHER-2positivepatientswas47.3%,whichmeanstheotherhalfofthepatientswerenoresponsetoHerceptintreatmentTheunderlyingmechanismisstillunclearComments(Responserate)TheresponserateofHerceptin[TITLE][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(Standardtechniques

forHER-2detection)标本储藏条件对IHC和FISH结果的影响CommentComments(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Comments(Predictivemarker)HE113OSinIHC2+/FISH+orIHC3+(exploratoryanalysis)1.00.80.60.40.20.0363432302826242220181614121086420Time(months)11.816.0FC+TFCEvents120

136HR0.6595%CI0.51,0.83Median

OS16.0

11.8Event0.10.30.50.70.921819840531242011228218196170170141142112122

96100758453653951281000No.

atrisk3920281311OSinIHC2+/FISH+orIHC3+(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研究设计:开放、单组、II期研究HER2+晚期胃癌曲妥珠47mTORmTOR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21.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47mTORmTOR是细胞代谢、生长、增殖和血管生成的核心调GRANITE-1研究N=656靶向组(439):BSC+Everolimus对照组(217):BSC+安慰剂R2012ASCOGIProbabilityofoverallsurvival(%)100806040200024681012Time(months)14CensoringTimesEverolimus+BSC(n/N=352/439)Placebo+BSC(n/N=180/217)Kaplan-MeiermediansEverolimus+BSC:5.39monthsPlacebo+BSC:4.34monthsHazardratio:0.90(95%CI,0.75-1.08)Log-rankP

value=0.1244No.ofpatientsstillatriskTime(months)EverolimusPlacebo16182022240246810121416182022242171721178260352816128410439355253195139875230136310GRANITE-1研究N=656靶向组(439):BSC+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.）mPFS1.44→1.68mos，HR0.66，P<0.001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%Everolimus用于胃癌的思考单药用于二线/三线并未显著胃癌靶向治疗课件AVAGAST:ARandomizedDouble-Blind

Placebo-ControlledPhaseIIIStudyStartingdoseofbev/placebo:30minutes,subsequentdoses:15minutesCapecitabine*/Cisplatin(XP)+Placeboq3wCapecitabine*/Cisplatin(XP)+Bevacizumabq3wLocallyadvancedormetastatic

gastriccancerR*5-FUalsoallowedifcapecontraindicatedCape1000

mg/m2oralbid,d1–14,1-weekrestCisplatin80

mg/m2d1Bevacizumab7.5mg/kgd1Maximumof6cyclesofcisplatinCapeandbevacizumab/placebountilPDStratificationfactors:1.Geographicregion2.Fluoropirimidinebackbone3.DiseasestatusAVAGAST:ARandomizedDouble-B病例特征

(I)NumberofpatientsN=774(%)XP+PlaceboN=387XP+BevN=387GenderMale258(67)257(66)Age,yearsMedian(range)59(22–82)58(22–81)ECOGPS0–1≥2367(95)20(5)365(94)22*(6)RegionAsiaEuropePan-America188(49)

124(32)

75(19)188(49)

125(32)

74(19)FluoropyrimidineCapecitabine

5-FU365(94)

22(6)364(94)

23(6)DiseasestatusLocallyadvancedMetastatic9(2)378(98)20(5)367(95)*1additionalpatienthadanECOGPSof4病例特征(I)XP+PlaceboXP+BevGe病例特征

(II)NumberofpatientsN=774(%)XP+PlaceboN=387XP+BevN=387PrimarysiteStomachGEJ338(87)49(13)333(86)54(14)HistologictypeIntestinalDiffuseMixed135(35)206(53)26(7)155(40)176(46)35(9)DiseasemeasurabilityMeasurableEvaluable297(77)90(23)311(80)76(20)Metastaticsites,n01≥28(2)131(34)247(64)8(2)131(34)247(64)PriorgastrectomyYes107(28)110(28)LivermetastasisYes126(33)130(34)病例特征(II)XP+PlaceboXP+BevP总生存387387343355271291204232146178981041519XP+PlaceboXP+BevNumberatrisk545000XP+PlaceboXP+BevHR=0.8795%CI0.73–1.03p=0.1002Survivalrate391518212400.00.10.20.30.40.50.60.70.80.91.0612Studymonth10.112.1总生存3873432712041469815XP+Pla无进展生存387387279306145201861235571323833151100XP+PlaceboXP+BevNumberatriskXP+PlaceboXP+BevHR=0.8095%CI0.68–0.93p=0.0037Progression-freesurvivalrate0.00.10.20.30.40.50.60.70.80.91.0391518212406125.36.7Studymonth无进展生存3872791458655323150XP+P最佳总体反应率XP+Placebo

N=387XP+Bev

N=387Patientswithmeasurabledisease297311Overallresponse111(37%)143(46%)95%CI31.9–43.140.3–51.7Difference9%95%CI0.6–16.6Pvalue(

2)0.0315Completeresponse3(1%)5(2%)Partialresponse108(36%)138(44%)Stabledisease90(30%)93(30%)Progressivedisease63(21%)44(14%)Notassessable33(11%)31(10%)最佳总体反应率XP+Placebo

N=387XP+总生存:亚组分析Pan-America2NoDiseasestatusECOGperformancePriorgastrectomyRegionSiteofprimarydiseaseNo.ofmetastaticsitesatbaselineDiseasemeasurabilityHistologictypeAllLocallyadvanced*Metastatic0YesEuropeAll

1AsiaStomachGEjunction1MeasurableNon-measurableIntestinalDiffuseMixedSubgroupCategory2HazardRatio01*29patientswithlocallyadvanceddiseaseonlyHR0.970.850.63总生存:亚组分析Pan-America2NoDiseas不同地理区域的患者特征%ofpatientsAsiaEuropePan-AmericaAge<65726877≥65283223ECOGPS0–197919623*94PrimarysiteStomach947884GEJ62216ExtentofdiseaseMetastatic999592Locallyadvanced158Priorgastrectomyyes322327no687773Measurablelesionyes738877no271223Livermetastasisyes273742no736358*1additionalpatienthadanECOGPSof4不同地理区域的患者特征%ofpatientsAsiaEu不同地理区域患者接受二线治疗情况RegionPatientsenteredPatientsreceivingsecond-linetreatment%Asia37624866Europe