胃癌靶向治療課件

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理解分子靶點理解療效與特異性毒性反應(yīng)藥物機(jī)理與臨床研究結(jié)果的解讀分子靶向治療藥物的應(yīng)用實踐做到真正的translationalresearch指導(dǎo)臨床研究設(shè)計指導(dǎo)臨床指南分子靶向治療——困惑的臨床理解分子靶點近十年的晚期胃癌臨床研究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)……近十年的晚期胃癌臨床研究MAGICinNEJM(Cun目前正在研究中的胃癌治療靶點與靶向藥物WongH,YauT.TheOncologist2012;17:346-358.西妥昔單抗帕尼單抗曲妥珠單抗貝伐珠單抗FigitumumabGDC-0449拉帕替尼厄洛替尼吉非替尼索拉非尼舒尼替尼依維莫司細(xì)胞生存/增殖GSK089RasRafMEKERKP13KAktmTORSmoGli-1Ptch-1PTENHhIGF-1RPDGFRVEGFRHER-2HER-1VEGFMet目前正在研究中的胃癌治療靶點與靶向藥物WongH,Yau

合理治療靶點的標(biāo)準(zhǔn)與腫瘤的惡性表型相關(guān)重要臟器與組織中很少表達(dá)分子特性與生物學(xué)行為相關(guān)能在臨床較易獲得的樣本中重復(fù)檢測與臨床預(yù)后相關(guān)當(dāng)該靶點被阻斷、干擾或抑制時，對高度表達(dá)該靶點的患者應(yīng)有一定的臨床反應(yīng)，對不表達(dá)該靶點者，應(yīng)無或產(chǎn)生較少臨床反應(yīng)合理治療靶點的標(biāo)準(zhǔn)與腫瘤的惡性表型相關(guān)胃癌的分子靶點尋找KRASMT <10%BRAFMT <5%EGFRMT <5%C-met擴(kuò)增 <10%(IHC>40%)HER-2過表達(dá) 10-25%胃癌的分子靶點尋找KRASMT <10%單藥應(yīng)用療效有限（Phase2）PhaseIIStudyRegimenNResponse(%)TTP/OSBang2007Sunitinib383%NSMuro2008RAD001240%NSGold2008Cetuximab552%1.8mos/4mosHecht2008Lapatinib210%--Lqbal2007477%2mos/5mos單藥應(yīng)用療效有限（Phase2）PhaseIIRegi靶向＋化療：成績較好（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＋化療：成績較好（Phase2）PhaseIISt鉑類藥物替換氟尿嘧啶類藥物替換分子靶向藥物添加藥物替換藥物基于優(yōu)效性檢驗的胃癌一線化療方案晚期胃癌藥物治療的優(yōu)化策略序貫治療誘導(dǎo)化療/維持化療其他策略目標(biāo)：延長生存氟尿嘧啶類分子靶向添加藥物替換藥物基于優(yōu)效性檢驗的晚期胃癌藥ToGA（XP/FP±H）AVAGAST（XP±BV）ToGAAVAGAST07/23/2007胃癌EGFR表達(dá)包括EGF家族在內(nèi)的各類生長因子及其受體在胃癌中呈過度表達(dá)

(GastricCancer2004;7:61-77)免疫組化染色提示胃癌組織中EGFR表達(dá)率為59,5％－86%(JCO2006;24:4922-4927;ASCO2007#4526)RT-PCR檢測提示胃癌組織中EGFR基因擴(kuò)增率約62%(WorldJGastroenterol2007;13:3605-3609)

EGFR表達(dá)升高與以下臨床病理因素相關(guān):

進(jìn)展期胃癌＋淋巴結(jié)轉(zhuǎn)移

生存期縮短

(EJC2001;37:S9-S15)07/23/2007胃癌EGFR表達(dá)包括EGF家族在內(nèi)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西妥昔單抗一線治療胃癌的嘗試方案病例數(shù)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西妥昔單抗一線治療胃癌的嘗試方案病例數(shù)R年齡≥18歲，KPS評分≥60分病理學(xué)和/或細(xì)胞學(xué)證實為胃腺癌，預(yù)計生存期＞3月局部晚期或轉(zhuǎn)移性癌，無法手術(shù)切除一線治療患者，接受輔助治療至少間隔6月以上血常規(guī)檢查正常：WBC≥3.0×109/L，中性粒細(xì)胞≥1.5×109/L，PLT≥80×109/LECOG評分為≤2無嚴(yán)重心、肺、肝、腎功能障礙，未伴發(fā)急性感染西妥昔單抗+FOLFOX4一線治療晚期胃癌臨床觀察ShiM,ZhangJ,etal,Hepatogastroenterology,2011年齡≥18歲，KPS評分≥60分西妥昔單抗+FOLFOX4一臨床療效評價例數(shù)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臨床療效評價例數(shù)治療前后CT病例1：胃癌肝轉(zhuǎn)移ShiM,ZhangJ,etal,Hepatogastroenterology,2011治療前后CT病例1：胃癌肝轉(zhuǎn)移ShiM,ZhangJ,治療前后CT病例2：胃癌肝多發(fā)轉(zhuǎn)移ShiM,ZhangJ,etal,Hepatogastroenterology,2011治療前后CT病例2：胃癌肝多發(fā)轉(zhuǎn)移ShiM,Zhang治療前后CT病例3：胃癌肝多發(fā)轉(zhuǎn)移ShiM,ZhangJ,etal,Hepatogastroenterology,2011治療前后CT病例3：胃癌肝多發(fā)轉(zhuǎn)移ShiM,ZhangPFS&OSmPFS=6.5個月mOS=10.6個月ShiM,ZhangJ,etal,Hepatogastroenterology,2011PFS&OSmPFS=6.5個月mOS=10.6個月Sh胃癌KRAS突變率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尚不能作為胃癌EGFR靶向抑制治療的療效預(yù)測標(biāo)志物胃癌KRAS突變率StudyNo.ofexamineCisplatin 80mg/m2d1Capecitabine 1000mg/m2twicedaily;d1-14q3wRANDOMUntilradiographicallydocumentedPDorunacceptabletoxicityPrimaryendpoint:PFStime

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

then250mg/m2perweekEXPAND

PhaseIIICisplatin 80mg/m2d1RUntEGFR單克隆抗體的分類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反應(yīng)發(fā)生率降低EGFR單克隆抗體的分類30%鼠源蛋白嵌合5%鼠源蛋白人如何改進(jìn)？進(jìn)行親和力設(shè)計，實現(xiàn)最適親和力

如何改進(jìn)？進(jìn)行親和力設(shè)計，實現(xiàn)最適親和力[TITLE][TITLE][TITLE][TITLE][TITLE][TITLE][TITLE][TITLE]皮疹與療效相關(guān)？皮疹與療效相關(guān)？ToGA研究中HER-2檢測情況HER2withIHC&FISHResults2484個進(jìn)展期胃癌蠟塊544HER2+(21,9%)IHC-FISH一致率87,3％與胃癌臨床病理因素的關(guān)系LocationCardia32,2%Noncardia19,9%P=0.02typeIntestinal:32,5%Diffuse:6%P=0.001ToGA研究中HER-2檢測情況HER2withIHCHER-2在胃癌表達(dá)AnnOncol,2008,19:1523外科雜志1996,1:25宮立群 133 中國 18,1％ IHCHER-2在胃癌表達(dá)AnnOncol,2008,19:ToGA研究設(shè)計HER2-陽性

晚期胃癌患者

(n=584)5-FU或卡培他濱a

+順鉑(n=290)R

a由研究者的判別來選擇

GEJ,胃食管連接部5-FU或卡培他濱a

+順鉑+赫賽汀(n=294)分層因素局部晚期或轉(zhuǎn)移性胃體部vs胃食管連接部可測量vs不可測量ECOG評分0-1vs2卡培他濱vs5-FU全球、多中心、隨機(jī)、開放III期臨床研究

1Bangetal;Abstract4556,ASCO20093807位患者接受篩選1810HER2-陽性(22.1%)ToGA研究設(shè)計HER2-陽性

晚期胃癌患者

(n=58患者的人口統(tǒng)計學(xué)以及基線特征特征F+C

n=290F+C+

赫賽汀

n=294性別,%

男性/女性

75/25

77/23中位年齡(年齡范圍)歲59.0(21-82)61.0(23-83)中位體重(體重范圍)公斤60.3(28-105)61.5(35-110)地區(qū),n(%)

亞洲

美洲

歐洲

其他

166(56)

26(9)

95(32)

9(3)

158(53)

27(9)

99(33)

14(5)胃癌的類型(中心實驗室評估結(jié)果)

腸型

彌漫型

混合型

74.2a

8.7a

17.1a

76.8b

8.9b

14.3b曾行胃部切除術(shù)21.424.1入組最多的為韓國，日本，中國和俄羅斯F,氟尿嘧啶;C,順鉑an=287;bn=293患者的人口統(tǒng)計學(xué)以及基線特征特征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張俊,中國醫(yī)學(xué)論壇報,20090723Cross-trialComparationof1stTheresponserateofHerceptin+CTinHER-2positivepatientswas47.3%,whichmeanstheotherhalfofthepatientswerenoresponsetoHerceptintreatmentTheunderlyingmechanismisstillunclearComments(Responserate)TheresponserateofHerceptin[TITLE][TITLE]

標(biāo)本儲藏條件對IHC和FISH結(jié)果的影響胃癌的異質(zhì)性胃癌細(xì)胞HER-2染色特征與乳腺癌的差異Comments(Standardtechniques

forHER-2detection)標(biāo)本儲藏條件對IHC和FISH結(jié)果的影響CommentComments(Predictivemarker)HER-2與胃癌預(yù)后不良相關(guān)，HER-2作為Herceptin治療胃癌的療效預(yù)測標(biāo)志物的價值？HER-2/neu信號通路內(nèi)的其他接頭蛋白或轉(zhuǎn)錄因子作為潛在療效預(yù)測標(biāo)志物的價值？EGFR單抗治療中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+(研究設(shè)計:開放、單組、II期研究主要終點:ORR次要終點:PFS,中國晚期胃癌患者HER2陽性率,OS,安全性

HER2+晚期胃癌之前未接受治療曲妥珠單抗8mg/kg首劑,然后6mg/kg每3周卡培他濱

1000mg/m2BIDD1-14每3周奧沙利鉑130mg/m2,D1每3周曲妥珠單抗6mg/kg每3周卡培他濱

1000mg/m2BIDD1-14每3周直到進(jìn)展6cycles第一階段CGOG1001（ML25578）:曲妥珠單抗聯(lián)合XELOX方案用于HER2陽性晚期胃癌的一線治療HER2+晚期胃癌之前未接受治療曲妥珠單抗8mg/kg首劑,然后6mg/kg每3周卡培他濱

1000mg/m2BIDD1-14每3周奧沙利鉑130mg/m2,D1每3周曲妥珠單抗6mg/kg每3周卡培他濱

1000mg/m2BIDD1-14每3周直到進(jìn)展6cycles第二階段如果16例患者中有7例以上患者緩解，研究進(jìn)入第二階段全部N=51研究設(shè)計:開放、單組、II期研究HER2+晚期胃癌曲妥珠47mTORmTOR是細(xì)胞代謝、生長、增殖和血管生成的核心調(diào)控者1,2mTOR是腫瘤生長開關(guān)1,2胰島素樣生長因子-1（IGF-1）等激活mTOR通路mTOR激活以下基因突變:PTEN,TSC2,NF1和VHL丟失抑制mTOR能抑制腫瘤的生長和增殖21.YaoJC,etal.BestPracClinEndocrinolMetab.2007;21:163-172.2.vonWichertG,etal.CancerRes.2000;60:4573-4581.mTOR:哺乳動物雷帕霉素靶蛋白47mTORmTOR是細(xì)胞代謝、生長、增殖和血管生成的核心調(diào)GRANITE-1研究N=656靶向組(439):BSC+Everolimus對照組(217):BSC+安慰劑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靶向組(439):BSC+Everolimus用于胃癌的思考單藥用于二線/三線并未顯著延長OSmOSHR0.90（N.S.）mPFS1.44→1.68mos，HR0.66，P<0.001疾病控制率22%→43%III期研究未能重復(fù)II期數(shù)據(jù)(n=53)OS10.1mos，PFS2.7mos，DCR56%Everolimus用于胃癌的思考單藥用于二線/三線并未顯著胃癌靶向治療課件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總生存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總生存3873432712041469815XP+Pla無進(jìn)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無進(jìn)展生存3872791458655323150XP+P最佳總體反應(yīng)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%)最佳總體反應(yīng)率XP+Placebo

N=387XP+總生存:亞組分析Pan-America2NoDiseasestatusECOGperformancePriorgastrectomyRegionSiteofprimarydiseaseNo.ofmetastaticsitesatbaselineDiseasemeasurabilityHistologictypeAllLocallyadvanced*Metastatic0YesEuropeAll

1AsiaStomachGEjunction1MeasurableNon-measurableIntestinalDiffuseMixedSubgroupCategory2HazardRatio01*29patientswithlocallyadvanceddiseaseonlyHR0.970.850.63總生存:亞組分析Pan-America2NoDiseas不同地理區(qū)域的患者特征%ofpatientsAsiaEuropePan-AmericaAge<65726877≥65283223ECOGPS0–197919623*94PrimarysiteStomach947884GEJ62216ExtentofdiseaseMetastatic999592Locallyadvanced158Priorgastrectomyyes322327no687773Measurablelesionyes738877no271223Livermetastasisyes273742no736358*1additionalpatienthadanECOGPSof4不同地理區(qū)域的患者特征%ofpatientsAsiaEu不同地理區(qū)域患者接受二線治療情況RegionPatientsenteredPatientsreceivingsecond-linetreatment%Asia37624866Europe