《胃癌靶向治療》

分子靶向治療——困惑的臨床理解分子靶點(diǎn)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(shí)踐做到真正的translationalresearch指導(dǎo)臨床研究設(shè)計(jì)指導(dǎo)臨床指南編輯ppt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)……編輯ppt目前正在研究中的胃癌治療靶點(diǎn)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合理治療靶點(diǎn)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(cè)與臨床預(yù)后相關(guān)當(dāng)該靶點(diǎn)被阻斷、干擾或抑制時(shí)，對(duì)高度表達(dá)該靶點(diǎn)的患者應(yīng)有一定的臨床反應(yīng)，對(duì)不表達(dá)該靶點(diǎn)者，應(yīng)無或產(chǎn)生較少臨床反應(yīng)編輯ppt胃癌的分子靶點(diǎn)尋找KRASMT <10%BRAFMT <5%EGFRMT <5%C-met擴(kuò)增 <10%(IHC>40%)HER-2過表達(dá) 10-25%編輯ppt單藥應(yīng)用療效有限（Phase2）PhaseIIStudyRegimenNResponse(%)TTP/OSBang2007Sunitinib383%NSMuro2008RAD001240%NSGold2008Cetuximab552%1.8mos/4mosHecht2008Lapatinib210%--Lqbal2007477%2mos/5mos編輯ppt靶向＋化療：成績(jī)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編輯ppt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(yàn)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(zhǎng)生存編輯pptToGA（XP/FP±H）AVAGAST（XP±BV）編輯ppt胃癌EGFR

表達(dá)包括EGF家族在內(nèi)的各類生長(zhǎng)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(cè)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)07/23/2007EGFreceptorsignalingpathway:

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;69:3019–3033編輯pptEGFRTKIinGC(Phase2)GastricCaseNumberResponse(%)Dragovich(erlotinib)250Doi(Gefitinib)751GEJunctionFerry(Gefitinib)2711Janmaat(Gefitinib)260Tew(Erlotinib)170Dragovich(Erlotinib)439Doi2036,ProcASCO22,2003;FerryClinCanRes,132:5669,2007,Jarmaat,JCO,24,2008編輯ppt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年齡≥18歲，KPS評(píng)分≥60分病理學(xué)和/或細(xì)胞學(xué)證實(shí)為胃腺癌，預(yù)計(jì)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(píng)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編輯ppt臨床療效評(píng)價(jià)

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編輯ppt治療前后CT病例1：胃癌肝轉(zhuǎn)移ShiM,ZhangJ,etal,Hepatogastroenterology,2011編輯ppt治療前后CT病例2：胃癌肝多發(fā)轉(zhuǎn)移ShiM,ZhangJ,etal,Hepatogastroenterology,2011編輯ppt治療前后CT病例3：胃癌肝多發(fā)轉(zhuǎn)移ShiM,ZhangJ,etal,Hepatogastroenterology,2011編輯pptPFS&OSmPFS=6.5個(gè)月mOS=10.6個(gè)月ShiM,ZhangJ,etal,Hepatogastroenterology,2011編輯ppt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(cè)標(biāo)志物編輯pptCisplatin 80mg/m2d1Capecitabine 1000mg/m2twicedaily;d1-14q3wRANDOM

Until

radiographically

documentedPDor

unacceptable

toxicity

Primary

endpoint:PFStime

(asassessed

byIndependentReview

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

then250mg/m2perweekEXPAND

PhaseIII編輯pptEGFR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)生率降低編輯ppt如何改進(jìn)？進(jìn)行親和力設(shè)計(jì)，實(shí)現(xiàn)最適親和力

編輯ppt[TITLE]編輯ppt[TITLE]編輯ppt[TITLE]編輯ppt[TITLE]編輯ppt皮疹與療效相關(guān)？編輯pptToGA研究中HER-2檢測(cè)情況HER2withIHC&FISHResults2484個(gè)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=0.001編輯pptHER-2在胃癌表達(dá)AnnOncol,2008,19:1523外科雜志1996,1:25宮立群 133 中國(guó) 18,1％ IHC編輯pptToGA研究設(shè)計(jì)HER2-陽(yáng)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(cè)量vs不可測(cè)量ECOG評(píng)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(yáng)性(22.1%)編輯ppt患者的人口統(tǒng)計(jì)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(shí)驗(yàn)室評(píng)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(guó)，日本，中國(guó)和俄羅斯F,氟尿嘧啶;C,順鉑an=287;bn=293編輯pptPrimaryendpoint: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,trastuzumab編輯pptSecondaryendpoint: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

5.5編輯pptSecondaryendpoint:

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(%)CRPRORR編輯pptCross-trialComparationof1stTxofGC張俊,中國(guó)醫(yī)學(xué)論壇報(bào),20090723編輯pptTheresponserateofHerceptin+CTinHER-2positivepatientswas47.3%,whichmeanstheotherhalfofthepatientswerenoresponsetoHerceptintreatmentTheunderlyingmechanismisstillunclearComments(Responserate)編輯ppt[TITLE]編輯ppt標(biāo)本儲(chǔ)藏條件對(duì)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)編輯pptComments(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(cè)標(biāo)志物的價(jià)值？HER-2/neu信號(hào)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(cè)標(biāo)志物的價(jià)值？EGFR單抗治療中KRAS的故事編輯ppt113OSinIHC2+/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.

atrisk39202813編輯ppt研究設(shè)計(jì):開放、單組、II期研究主要終點(diǎn):ORR次要終點(diǎn):PFS,中國(guó)晚期胃癌患者HER2陽(yáng)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(yáng)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=5143mTORmTOR是細(xì)胞代謝、生長(zhǎng)、增殖和血管生成的核心調(diào)控者1,2mTOR是腫瘤生長(zhǎng)開關(guān)1,2胰島素樣生長(zhǎng)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(zhǎng)和增殖21.YaoJC,etal.BestPracClinEndocrinolMetab.2007;21:163-172.2.vonWichertG,etal.CancerRes.2000;60:4573-4581.mTOR:哺乳動(dòng)物雷帕霉素靶蛋白GRANITE-1研究N=656靶向組(439):BSC+Everolimus對(duì)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)EverolimusPlacebo16182022240246810121416182022242171721178260352816128410439355253195139875230136310Everolimus用于胃癌的思考單藥用于二線/三線并未顯著延長(zhǎng)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%AVAGAST:ARandomizedDouble-Blind

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

gastriccancerR*5-FUalsoallowedifcapecontraindicatedCape1000

mg/m2

oralbid,d1–14,1-weekrestCisplatin80

mg/m2d1Bevacizumab7.5mg/kgd1Maximumof6cyclesofcisplatinCapeandbevacizumab/placebountilPDStratificationfactors:1.Geographicregion2.Fluoropirimidinebackbone3.Diseasestatus編輯ppt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編輯ppt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)編輯ppt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編輯ppt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編輯ppt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%)編輯ppt總生存:亞組分析Pan-America2NoDiseasestatusECOGperformancePriorgastrectomyRegionSiteofprimarydiseaseNo.ofmetastaticsitesatbaselineDiseasemeasurabilityHistologictypeAllLocallyadvanced*Metastatic0YesEuropeAll1AsiaStomachGEjunction1MeasurableNon-measurableIntestinalDiffuseMixedSubgroupCategory2HazardRatio01*29patientswithlocallyadvanceddiseaseonlyHR0.970.850.63編輯ppt不同地理區(qū)域的患者特征%ofpatientsAsiaEuropePan-AmericaAge<65726877≥65283223ECOGPS0–197919623*94PrimarysiteStomach947884GEJ62216ExtentofdiseaseMetastatic999592Locallyadvanced158Priorgastrectomyyes322327no687773Measurablelesionyes738877no271223Livermetastasisyes273742no736358*1additionalpatienthadanECOGPSof4編輯ppt不同地理區(qū)域患者接受二線治療情況RegionPatientsenteredPatientsreceivingsecond-linetreatment%Asia37624866Euro