肺癌的生物靶向治療進展課件

肺癌的生物靶向治療進展上海市肺科醫(yī)院腫瘤科肺癌的生物靶向治療進展CurrentAnti-CancerApproachesSurgeryChemo-therapyRadiationHormonaltherapyTargetedtherapyRemoveknowntumormassesKillrapidlydividingtumorcells,

includingtumorcellsinadjacenttissuesKillrapidlydividingtumorcellsInhibitthegrowthandsurvivalofhormone-dependenttumorcellsSpecificallyinhibitprocesses

requiredfortumorcellgrowth肺癌的生物靶向治療進展Whydoweneednewanticanceragents?*1-yearsurvivalrateDatafromtheEUROCAREIIstudy80706050403020100Relative5-year

survivalrate(%) Breast Colon Kidney Liver Lung* Ovary Pancreas1978–19801984–19861987–1989肺癌的生物靶向治療進展Whatmakesanidealtherapeutictarget?PresentinthemajorityofpatientswithspecifictumortypeCausativelinkwithtumourigenesisEssentialfunctionintumorcells肺癌的生物靶向治療進展AssessingnoveltargetedagentsTypicalcytotoxicMTDOBD

ToxicityAntitumoureffectEffectTargetDoseOBD>MTDAdaptedfromRowinsky2000TargetToxicityAntitumour

effectOBDMTDEffectOBD<MTDNoveltargetedagentsOBD,optimalbiologicaldose

MTD,maximumtolerateddoseDose肺癌的生物靶向治療進展EGFRIressa,Tarceva,C225血管生成

AvastinCOX-2Celecoxib肺癌的生物靶向治療進展EGFRexpressioninhumantumours

Highexpressionisgenerallyassociatedwithinvasionmetastasislate-stagediseasechemotherapyresistancehormonaltherapyresistancepooroutcomeEGFRhighlyexpressedinNSCLC肺癌的生物靶向治療進展Extensiveclinicalexperience

withgefitinibMonotherapy IDEAL1 IDEAL2 5PhaseItrialsCombinationtherapy INTACT1 INTACT2ExpandedAccessProgrammePost-marketinguseinJapanOthersalesOtherNSCLCstudiesTrialsinothertumourtypesn209216270720684~39,200~39,100~9100~6002600TOTAL~92,750Dataasof3Sept2003IDEAL,IRESSADoseEvaluationinAdvancedLungcancerINTACT,IRESSANSCLCTrialAssessingCombinationTreatment肺癌的生物靶向治療進展RandomisationGefitinib250mgoncedailyGefitinib500mgoncedaily

Patients

AdvancedNSCLC

havingreceived

1or2(IDEAL1)

or>2(IDEAL2)

previous

chemotherapy

regimensContinuegefitinibuntildisease

progressionorunacceptabletoxicityPrimaryendpointsResponserate(bothtrials)Safetyprofile(IDEAL1)Symptomrelief(IDEAL2)IDEAL1:platinum,1or2priorregimens(n=209)

IDEAL2:platinumanddocetaxel,>2priorregimens(n=216)GefitinibPhaseIIstudies:

IDEAL1&2肺癌的生物靶向治療進展Tumourresponse:IDEAL1&2

(250mg/day)Objectiveresponserate=CR+PR

Diseasecontrolrate=CR+PR+SDPatients(%)Objective

response

rateDisease

control

rateObjective

response

rateDisease

control

rateIDEAL1IDEAL2Fukuokaetal2003a;Krisetal2003肺癌的生物靶向治療進展 USEAPexperiencein21064NSCLC

III/IVNSCLC化療失敗或不能耐受F/M9979/11040年齡67歲白人87.8%MST5.3m1年生存29.9%女性/東方人,III期生存期長治療相關(guān)SAE2.3%SAE停藥1.1%治療相關(guān)性死亡0.3%IRESSA250mg/dOchsJ,etal.PASCO2004;A7060肺癌的生物靶向治療進展Characterisationoftumourresponse>10%,irrespectiveofpriortreatmentsandpoorperformancestatus(PS)[250mg/day]>65%ofresponsesachievedwithinfirst4weeks

(250mg/day)Meantumourreductioninpatientswithapartialresponsewas>80%IDEAL1:median13(range2-20+)months(250mg/day)

IDEAL2:median7(range2-19+)months(250mg/day)ResponserateRapidDurableSizeableFukuokaetal2003b肺癌的生物靶向治療進展PhaseIIIstudies:INTACT1&2RandomiseContinuegefitinib

orplacebountil

diseaseprogressionChemotherapya

x6cycles250mg/day

gefitinib+Chemotherapya

x6cycles500mg/day

gefitinib+Chemotherapya

x6cyclesPlacebo+aGemcitabine/cisplatin(INTACT1n=1093)

orpaclitaxel/carboplatin(INTACT2n=1037)EligibilitycriteriaHistologically/cytologicallyconfirmedNSCLCLocallyadvancedstageIIIdiseasenotcurablewithsurgeryorradiotherapy,orstageIVdiseaseAge>18yearsWorldHealthOrganizationPS0-2Johnsonetal2002;Giacconeetal2002肺癌的生物靶向治療進展Gefitinib聯(lián)合健擇或諾維本一線治療≥70歲或PS2NSCLC意大利多中心II期研究對象:≥70歲PS0-2,可測量病灶方案:Gefitinib250mg/d,至PDA組:NVB30mg/m2d1,8q21dB組:GEM1200mg/m2d1,8q21d×6周期Scagliotti,etal.PASCO2004;A7081肺癌的生物靶向治療進展IRESSA聯(lián)合NVB或健擇治療70歲以及老年NSCLC---II期IRESSA+NVBIRESSA+健擇N2435中位年齡7274PS0-19691鱗癌1731G3/4中72%11.4%死亡3例0CR/PR/SD1/3/70/3/13PD69MST275天275天PASCOA7081，2004肺癌的生物靶向治療進展IRESSA對BAC的療效-SWOGS0126對象138例BAC(102初治,36二線）、年齡68，女性51%、PS0/186%Gefitinib500mg初治RR21%,CR6%；MST12月復(fù)治RR10%，CR0%；MST10月1年生存50%女性生存16，男性7月，p=.003皮疹者生存12月,無皮疹5個月,p=0.01PASCO2004；A7014肺癌的生物靶向治療進展AssociationbetweenactivationofErbBpathwaygenesandsurvivalfollowinggefitinibinNSCLCErbB1ErbB2pMAPKNpMAPKCpAKTNpAKTCKi-67-0.0280.0580.2250.1490.1230.163ErbB10.022-0.065-0.0940.1160.105ErbB20.450*0.478*0.0770.075pMAPKN0.705*0.2010.245*pMAPKC0.030.101pAKTN0.805*68例初治,31例復(fù)治BAC,IHCPASCO2004;A7015肺癌的生物靶向治療進展1.低pMAPK患者生存期長(p=0.02),低ErbB2和低pMAPK聯(lián)合也預(yù)測病人對Gefitinib的反應(yīng).2.ErbB1,pAKT,Ki-67水平不能預(yù)測Gefitinib療效肺癌的生物靶向治療進展AssociationofpapillarysubtypeoflungadenocarinomawithresponsetoGefitinib

對象:術(shù)后復(fù)發(fā)肺腺癌36例方法:EGFR,p-EGFR,和c-erbB-2IHC表達,WHO組織學分類結(jié)果:BAC7例,Acinar5例,乳狀狀17例實體腺癌伴有粘液7例乳頭狀腺癌MST>非乳頭狀(p=0.03)EGFR,p-EGFR,c-erbB-2無相關(guān)性Johnson,etalPASCO2004;A7080肺癌的生物靶向治療進展EAPexperienceinPoorPSptswithNSCLC晚期NSCLC化療失敗82%放療史79%PS284例PS313例PS>320例M/F72/45年齡66.9歲III/IV18/92腺癌54%60例可評價療效PR3.4%,SD38.3%治療時間:1月(0-29月)MST2月,1年生存15.7%CALGB9730PS2NSCLC初治患者泰素單藥:MST2.4月,1年生存10%PASCO2004;A7082肺癌的生物靶向治療進展結(jié)論----IRESSA二線或三線治療晚期不可手術(shù)NSCLC療效確切只有少部分病人有效,東方人,女性,腺癌一線治療肺泡細胞II期研究結(jié)果令人鼓舞,有待III期結(jié)果的證實預(yù)測IRESSA療效的生物標記目前尚未完全肯定肺癌的生物靶向治療進展Erlotinib單藥二線治療NSCLC(NCICCTG)試驗731IIIB/IV期，PS0-3，1-3個方案中位年齡

61y;64%male;67%PS0,1.2priorregimens50%,含鉑93%，泰素

37%根據(jù)中心、分期、PS、對化療最佳反應(yīng)、化療方案數(shù)、含鉑與否進行分層主要終點：OS，次要：PFS、RR、QOL、毒性Shepherd,etalPASCO2004;A7022肺癌的生物靶向治療進展TARCEVA二線結(jié)果TarcevaN=488PlaceboN=243HazardratioPOS6.7m4.7m0.730.001PFS2.23m1.84m0.61<0.001TTDS咳4.9m3.68m0.04TTDS-dyspnea4.73m2.89m0.01TTDS-pain2.79m1.91m0.02肺癌的生物靶向治療進展TalentandTribute:StudydesignPatientswithHER1/EGFR-positiveor–negative,stageIIIB/IVNSCLC,RandomizationDailyoralerlotinib+Placebo+6cyclesof6cyclesofchemotherapychemotherapyDailyoralerlotinibalonePlaceboUntilPDUntilPDErlotinib:150mg/d,p.o..Tribute:CBP/Tax(n=1079).Talent:Gem/DDP(n=1137).80%powertodetecta25%survivalbenefit,alpha=0.05;similarpowertodetecta33%1yearsurvivalbenefit.肺癌的生物靶向治療進展Talent療效與毒副反應(yīng)

Erlotinib95%CIPBO95%CIOS(days)301274–315309282–343TTP(days)G3/4腹瀉G3/4皮疹1676%10%146–183179<1%<1%154–202Tarveva聯(lián)合GP方案不改善生存與其它治療結(jié)果肺癌的生物靶向治療進展TRIBUTE的療效與毒副反應(yīng)TarcevaPlaceboHRP-值MST10.8m10.6m0.990.95OR%21.519.3--0.36OR時間5.5m5.0m0.85.032TTP5.1m4.9m0.940.36總體副反應(yīng)99.5%99.5%G3/4腹瀉與皮疹47.7%43.2%SAE死亡5327肺癌的生物靶向治療進展TRIBUTE的亞組分析單因素分析:分期,體重下降,年齡,性別,種族,PS,EGFR狀態(tài),組織學類型不能預(yù)測病人對Tarceva的反應(yīng)不吸煙者A組MST(44例)為23月,相同對照組為10月,HR0.49,95%CI0.28-0.85Miller,etal.PASCO2004;A7071肺癌的生物靶向治療進展對象40例復(fù)發(fā)NSCLC，年齡59歲,21女/19男

腺癌30例,2個方案24例，3方案3例方法:II期劑量----Tarceva150mg/dBevacizumab15mg/kgIV21天為一周期Tarceva聯(lián)合Avastin二線治療NSCLCI/II期研究Sandler,etal.PASCO2004肺癌的生物靶向治療進展Tarceva聯(lián)合Bevacizumab治療復(fù)發(fā)的NSCLC療效與毒性I期未達到劑量限制性毒性副作用輕中度，皮疹、腹瀉和蛋白尿兩藥間無相互作用PR7例

(17.5%)、MR2例

(5%)、SD14例(35%)MST9.3月，

TTP4.6月肺癌的生物靶向治療進展結(jié)論-Tarceva

二線或三線治療不可手術(shù)NSCLC有效,與IRESSA相似聯(lián)合標準化療一線治療NSCLC不改善療效----吸煙影響聯(lián)合健擇治療高齡NSCLC可能有效---II期結(jié)果肺癌的生物靶向治療進展

Anti-EGFR

monoclonalantibodies肺癌的生物靶向治療進展C225聯(lián)合NP治療晚期NSCLC—隨機II期

對象：初治、中位年齡58y(34-75)、中位KPS90、IV期92%、腺癌42%、42%鱗癌；101/112腫瘤表達EGFR.DDP+NVB+C225DDP+NVB例數(shù)43(10f,33m)43(12f,31m)RR31.7%20%SD/PD18/317/13TTP4.74.2肺癌的生物靶向治療進展泰索帝聯(lián)合IMC-C225(Cetuximab)二線治療NSCLC:研究設(shè)計繼續(xù)應(yīng)用泰索帝/C225化療耐藥或抗拒NSCLCEGFR1+(IHC)DAY1DAY8DAY15泰索帝75mg/m2q3wksCetuximab400mg/m2IVCetuximab250mg/m2IVCetuximab250mg/m2IV退出研究疾病進展

緩解或疾病穩(wěn)定

E.S.Kim,etal.Proc.ASCO2003(abs2581)

肺癌的生物靶向治療進展療效：緩解與生存CR(%): 1(1.9)

PR(%):

11(20.4)SD(%) 18(33.3)疾病控制率(CR+PR+SD) 30(55.6)

PFS:2.6月中位生存： 7.5月

(N=54)22.3%E.S.Kim,etal.Proc.ASCO2003(abs2581)

肺癌的生物靶向治療進展C225versusIressaPropertyC225Iressa靶點EGFREGFR或variableMOA/活性干擾細胞周期,誘導同左凋亡,抗血管生成,

下調(diào)MMP,ADCCN/A半衰期6天6-12小時給藥法每周每日AES痤瘡樣皮疹,過敏(2%)痤瘡樣皮疹,腹瀉用法靜注口服活性無-20%篩選參數(shù)IHC無肺癌的生物靶向治療進展CetuximabastherapyforrecurrentNSCLC---PhaseIItrialIII/IV期NSCLC一線化療失敗PS0-1分EGFR陽性或陰性Cetuximab400mg/m2首劑,250mg/m2/周29例EGFR陽性

PR2例

SD5例

G3/4皮疹,疲乏

N/VLynchTJ,etal.PASCO2004;A7084肺癌的生物靶向治療進展所有病人均可從EGFR分子靶向藥物治療中獲益？女性、不吸煙、腺癌、血源性肺轉(zhuǎn)移及BACIdeal2250mg500mgTotalMen3%3%3%Woman24%16%19%Adeno14%12%13%Non-adeno6%2%4%Total12%9%10%肺癌的生物靶向治療進展Schedule-dependentinteractionbewteenEGFRIandG2/MblockingagentsG2/MB與EGFRI同時應(yīng)用或先用G2/MB--細胞周期停止于G2/M期.先用EGFRI,后用G2/MB細胞周期停止于G1期,G2/MB作用減弱---生存增加,凋亡減少PiperdiB,etal.ASCO2004;A7028肺癌的生物靶向治療進展EGFR受體突變與Iressa療效Science,NENGJMED2004EGFRmutant---15/58unselectedtumorfromJapanand1/61fromUSA.Adenocarcinoma:15/70,other1/49Female9/45;Male7/74Japanwomen8/14肺癌的生物靶向治療進展COX-2AngiogenesisApoptosisdisturbanceProliferationImmuno-escape肺癌的生物靶向治療進展Cox-2花生四稀酸Caspase-3凋亡↑ceramide凋亡↑PGG2PGH2TXA2PGI2PGF2αPGE2PGD2↑angiogenesis,↓apoptosis,↓immunesurveillanceCox-2生長因子,腫瘤,炎癥肺癌的生物靶向治療進展Celecoxib+TaxolinthetreatmentofpreteatedNSCLC---PhaseII年齡60歲M/F43/10PS0/1/2=31/20/2腺/非腺:30/23一線含鉑方案2.3%CR,23.3%PR41.9%SDTTP4,MST7G3/4中性粒減少4/2G3神經(jīng)/疲乏/貧血=3/1/1泰素80mg/m2/w*6wCelecoxib400mgbidStaniSC,etal.PASCO2004;A7337肺癌的生物靶向治療進展泰素帝聯(lián)合COX-2抑制劑二線治療晚期NSCLC鉑治療進展或泰素帝75mg/m2/3w×6cylces復(fù)發(fā)NSCLC+celebrex400mg,bid至PD.中位年齡:60.4以前化療周期數(shù)1.5Primaryendpoint:RR,overallsurvivalTTP,toxicitiesNugentFW,etal.PASCO2003;A2697肺癌的生物靶向治療進展ResultsRR:13.3%(CR1例,PR3例),53.3%SDTTP20.6周,MST11.3月G3/4毒性:中性球減少29.4%,6例發(fā)熱性中性球減少,1例死于敗血癥.Celebrex不增加毒性.兩者聯(lián)合安全有效,與泰素帝單藥相比,延長TTP和生存期.肺癌的生物靶向治療進展TumourangiogenesisTumour4.Appearance

ofnew

tumour

vasculature1.Secretionofangiogenicfactors3.Endothelial

cellproliferation

andmigration2.Proteolyticdestructionof

extracellularmatrixSproutingcapillary肺癌的生物靶向治療進展AvastinpluschemoinNSCLC:PhaseIItrialNSCLCTax/CBP(200mg/m2/AUC6)StageIIIB/IVTax/CBP+Avastin7.5mg/kgNoprior