肺癌的生物靶向治疗进展

肺癌的生物靶向治疗进展上海市肺科医院肿瘤科CurrentAnti-CancerApproachesSurgeryChemo-therapyRadiationHormonaltherapyTargetedtherapyRemoveknowntumormassesKillrapidlydividingtumorcells,includingtumorcellsinadjacenttissuesKillrapidlydividingtumorcellsInhibitthegrowthandsurvivalofhormone-dependenttumorcellsSpecificallyinhibitprocessesrequiredfortumorcellgrowthWhydoweneednewanticanceragents?*1-yearsurvivalrateDatafromtheEUROCAREIIstudy80706050403020100Relative5-yearsurvivalrate(%)BreastColonKidneyLiverLung*OvaryPancreas1978–19801984–19861987–1989Whatmakesanidealtherapeutictarget?•Presentinthemajorityofpatientswithspecifictumortype•Causativelinkwithtumourigenesis•EssentialfunctionintumorcellsAssessingnoveltargetedagentsTypicalcytotoxicMTDOBDToxicityAntitumoureffectTargetDoseOBDMTDAdaptedfromRowinsky2000TargetToxicityAntitumoureffectOBDMTDOBDMTDNoveltargetedagentsOBD,optimalbiologicaldoseMTD,maximumtolerateddoseDose•EGFRIressa,Tarceva,C225•血管生成Avastin•COX-2CelecoxibEGFRexpressioninhumantumours•Highexpressionisgenerallyassociatedwith–invasion–metastasis–late-stagedisease–chemotherapyresistance–hormonaltherapyresistance–pooroutcome•EGFRhighlyexpressedinNSCLCExtensiveclinicalexperiencewithgefitinibMonotherapyIDEAL1IDEAL25PhaseItrialsCombinationtherapyINTACT1INTACT2ExpandedAccessProgrammePost-marketinguseinJapanOthersalesOtherNSCLCstudiesTrialsinothertumourtypesn209216270720684~39,200~39,100~9100~6002600TOTAL~92,750Dataasof3Sept2003IDEAL,IRESSADoseEvaluationinAdvancedLungcancerINTACT,IRESSANSCLCTrialAssessingCombinationTreatmentRandomisationGefitinib250mgoncedailyGefitinib500mgoncedailyPatientsAdvancedNSCLChavingreceived1or2(IDEAL1)or2(IDEAL2)previouschemotherapyregimensContinuegefitinibuntildiseaseprogressionorunacceptabletoxicityPrimaryendpointsResponserate(bothtrials)Safetyprofile(IDEAL1)Symptomrelief(IDEAL2)IDEAL1:platinum,1or2priorregimens(n=209)IDEAL2:platinumanddocetaxel,2priorregimens(n=216)GefitinibPhaseIIstudies:IDEAL1&2Tumourresponse:IDEAL1&2(250mg/day)Objectiveresponserate=CR+PRDiseasecontrolrate=CR+PR+SD18.454.40102030405060Patients(%)ObjectiveresponserateDiseasecontrolrate11.842.20102030405060ObjectiveresponserateDiseasecontrolrateIDEAL1IDEAL2Fukuokaetal2003a;Krisetal2003USEAPexperiencein21064NSCLCIII/IVNSCLC化疗失败或不能耐受F/M9979/11040年龄67岁白人87.8%MST5.3m1年生存29.9%女性/东方人,III期生存期长治疗相关SAE2.3%SAE停药1.1%治疗相关性死亡0.3%IRESSA250mg/dOchsJ,etal.PASCO2004;A7060Characterisationoftumourresponse10%,irrespectiveofpriortreatmentsandpoorperformancestatus(PS)[250mg/day]65%ofresponsesachievedwithinfirst4weeks(250mg/day)Meantumourreductioninpatientswithapartialresponsewas80%IDEAL1:median13(range2-20+)months(250mg/day)IDEAL2:median7(range2-19+)months(250mg/day)ResponserateRapidDurableSizeableFukuokaetal2003bPhaseIIIstudies:INTACT1&2RandomiseContinuegefitiniborplacebountildiseaseprogressionChemotherapyax6cycles250mg/daygefitinib+Chemotherapyax6cycles500mg/daygefitinib+Chemotherapyax6cyclesPlacebo+aGemcitabine/cisplatin(INTACT1n=1093)orpaclitaxel/carboplatin(INTACT2n=1037)EligibilitycriteriaHistologically/cytologicallyconfirmedNSCLCLocallyadvancedstageIIIdiseasenotcurablewithsurgeryorradiotherapy,orstageIVdiseaseAge18yearsWorldHealthOrganizationPS0-2Johnsonetal2002;Giacconeetal2002Gefitinib联合健择或诺维本一线治疗≥70岁或PS2NSCLC•意大利多中心II期研究•对象:≥70岁PS0-2,可测量病灶•方案:Gefitinib250mg/d,至PDA组:NVB30mg/m2d1,8q21dB组:GEM1200mg/m2d1,8q21d×6周期Scagliotti,etal.PASCO2004;A7081IRESSA联合NVB或健择治疗70岁以及老年NSCLC---II期IRESSA+NVBIRESSA+健择N2435中位年龄7274PS0-19691鳞癌1731G3/4中72%11.4%死亡3例0CR/PR/SD1/3/70/3/13PD69MST275天275天PASCOA7081，2004IRESSA对BAC的疗效-SWOGS0126•对象138例BAC(102初治,36二线）、年龄68，女性51%、PS0/186%•Gefitinib500mg•初治RR21%,CR6%；MST12月•复治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,无皮疹5个月,p=0.01PASCO2004；A7014AssociationbetweenactivationofErbBpathwaygenesandsurvivalfollowinggefitinibinNSCLCErbB1ErbB2pMAPKNpMAPKCpAKTNpAKTCKi-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例复治BAC,IHCPASCO2004;A70151.低pMAPK患者生存期长(p=0.02),低ErbB2和低pMAPK联合也预测病人对Gefitinib的反应.2.ErbB1,pAKT,Ki-67水平不能预测Gefitinib疗效AssociationofpapillarysubtypeoflungadenocarinomawithresponsetoGefitinib对象:术后复发肺腺癌36例方法:EGFR,p-EGFR,和c-erbB-2IHC表达,WHO组织学分类结果:BAC7例,Acinar5例,乳状状17例实体腺癌伴有粘液7例乳头状腺癌MST非乳头状(p=0.03)EGFR,p-EGFR,c-erbB-2无相关性Johnson,etalPASCO2004;A7080EAPexperienceinPoorPSptswithNSCLC晚期NSCLC化疗失败82%放疗史79%PS284例PS313例PS320例M/F72/45年龄66.9岁III/IV18/92腺癌54%60例可评价疗效PR3.4%,SD38.3%治疗时间:1月(0-29月)MST2月,1年生存15.7%CALGB9730PS2NSCLC初治患者泰素单药:MST2.4月,1年生存10%PASCO2004;A7082结论----IRESSA•二线或三线治疗晚期不可手术NSCLC疗效确切•只有少部分病人有效,东方人,女性,腺癌•一线治疗肺泡细胞II期研究结果令人鼓舞,有待III期结果的证实•预测IRESSA疗效的生物标记目前尚未完全肯定Erlotinib单药二线治疗NSCLC(NCICCTG)试验731IIIB/IV期，PS0-3，1-3个方案中位年龄61y;64%male;67%PS0,1.2priorregimens50%,含铂93%，泰素37%根据中心、分期、PS、对化疗最佳反应、化疗方案数、含铂与否进行分层主要终点：OS，次要：PFS、RR、QOL、毒性Shepherd,etalPASCO2004;A7022TARCEVA二线结果TarcevaN=488PlaceboN=243HazardratioPOS6.7m4.7m0.730.001PFS2.23m1.84m0.610.001TTDS咳4.9m3.68m0.04TTDS-dyspnea4.73m2.89m0.01TTDS-pain2.79m1.91m0.02Talentand