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-CancerApproaches,Whydoweneednewanticanceragents?,*1-yearsurvivalrate,DatafromtheEUROCAREIIstudy,80706050403020100,Relative5-yearsurvivalrate(%),BreastColonKidneyLiverLung*OvaryPancreas,197819801984198619871989,Whatmakesanidealtherapeutictarget?,PresentinthemajorityofpatientswithspecifictumortypeCausativelinkwithtumourigenesisEssentialfunctionintumorcells,Assessingnoveltargetedagents,Typicalcytotoxic,MTD,OBD,Toxicity,Antitumoureffect,Effect,Target,Dose,OBDMTD,AdaptedfromRowinsky2000,Target,Toxicity,Antitumoureffect,OBD,MTD,Effect,OBD2(IDEAL2)previouschemotherapyregimens,Continuegefitinibuntildiseaseprogressionorunacceptabletoxicity,Primaryendpoints,Responserate(bothtrials)Safetyprofile(IDEAL1)Symptomrelief(IDEAL2),IDEAL1:platinum,1or2priorregimens(n=209)IDEAL2:platinumanddocetaxel,2priorregimens(n=216),GefitinibPhaseIIstudies:IDEAL1Krisetal2003,USEAPexperiencein21064NSCLC,III/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/d,OchsJ,etal.PASCO2004;A7060,Characterisationoftumourresponse,10%,irrespectiveofpriortreatmentsandpoorperformancestatus(PS)250mg/day65%ofresponsesachievedwithinfirst4weeks(250mg/day)Meantumourreductioninpatientswithapartialresponsewas80%IDEAL1:median13(range2-20+)months(250mg/day)IDEAL2:median7(range2-19+)months(250mg/day),Responserate,Rapid,Durable,Sizeable,Fukuokaetal2003b,PhaseIIIstudies:INTACT1Giacconeetal2002,Gefitinib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/m2d1,8q21d6周期,Scagliotti,etal.PASCO2004;A7081,IRESSA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,PASCOA7081，2004,IRESSA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=0.01,PASCO2004；A7014,AssociationbetweenactivationofErbBpathwaygenesandsurvivalfollowinggefitinibinNSCLC,68例初治,31例复治BAC,IHC,PASCO2004;A7015,1.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;A7080,EAPexperienceinPoorPSptswithNSCLC,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;A7022,TARCEVA二线结果,TalentandTribute:StudydesignPatientswithHER1/EGFR-positiveornegative,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.,Talent疗效与毒副反应,Tarveva联合GP方案不改善生存与其它治疗结果,TRIBUTE的疗效与毒副反应,TRIBUTE的亚组分析,单因素分析:分期,体重下降,年龄,性别,种族,PS,EGFR状态,组织学类型不能预测病人对Tarceva的反应不吸烟者A组MST(44例)为23月,相同对照组为10月,HR0.49,95%CI0.28-0.85,Miller,etal.PASCO2004;A7071,对象40例复发NSCLC，年龄59岁,21女/19男腺癌30例,2个方案24例，3方案3例方法:II期剂量-Tarceva150mg/dBevacizumab15mg/kgIV21天为一周期,Tarceva联合Avastin二线治疗NSCLCI/II期研究,Sandler,etal.PASCO2004,Tarceva联合Bevacizumab治疗复发的NSCLC疗效与毒性,I期未达到剂量限制性毒性副作用轻中度，皮疹、腹泻和蛋白尿两药间无相互作用PR7例(17.5%)、MR2例(5%)、SD14例(35%)MST9.3月，TTP4.6月,结论-Tarceva,二线或三线治疗不可手术NSCLC有效,与IRESSA相似联合标准化疗一线治疗NSCLC不改善疗效-吸烟影响联合健择治疗高龄NSCLC可能有效-II期结果,Anti-EGFRmonoclonalantibodies,C225联合NP治疗晚期NSCLC随机II期,对象：初治、中位年龄58y(34-75)、中位KPS90、IV期92%、腺癌42%、42%鳞癌；101/112肿瘤表达EGFR.DDP+NVB+C225DDP+NVB例数43(10f,33m)43(12f,31m)RR31.7%20%SD/PD18/317/13TTP4.74.2,泰索帝联合IMC-C225(Cetuximab)二线治疗NSCLC:研究设计,继续应用泰索帝/C225,化疗耐药或抗拒NSCLCEGFR1+(IHC),DAY1,DAY8,DAY15,泰索帝75mg/m2q3wks,Cetuximab400mg/m2IV,Cetuximab250mg/m2IV,Cetuximab250mg/m2IV,退出研究,疾病进展,缓解或疾病稳定,E.S.Kim,etal.Proc.ASCO2003(abs2581),疗效：缓解与生存,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),C225versusIressa,PropertyC225Iressa靶点EGFREGFR或variableMOA/活性干扰细胞周期,诱导同左凋亡,抗血管生成,下调MMP,ADCCN/A半衰期6天6-12小时给药法每周每日AES痤疮样皮疹,过敏(2%)痤疮样皮疹,腹泻用法静注口服活性无-20%筛选参数IHC无,CetuximabastherapyforrecurrentNSCLC-PhaseIItrial,III/IV期NSCLC一线化疗失败PS0-1分EGFR阳性或阴性,Cetuximab400mg/m2首剂,250mg/m2/周,29例EGFR阳性PR2例SD5例G3/4皮疹,疲乏N/V,LynchTJ,etal.PASCO2004;A7084,所有病人均可从EGFR分子靶向药物治疗中获益？,女性、不吸烟、腺癌、血源性肺转移及BACIdeal2250mg500mgTotalMen3%3%3%Woman24%16%19%Adeno14%12%13%Non-adeno6%2%4%Total12%9%10%,Schedule-dependentinteractionbewteenEGFRIandG2/Mblockingagents,G2/MB与EGFRI同时应用或先用G2/MB-细胞周期停止于G2/M期.先用EGFRI,后用G2/MB细胞周期停止于G1期,G2/MB作用减弱-生存增加,凋亡减少,PiperdiB,etal.ASCO2004;A7028,EGFR受体突变与Iressa疗效,Science,NENGJMED2004EGFRmutant-15/58unselectedtumorfromJapanand1/61fromUSA.Adenocarcinoma:15/70,other1/49Female9/45;Male7/74Japanwomen8/14,COX-2,AngiogenesisApoptosisdisturbanceProliferationImmuno-escape,Cox-2,花生四稀酸,Caspase-3,凋亡,ceramide,凋亡,PGG2,PGH2,TXA2,PGI2,PGF2,PGE2,PGD2,angiogenesis,apoptosis,immunesurveillance,Cox-2,生长因子,肿瘤,炎症,Celecoxib+TaxolinthetreatmentofpreteatedNSCLC-PhaseII,年龄60岁M/F43/10PS0/1/2=31/20/2腺/非腺:30/23一线含铂方案,2.3%CR,23.3%PR41.9%SDTTP4,MST7G3/4中性粒减少4/2G3神经/疲乏/贫血=3/1/1,泰素80mg/m2/w*6wCelecoxib400mgbid,StaniSC,etal.PASCO2004;A7337,泰素帝联合COX-2抑制剂二线治疗晚期NSCLC,铂治疗进展或泰素帝75mg/m2/3w6cylces复发NSCLC+celebrex400mg,bid至PD.中位年龄:60.4以前化疗周期数1.5Primaryendpoint:RR,overallsurvivalTTP,toxicities,NugentFW,etal.PASCO2003;A2697,Results,RR:13.3%(CR1例,PR3例),53.3%SDTTP20.6周,MST11.3月G3/4毒性:中性球减少29.4%,6例发热性中性球减少,1例死于败血症.Celebrex不增加毒性.两者联合安全有效,与泰素帝单药相比,延长TTP和生存期.,Tumourangiogenesis,Tumour,4.Appearanceofnewtumourvasculature,1.Secretionofangiogenicfactors,3.Endothelialcellproliferationandmigration,2.Proteolyticdestructionofextracellularmatrix,Sproutingcapillary,AvastinpluschemoinNSCLC:PhaseIItrial,NSCLCTax/CBP(200mg/m2/AUC6)StageIIIB/IVTax/CBP+Avastin7.5mg/kgNopriorchemoTax/CBP+Avastin15mg/kg1stendpoint:TTP,OR,Safety2n