肺癌的生物靶向治疗进展.ppt

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1、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上海市肺科医院肿瘤科CurrentAnti-CancerApproachesSurgeryChemo-therapyRadiationHormonaltherapyTargetedtherapyRemove known tumor massesKill rapidly dividing tumor cells,including tumor cells in adjacent tissuesKill rapidly dividing tumor cellsInhibit the growth and survival of hor

2、mone-dependent tumor cellsSpecifically inhibit processes required for tumor cell growthWhy do we need new anticancer agents?*1-year survival rateData from the EUROCARE II study80706050403020100Relative 5-yearsurvival rate(%)BreastColonKidneyLiverLung*Ovary Pancreas197819801984198619871989What makes

3、an ideal therapeutic target?Present in the majority of patients with specific tumor typeCausative link with tumourigenesisEssential function in tumor cellsAssessing novel targeted agentsTypical cytotoxicMTD OBD ToxicityAntitumoureffectEffectTargetDoseOBD MTDAdapted from Rowinsky 2000TargetToxicityAn

4、titumoureffectOBDMTDEffectOBD 2(IDEAL 2)previouschemotherapyregimensContinue gefitinib until diseaseprogression or unacceptable toxicityPrimary endpointslResponse rate(both trials)lSafety profile(IDEAL 1)lSymptom relief(IDEAL 2)IDEAL 1:platinum,1 or 2 prior regimens(n=209)IDEAL 2:platinum and doceta

5、xel,2 prior regimens(n=216)Gefitinib Phase II studies:IDEAL 1&2 Tumour response:IDEAL 1&2(250 mg/day)Objective response rate=CR+PRDisease control rate=CR+PR+SDPatients(%)ObjectiveresponserateDiseasecontrolrateObjectiveresponserateDiseasecontrolrateIDEAL 1IDEAL 2Fukuoka et al 2003a;Kris et al 2003US

6、EAP experience in 21064 NSCLC III/IV NSCLC化疗失败或不能耐受化疗失败或不能耐受F/M 9979/11040年龄年龄67岁岁白人白人87.8%MST 5.3m1年生存年生存29.9%女性女性/东方人东方人,III期期生存期长生存期长治疗相关治疗相关SAE2.3%SAE停药停药1.1%治疗相关性死亡治疗相关性死亡0.3%IRESSA250mg/dOchs J,e tal.P ASCO 2004;A7060Characterisation of tumour response 10%,irrespective of prior treatments and

7、poor performance status(PS)250 mg/day65%of responses achieved within first 4 weeks(250 mg/day)Mean tumour reduction in patients with a partial response was 80%IDEAL 1:median 13(range 2-20+)months(250 mg/day)IDEAL 2:median 7(range 2-19+)months(250 mg/day)Response rateRapidDurableSizeableFukuoka et al

8、 2003bPhase III studies:INTACT 1&2RandomiseContinue gefitinibor placebo untildisease progressionChemotherapyax 6 cycles250 mg/daygefitinib+Chemotherapyax 6 cycles500 mg/daygefitinib+Chemotherapyax 6 cyclesPlacebo+aGemcitabine/cisplatin(INTACT 1 n=1093)or paclitaxel/carboplatin(INTACT 2 n=1037)Eligib

9、ility criterialHistologically/cytologically confirmed NSCLClLocally advanced stage III disease not curable with surgery or radiotherapy,or stage IV diseaselAge 18 yearslWorld Health Organization PS 0-2Johnson et al 2002;Giaccone et al 2002Gefitinib联合健择或诺维本一联合健择或诺维本一线治疗线治疗70岁或岁或PS2NSCLC意大利多中心意大利多中心II

10、期研究期研究对象对象:70岁岁PS0-2,可测量病灶可测量病灶方案方案:Gefitinib250mg/d,至至PDA组组:NVB30mg/m2d1,8q21dB组组:GEM1200mg/m2d1,8q21d6周期周期Scagliotti,et al.P ASCO 2004;A7081IRESSA联合NVB或健择治疗70岁以及老年NSCLC-II期IRESSA+NVBIRESSA+健择健择N2435中位年龄中位年龄7274PS0-19691鳞癌鳞癌1731G3/4中中72%11.4%死亡死亡3例例0CR/PR/SD1/3/70/3/13PD69MST275天天275天天PASCO A7081，2

11、004IRESSA对BAC的疗效-SWOG S0126对象对象138例例BAC(102初治初治,36二线二线）、年龄）、年龄68，女性，女性51%、PS0/186%Gefitinib500mg初治初治RR21%,CR6%；MST12月月复治复治RR10%，CR0%；MST10月月1年生存年生存50%女性生存女性生存16，男性，男性7月，月，p=.003皮疹者生存皮疹者生存12月月,无皮疹无皮疹5个月个月,p=0.01P ASCO 2004；A7014AssociationbetweenactivationofErbBpathwaygenesandsurvivalfollowinggefitin

12、ibinNSCLCErbB1ErbB2pMAPKNpMAPKCpAKTN pAKTCKi-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例初治例初治,31例复治例复治BAC,IHCP ASCO 2004;A70151.低低pMAPK患者生存期长患者生存期长(p=0.02),低低ErbB2和低和低pMAPK联合也预测病人对联合也预测病人对Gefitinib的反

13、应的反应.2.ErbB1,pAKT,Ki-67水平不能预测水平不能预测Gefitinib疗效疗效Association of papillary subtype of lung adenocarinoma with response to Gefitinib对象对象:术后复发肺腺癌术后复发肺腺癌36例例方法方法:EGFR,p-EGFR,和和c-erbB-2IHC表表达达,WHO组织学分类组织学分类结果结果:BAC7例例,Acinar5例例,乳状状乳状状17例例实体腺癌伴有粘液实体腺癌伴有粘液7例例乳头状腺癌乳头状腺癌MST非乳头状非乳头状(p=0.03)EGFR,p-EGFR,c-erbB-2

14、无相关性无相关性Johnson,et al P ASCO 2004;A7080EAP experience in Poor PS pts with NSCLC晚期NSCLC化疗失败 82%放疗史79%PS 2 84例PS 3 13例PS3 20例M/F 72/45年龄66.9岁III/IV 18/92腺癌 54%60例可评价疗效PR 3.4%,SD 38.3%治疗时间治疗时间:1月月(0-29月月)MST 2月月,1年生存年生存 15.7%CALGB9730 PS 2 NSCLC 初治患者初治患者 泰素单药泰素单药:MST 2.4月月,1年生存年生存10%P ASCO 2004;A7082结论

15、结论-IRESSA二线或三线治疗晚期不可手术二线或三线治疗晚期不可手术NSCLC疗疗效确切效确切只有少部分病人有效只有少部分病人有效,东方人东方人,女性女性,腺癌腺癌一线治疗肺泡细胞一线治疗肺泡细胞II期研究结果令人鼓舞期研究结果令人鼓舞,有待有待III期结果的证实期结果的证实预测预测IRESSA疗效的生物标记目前尚未完疗效的生物标记目前尚未完全肯定全肯定Erlotinib单药二线治疗单药二线治疗NSCLC(NCICCTG)试验试验731IIIB/IV期，期，PS0-3，1-3个方案个方案中位年龄中位年龄61y;64%male;67%PS0,1.2priorregimens50%,含铂含铂93

16、%，泰素泰素37%根据中心、分期、根据中心、分期、PS、对化疗最佳反应、化对化疗最佳反应、化疗方案数、含铂与否进行分层疗方案数、含铂与否进行分层主要终点：主要终点：OS，次要：次要：PFS、RR、QOL、毒性毒性Shepherd,etalPASCO2004;A7022TARCEVA二线结果TarcevaN=488PlaceboN=243Hazard ratioPOS6.7m4.7m0.730.001PFS2.23m1.84m0.610.001TTDS咳4.9m3.68m0.04TTDS-dyspnea4.73m2.89m0.01TTDS-pain2.79m1.91m0.02Talent and

17、 Tribute:Study designPatients with HER1/EGFR-positive or negative,stage IIIB/IV NSCLC,RandomizationDaily oral erlotinib+Placebo+6 cycles of 6 cycles of chemotherapy chemotherapyDaily oral erlotinib alone PlaceboUntil PD Until PDErlotinib:150mg/d,p.o.Tribute:CBP/Tax(n=1079).Talent:Gem/DDP(n=1137).80%

18、power to detect a 25%survival benefit,alpha=0.05;similar power to detect a 33%1 year survival benefit.Talent疗效与毒副反应Erlotinib95%CIPBO95%CIOS(days)301274315309282343TTP(days)G3/4腹泻腹泻G3/4皮疹皮疹1676%10%1461831791%1%154202Tarveva联合联合GP方案不改善生存与其它治疗结果方案不改善生存与其它治疗结果TRIBUTE 的疗效与毒副反应TarcevaPlaceboHRP-值MST10.8m1

19、0.6m0.990.95OR%21.519.3-0.36OR 时间5.5m5.0m0.85.032TTP5.1m4.9m0.940.36总体副反应99.5%99.5%G3/4腹泻与皮疹47.7%43.2%SAE死亡5327TRIBUTE的亚组分析的亚组分析单因素分析单因素分析:分期分期,体重下降体重下降,年龄年龄,性别性别,种族种族,PS,EGFR状态状态,组织学类型不能预组织学类型不能预测病人对测病人对Tarceva的反应的反应不吸烟者不吸烟者A组组MST(44例例)为为23月月,相同对相同对照组为照组为10月月,Miller,et al.P ASCO 2004;A7071对象对象40例复发

20、例复发NSCLC，年龄，年龄59岁岁,21女女/19男男腺癌腺癌30例例,2个方案个方案24例，例，3方案方案3例例方法方法:II期剂量期剂量-Tarceva150mg/dBevacizumab15mg/kgIV21天为一周期天为一周期Tarceva联合联合Avastin二线治疗二线治疗NSCLC I/II期研究期研究Sandler,et al.P ASCO 2004Tarceva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期未达到剂量限制性毒性副作用副作用轻中度，皮疹、腹泻和蛋白尿轻中度，皮疹、腹泻和蛋白尿两药间无相互作用两药间无相互作用PR7例例(17.

21、5%)、MR2例例(5%)、SD14例例(35%)MST9.3月，月，TTP4.6月月结论结论-Tarceva二线或三线治疗不可手术二线或三线治疗不可手术NSCLC有效有效,与与IRESSA相似相似联合标准化疗一线治疗联合标准化疗一线治疗NSCLC不改善疗不改善疗效效-吸烟影响吸烟影响联合健择治疗高龄联合健择治疗高龄NSCLC可能有效可能有效-II期结果期结果 Anti-EGFR monoclonal antibodiesC225联合联合NP治疗晚期治疗晚期NSCLC随机随机II期期 对象：初治、中位年龄对象：初治、中位年龄58y(34-75)、中位、中位KPS90、IV期期92%、腺癌、腺癌

22、42%、42%鳞癌；鳞癌；101/112肿瘤表达肿瘤表达EGFR.DDP+NVB+C225DDP+NVB例数例数43(10f,33m)43(12f,31m)RR31.7%20%SD/PD18/317/13TTP4.74.2泰索帝联合泰索帝联合IMC-C225(Cetuximab)二线治疗二线治疗NSCLC:研究设计研究设计继续应用继续应用 泰索帝泰索帝/C225化疗耐药或抗拒化疗耐药或抗拒 NSCLCEGFR 1+(IHC)DAY 1DAY 8DAY 15泰索帝泰索帝 75 mg/m2 q3 wksCetuximab 400 mg/m2 IVCetuximab 250 mg/m2 IVCetu

23、ximab 250 mg/m2 IV退出研究退出研究疾病进展疾病进展 缓解或疾病稳定缓解或疾病稳定 E.S.Kim,et al.Proc.ASCO 2003(abs 2581)疗效：缓解与生存疗效：缓解与生存CR(%):1(1.9)PR(%):11(20.4)SD(%)18(33.3)疾病控制率疾病控制率(CR+PR+SD)30(55.6)PFS:2.6月月中位生存：中位生存：7.5月月(N=54)22.3%E.S.Kim,et al.Proc.ASCO 2003(abs 2581)C225 versus IressaPropertyC225Iressa靶点靶点EGFREGFR或或variab

24、leMOA/活性活性干扰细胞周期干扰细胞周期,诱导诱导同左同左凋亡凋亡,抗血管生成抗血管生成,下调下调MMP,ADCCN/A半衰期半衰期6天天6-12小时小时给药法给药法每周每周每日每日AES痤疮样皮疹痤疮样皮疹,过敏过敏(2%)痤疮样皮疹痤疮样皮疹,腹泻腹泻用法用法静注静注口服口服活性活性无无-20%筛选参数筛选参数IHC无无Cetuximab as therapy for recurrent NSCLC-Phase II trialIII/IV期期NSCLC一线化疗失败一线化疗失败PS 0-1分分EGFR 阳性或阳性或阴性阴性Cetuximab 400mg/m2首剂首剂,250mg/m2/

25、周周 29例例EGFR阳性阳性 PR 2例例 SD 5例例 G3/4 皮疹皮疹,疲乏疲乏 N/VLynch TJ,et al.P ASCO 2004;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BAC Ideal 2 250mg 500mg Total Men 3%3%3%Woman 24%16%19%Adeno 14%12%13%Non-adeno 6%2%4%Total 12%9%10%Schedule-dependentinteractionbewteenEGFRIandG2/MblockingagentsG2/MB 与EGFRI 同时应用或

26、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Piperdi B,et al.ASCO 2004;A7028EGFR受体突变与Iressa疗效Science,N ENG J MED 2004 EGFR mutant-15/58 unselected tumor from Japan and 1/61 from USA.Adenocarcinoma:15/70,other 1/49 Female 9/45;Male 7/74 Japan women 8/14COX-2AngiogenesisApoptosis

27、disturbanceProliferationImmuno-escapeCox-2花生四稀酸Caspase-3凋亡ceramide凋亡PGG2PGH2TXA2PGI2PGF2PGE2PGD2angiogenesis,apoptosis,immune surveillanceCox-2生长因子生长因子,肿瘤肿瘤,炎症炎症Celecoxib+Taxol in the treatment of preteated NSCLC-Phase II年龄年龄60岁岁M/F43/10PS0/1/2=31/20/2腺腺/非腺非腺:30/23一线含铂方案一线含铂方案2.3%CR,23.3%PR41.9%SDTT

28、P 4,MST 7G3/4 中性粒减少中性粒减少 4/2G3神经神经/疲乏疲乏/贫血贫血=3/1/1泰素泰素80mg/m2/w*6wCelecoxib 400mg bidS tani SC,et al.P ASCO 2004;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75 mg/m2/3w6cylces复发NSCLC +celebrex 400mg,bid 至PD.中位年龄:60.4以前化疗周期数1.5Primary endpoint:RR,overall survival TTP,toxicitiesNugent FW,et al.P ASCO 2003;

29、A2697ResultsRR:13.3%(CR 1例,PR3例),53.3%SDTTP 20.6周,MST 11.3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.Tumour angiogenesisTumour4.Appearance of new tumour vasculature1.Secretion ofangiogenicfactors3.Endothelial cell proliferation and migration2.Proteolyticdestructi

30、on of extracellular matrixSprouting capillaryAvastin plus chemo in NSCLC:Phase II trialNSCLC Tax/CBP(200mg/m2/AUC 6)Stage IIIB/IV Tax/CBP+Avastin 7.5mg/kgNo prior chemo Tax/CBP+Avastin 15mg/kg1st endpoint:TTP,OR,Safety2nd:SurvivalDeVore RF,et al.P ASCO 2000;A1896Tax/CBP联合rhuMAb VEGF治疗晚期NSCLC 单纯化疗 Rh

31、uMAb VEGF+化疗 7.5mg/kg 15mg/kg 例数 32 32 32RR(%)19%28%31.5%死亡 20 23 21MST 14.9月 11.6月 17.7月 Avastiss Efficacy in non-squamous Carcinoma 对照组 7.5mg 15mgN 25 22 32RR 12%31%31%TTP 3.9m 4.4m 7.4mMST 12.3m 14.1m 17.9m每周泰素联合IRESSA治疗IRESSA失败NSCLC入选对象：入选对象：20例，可测量病灶例，可测量病灶PS0-2G(250mg/day)，P(60mg/m2)D1,8,15q4w

32、.主要终点为主要终点为RR，次要：毒性，次要：毒性,TTP和和OS年龄年龄64岁岁;IIIB/IV4/16;腺腺/鳞癌鳞癌12/518例含铂，例含铂，16例含紫杉醇例含紫杉醇中位周期中位周期2PR6(30%)，SD6(30%)中位中位TTP97天，天，MST157天天G3/4中性球中性球10%,G3肺毒性肺毒性(10%).结论结论Gefitinib和Tarceva单药二线或三线治疗NSCLC有效COX-2抑制剂联合化疗泰杉醇二线治疗可能效EGFR抑制联合VEGF单抗能增强疗效Conclusions(2)C225二线治疗同样有效,一线联合化疗,能增加化疗的疗效These data support the use of gefitinib 250 mg/day as an important novel treatment option for patients with pretreated advanced NSCLC谢谢大家