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1、肺癌的生物靶向治疗进展,上海市肺科医院肿瘤科,Current Anti-Cancer Approaches,Why do we need new anticancer agents?,*1-year survival rate,Data from the EUROCARE II study,80706050403020100,Relative 5-yearsurvival rate(%),BreastColonKidneyLiverLung*OvaryPancreas,197819801984198619871989,What makes an ideal therapeutic target
2、?,Present in the majority of patients with specific tumor typeCausative link with tumourigenesisEssential function in tumor cells,Assessing novel targeted agents,Typical cytotoxic,MTD,OBD,Toxicity,Antitumoureffect,Effect,Target,Dose,OBD MTD,Adapted from Rowinsky 2000,Target,Toxicity,Antitumoureffect
3、,OBD,MTD,Effect,OBD MTD,Novel targeted agents,OBD,optimal biological doseMTD,maximum tolerated dose,Dose,EGFR Iressa,Tarceva,C225血管生成 AvastinCOX-2 Celecoxib,EGFR expression in human tumours,High expression is generally associated withinvasionmetastasislate-stage diseasechemotherapy resistancehormona
4、l therapy resistancepoor outcomeEGFR highly expressed in NSCLC,Extensive clinical experiencewith gefitinib,MonotherapyIDEAL 1 IDEAL 2 5 Phase I trialsCombination therapyINTACT 1INTACT 2Expanded Access ProgrammePost-marketing use in JapanOther salesOther NSCLC studiesTrials in other tumour types,n,20
5、9216270720684,39,20039,10091006002600,TOTAL,92,750,Data as of 3 Sept 2003,IDEAL,IRESSA Dose Evaluation in Advanced Lung cancer,INTACT,IRESSA NSCLC Trial Assessing Combination Treatment,Randomisation,Gefitinib 250 mgonce daily,Gefitinib 500 mgonce daily,PatientsAdvanced NSCLC having received 1 or 2(I
6、DEAL 1)or 2(IDEAL 2)previouschemotherapyregimens,Continue gefitinib until diseaseprogression or unacceptable toxicity,Primary endpoints,Response rate(both trials)Safety profile(IDEAL 1)Symptom relief(IDEAL 2),IDEAL 1:platinum,1 or 2 prior regimens(n=209)IDEAL 2:platinum and docetaxel,2 prior regimen
7、s(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+SD,Patients(%),Objectiveresponserate,Diseasecontrolrate,Objectiveresponserate,Diseasecontrolrate,IDEAL 1,IDEAL 2,Fukuoka et al 2003a;Kris et al 2003,US EAP expe
8、rience in 21064 NSCLC,III/IV NSCLC化疗失败或不能耐受F/M 9979/11040年龄67岁白人87.8%,MST 5.3m1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,Ochs J,e tal.P ASCO 2004;A7060,Characterisation of tumour response,10%,irrespective of prior treatments and poor performance status(PS)250 mg/day65%of r
9、esponses 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 rate,Rapid,Durable,Sizeable,Fukuoka et al 2003b,Phase III studies:INTACT 1&2,Ran
10、domise,Continue gefitinibor placebo untildisease progression,aGemcitabine/cisplatin(INTACT 1 n=1093)or paclitaxel/carboplatin(INTACT 2 n=1037),Eligibility criteriaHistologically/cytologically confirmed NSCLCLocally advanced stage III disease not curable with surgery or radiotherapy,or stage IV disea
11、seAge 18 yearsWorld Health Organization PS 0-2,Johnson et al 2002;Giaccone et al 2002,Gefitinib联合健择或诺维本一线治疗70岁或PS 2 NSCLC,意大利多中心II期研究对象:70岁 PS 0-2,可测量病灶方案:Gefitinib 250mg/d,至PD A组:NVB 30mg/m2 d1,8 q21d B组:GEM 1200mg/m2 d1,8 q21d 6周期,Scagliotti,et al.P ASCO 2004;A7081,IRESSA联合NVB或健择治疗70岁以及老年NSCLC-II期
12、,IRESSA+NVB IRESSA+健择N 24 35中位年龄 72 74PS 0-1 96 91鳞癌 17 31G3/4 中 72%11.4%死亡 3例 0CR/PR/SD 1/3/7 0/3/13PD 6 9MST 275天 275天,PASCO A7081，2004,IRESSA对BAC的疗效-SWOG S0126,对象 138例BAC(102初治,36二线）、年龄68，女性51%、PS 0/1 86%Gefitinib 500 mg 初治 RR 21%,CR 6%；MST 12月复治 RR 10%，CR 0%；MST 10月1年生存 50%女性生存16，男性 7月，p=.003皮疹者
13、生存12月,无皮疹5个月,p=0.01,P ASCO 2004；A7014,Association between activation of ErbB pathway genes and survival following gefitinib in NSCLC,68例初治,31例复治BAC,IHC,P ASCO 2004;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,Association of papillary subtype of l
14、ung adenocarinoma with response to Gefitinib,对象:术后复发肺腺癌 36例方法:EGFR,p-EGFR,和c-erbB-2 IHC表达,WHO组织学分类结果:BAC 7例,Acinar 5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,et al P ASCO 2004;A7080,EAP 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
15、/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:1月(0-29月)MST 2月,1年生存 15.7%,CALGB9730 PS 2 NSCLC 初治患者 泰素单药:MST 2.4月,1年生存10%,P ASCO 2004;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(NCIC CTG)试验,731 I
16、IIB/IV期，PS0-3，1-3个方案中位年龄 61y;64%male;67%PS 0,1.2 prior regimens 50%,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,et al PASCO 2004;A7022,TARCEVA二线结果,Talent and Tribute:Study designPatients with HER1/EGFR-positive or negative,stage IIIB/IV NSCLC,RandomizationDaily oral
17、 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%power to detect a 25%survival benefit,alpha=0.05;similar power to detect a 33%1 year survival benefit.,Talent
18、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,Miller,et al.P ASCO 2004;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-Tarceva 150mg/d Bevacizumab 15mg/kg IV 21天为一周期,Tarceva联合Avastin二
19、线治疗NSCLC I/II期研究,Sandler,et al.P ASCO 2004,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PR 7例(17.5%)、MR 2例(5%)、SD 14例(35%)MST 9.3月，TTP 4.6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-EGFR monoclonal antibodies,C225联合NP治疗晚期
20、NSCLC随机II期,对象：初治、中位年龄 58 y(34-75)、中位KPS 90、IV期92%、腺癌42%、42%鳞癌；101/112肿瘤表达 EGFR.DDP+NVB+C225 DDP+NVB例数 43(10 f,33 m)43(12 f,31 m)RR 31.7%20%SD/PD 18/3 17/13TTP 4.7 4.2,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 NSCLCEGFR 1+(IHC),DAY 1,DAY 8,DAY 15,泰索帝 75 mg/m2 q3 wks,Cetuximab 400 m
21、g/m2 IV,Cetuximab 250 mg/m2 IV,Cetuximab 250 mg/m2 IV,退出研究,疾病进展,缓解或疾病稳定,E.S.Kim,et al.Proc.ASCO 2003(abs 2581),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,et al.Proc.ASCO 2003(abs 2581),C225 versus Iressa,Property C225 Iressa靶点 EGFR E
22、GFR 或variableMOA/活性 干扰细胞周期,诱导 同左 凋亡,抗血管生成,下调MMP,ADCC N/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,Cetuximab as therapy for recurrent NSCLC-Phase II trial,III/IV期NSCLC一线化疗失败PS 0-1分EGFR 阳性或阴性,Cetuximab 400mg/m2首剂,250mg/m2/周,29例EGFR阳性 PR 2例 SD 5例 G3/4 皮疹,疲乏 N/V,Lynch TJ,e
23、t 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-dependent interaction bewteen EGFRI and G2/M blocking agents,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,
24、G2/MB作用减弱-生存增加,凋亡减少,Piperdi B,et al.ASCO 2004;A7028,EGFR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 8/14,COX-2,AngiogenesisApoptosis disturbanceProliferationImmuno-escape,Cox-
25、2,花生四稀酸,Caspase-3,凋亡,ceramide,凋亡,PGG2,PGH2,TXA2,PGI2,PGF2,PGE2,PGD2,angiogenesis,apoptosis,immune surveillance,Cox-2,生长因子,肿瘤,炎症,Celecoxib+Taxol in the treatment of preteated NSCLC-Phase II,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%SDTTP 4,MST 7G3/4 中性粒减少 4/2G3神经/疲乏/贫血=3/1/1,泰素8
26、0mg/m2/w*6wCelecoxib 400mg bid,S 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,toxicities,Nugent FW,et al.P ASCO 2003;A2697,Results,RR:13.3%(CR 1例,PR3例),53.3%SDTTP 20.6周,
27、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 angiogenesis,Tumour,4.Appearance of new tumour vasculature,1.Secretion ofangiogenicfactors,3.Endothelial cell proliferation and migration,2.Proteolyticdestruction of extracellular matrix,Sprouting capilla
28、ry,Avastin plus chemo in NSCLC:Phase II trial,NSCLC 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:Survival,DeVore RF,et al.P ASCO 2000;A1896,Tax/CBP联合rhuMAb VEGF治疗晚期NSCLC,单纯化疗 RhuMAb VEGF+化疗 7.5mg/kg 15mg/kg 例数 32 32
29、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：20例，可测量病灶 PS 0-2 G(250 mg/day)，P(60 mg/m2)D1,8,15q4w.主要终点为RR，次要：毒性,TTP和OS 年龄64岁;IIIB/IV 4/16;腺/鳞
30、癌12/5 18例含铂，16例含紫杉醇中位周期2 PR 6(30%)，SD 6(30%)中位TTP 97天，MST 157天 G3/4中性球 10%,G3肺毒性(10%).,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,
