肺癌的生物靶向治疗进展课件

1、肺癌的生物靶向治疗进展上海市肺科医院肿瘤科第1页，共52页。Current Anti-Cancer ApproachesSurgeryChemo-therapyRadiationHormonaltherapyTargetedtherapyRemove known tumor massesKill rapidly dividing tumor cells, including tumor cells in adjacent tissuesKill rapidly dividing tumor cellsInhibit the growth and survival of hormone-depe

2、ndent tumor cellsSpecifically inhibit processes required for tumor cell growth第2页，共52页。Why do we need new anticancer agents?*1-year survival rateData from the EUROCARE II study80706050403020100Relative 5-yearsurvival rate (%)BreastColonKidneyLiverLung*OvaryPancreas197819801984198619871989第3页，共52页。Wh

3、at makes an ideal therapeutic target?Present in the majority of patients with specific tumor typeCausative link with tumourigenesisEssential function in tumor cells第4页，共52页。Assessing novel targeted agentsTypical cytotoxicMTDOBD ToxicityAntitumoureffectEffectTargetDoseOBD MTDAdapted from Rowinsky 200

4、0TargetToxicityAntitumoureffectOBDMTDEffectOBD 2 (IDEAL 2)previouschemotherapyregimensContinue gefitinib until diseaseprogression or unacceptable toxicityPrimary endpointsResponse rate (both trials)Safety profile (IDEAL 1)Symptom relief (IDEAL 2)IDEAL 1: platinum, 1 or 2 prior regimens (n=209)IDEAL

5、2: platinum and docetaxel, 2 prior regimens (n=216)Gefitinib Phase II studies: IDEAL 1 & 2 第9页，共52页。Tumour response: IDEAL 1 & 2 (250 mg/day)Objective response rate = CR + PRDisease control rate = CR + PR + SDPatients (%)ObjectiveresponserateDiseasecontrolrateObjectiveresponserateDiseasecontrolrateI

6、DEAL 1IDEAL 2Fukuoka et al 2003a; Kris et al 2003第10页，共52页。US EAP experience 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/dOchs J, e tal. P ASCO 2004; A7060第11页，共52页。Characterisation of tumour response 10%, i

7、rrespective of prior treatments and 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

8、) Response rateRapidDurableSizeableFukuoka et al 2003b第12页，共52页。Phase III studies: INTACT 1 & 2RandomiseContinue gefitinibor placebo untildisease progressionChemotherapyax 6 cycles250 mg/daygefitinib+Chemotherapyax 6 cycles500 mg/daygefitinib+Chemotherapyax 6 cyclesPlacebo+aGemcitabine/cisplatin (IN

9、TACT 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 diseaseAge 18 yearsWorld Health Organization PS 0-2Johnson et al 2002; Giaccone et al 200

10、2第13页，共52页。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第14页，共52页。IRESSA联合NVB或健择治疗70岁以及老年NSCLC-II期 IRESSA+NVB IRESSA+健择N 24 35中位年龄 72 74PS 0-1 96 91鳞癌 17 31G3/

11、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第15页，共52页。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皮疹者生存12月,无皮疹5个月,p=0.01P ASCO 2004； A7014第16页，

12、共52页。Association between activation of ErbB pathway genes and survival following gefitinib in NSCLCErbB1ErbB2pMAPK NpMAPKCpAKTNpAKTCKi-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*pMAPK C0.030.101pAKTN0.805*68例初治, 31例复治BAC, IHCP A

13、SCO 2004; A7015第17页，共52页。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疗效第18页，共52页。Association of papillary subtype of lung 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

14、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第19页，共52页。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/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

15、患者 泰素单药: MST 2.4月,1年生存10%P ASCO 2004; A7082第20页，共52页。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第21页，共52页。Erlotinib单药二线治疗NSCLC (NCIC CTG)试验731 IIIB/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、

16、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第22页，共52页。TARCEVA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-pain2.79m1.91m0.02第23页，共52页。Talent and Tribute : Study designPatient

17、s 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% power to detect

18、a 25% survival benefit, alpha=0.05; similar power to detect a 33% 1 year survival benefit.第24页，共52页。Talent疗效与毒副反应Erlotinib95% CIPBO95% CIOS (days)301274315309282343TTP (days)G3/4腹泻G3/4皮疹1676%10%1461831791%1%154202Tarveva联合GP方案不改善生存与其它治疗结果第25页，共52页。TRIBUTE 的疗效与毒副反应TarcevaPlaceboHRP-值MST10.8m10.6m0.99

19、0.95OR%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5327第26页，共52页。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,HR 0.49, 95%CI 0.28-0.85Miller, et al. P ASCO 2004; A7071第27页，共52页。对象 40例复发NSCLC，年龄59岁

20、, 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二线治疗NSCLC I/II期研究Sandler, et al. P ASCO 2004第28页，共52页。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 第29页，共52页。结论-Tar

21、ceva 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期结果第30页，共52页。 Anti-EGFR monoclonal antibodies第31页，共52页。C225联合NP治疗晚期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

22、 18/ 3 17/13TTP 4.7 4.2第32页，共52页。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 1DAY 8DAY 15泰索帝 75 mg/m2 q3 wksCetuximab 400 mg/m2 IVCetuximab 250 mg/m2 IVCetuximab 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) 第33页，共52页。疗效：缓解与生存CR (%):1

23、(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) 第34页，共52页。C225 versus IressaProperty C225 Iressa靶点 EGFR EGFR 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

24、静注 口服活性 无 -20%筛选参数 IHC 无 第35页，共52页。Cetuximab as therapy for recurrent NSCLC- Phase II trialIII/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/VLynch TJ, et al. P ASCO 2004; A7084第36页，共52页。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 500

25、mg Total Men 3% 3% 3% Woman 24% 16% 19% Adeno 14% 12% 13%Non-adeno 6% 2% 4%Total 12% 9% 10% 第37页，共52页。Schedule-dependent interaction bewteen EGFRI and G2/M blocking agentsG2/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Piperdi B, et al. ASCO 2004; A7028第38页，共52页。

26、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第39页，共52页。COX-2AngiogenesisApoptosis disturbanceProliferationImmuno-escape第40页，共52页。Cox-2花生四稀酸Caspase-3凋亡ceramide凋亡PGG

27、2PGH2TXA2PGI2PGF2PGE2PGD2angiogenesis, apoptosis, immune surveillanceCox-2生长因子,肿瘤,炎症第41页，共52页。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80mg/m2 /w*6wCelecoxib 400mg bi

28、dS tani SC, et al. P ASCO 2004; A7337第42页，共52页。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; A2697第43页，共52页。ResultsRR: 13.3%( CR 1例,PR3例),53.3% SDTTP 20.6周,M

29、ST 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.第44页，共52页。Tumour angiogenesisTumour4. Appearance of new tumour vasculature1. Secretion ofangiogenicfactors3. Endothelial cell proliferation and migration2. Proteolyticdestruction of extracellular matrixSprouting capillary第45页，共52页。Avastin plus chemo in NSCLC: Phase II trialNSCLC Tax/CB