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,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,80 70 60 50 40 30 20 10 0,Relative 5-year survival rate (%),Breast Colon Kidney Liver Lung* Ovary Pancreas,19781980 19841986 19871989,What makes an ideal

2、therapeutic target?,Present in the majority of patients with specific tumor type Causative link with tumourigenesis Essential function in tumor cells,Assessing novel targeted agents,Typical cytotoxic,MTD,OBD,Toxicity,Antitumour effect,Effect,Target,Dose,OBD MTD,Adapted from Rowinsky 2000,Target,Toxi

3、city,Antitumour effect,OBD,MTD,Effect,OBD MTD,Novel targeted agents,OBD, optimal biological dose MTD, maximum tolerated dose,Dose,EGFRIressa, Tarceva, C225 血管生成Avastin COX-2 Celecoxib,EGFR expression in human tumours,High expression is generally associated with invasion metastasis late-stage disease

4、 chemotherapy resistance hormonal therapy resistance poor outcome EGFR highly expressed in NSCLC,Extensive clinical experience with gefitinib,Monotherapy IDEAL 1 IDEAL 2 5 Phase I trials Combination therapy INTACT 1INTACT 2 Expanded Access Programme Post-marketing use in Japan Other sales Other NSCL

5、C studies Trials in other tumour types,n,209 216 270 720 684,39,200 39,100 9100 600 2600,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 mg once daily,Gefitinib 500 mg onc

6、e daily,Patients Advanced NSCLC having received 1 or 2 (IDEAL 1) or 2 (IDEAL 2) previous chemotherapy regimens,Continue gefitinib until disease progression or unacceptable toxicity,Primary endpoints,Response rate (both trials) Safety profile (IDEAL 1) Symptom relief (IDEAL 2),IDEAL 1: platinum, 1 or

7、 2 prior regimens (n=209) IDEAL 2: platinum and docetaxel, 2 prior regimens (n=216),Gefitinib Phase II studies: IDEAL 1 & 2,Tumour response: IDEAL 1 & 2 (250 mg/day),Objective response rate = CR + PR Disease control rate = CR + PR + SD,Patients (%),Objective response rate,Disease control rate,Object

8、ive response rate,Disease control rate,IDEAL 1,IDEAL 2,Fukuoka et al 2003a; Kris et al 2003,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 5.3m 1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%,IRESSA 250mg/d,Ochs J, e tal. P ASCO 2004; A7060,Chara

9、cterisation of tumour response,10%, irrespective of prior treatments and poor performance status (PS) 250 mg/day 65% 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:

10、 median 7 (range 2-19+) months (250 mg/day),Response rate,Rapid,Durable,Sizeable,Fukuoka et al 2003b,Phase III studies: INTACT 1 & 2,Randomise,Continue gefitinib or placebo until disease progression,aGemcitabine/cisplatin (INTACT 1 n=1093) or paclitaxel/carboplatin (INTACT 2 n=1037),Eligibility crit

11、eria Histologically/cytologically confirmed NSCLC Locally advanced stage III disease not curable with surgery or radiotherapy, or stage IV disease Age 18 years World 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

12、 方案: Gefitinib 250mg/d, 至PDA组: NVB 30mg/m2 d1,8 q21dB组: GEM 1200mg/m2 d1,8 q21d6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,IRESSA+NVB IRESSA+健择 N 24 35 中位年龄 72 74 PS 0-1 96 91 鳞癌 17 31 G3/4 中 72% 11.4% 死亡 3例 0 CR/PR/SD 1/3/7 0/3/13 PD 6 9 MST 275天 275天,PASCO A7081， 200

13、4,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=0.01,P ASCO 2004； A7014,Association between activation of ErbB pathway genes and survival following gefitinib

14、 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 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, Ac

15、inar 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/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%,

16、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 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

17、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 design Patients with HER1/EGFR-positive or negative, stage IIIB/IV NSCLC, RandomizationDaily oral erlotinib+ Placebo+6 cycles of 6 cycles of chemotherapy chemothe

18、rapyDaily 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,

19、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 0.28-0.85,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/dBevacizumab 15mg/kg IV 21天为一周期,Tarceva联合Avastin二线治疗NSCLC I/II期研究,

20、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NSCLC随

21、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 17/13 TTP 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 NSCLC EGFR 1+ (IHC),DAY 1,DAY 8,DAY 15,泰索帝 75 mg/m2 q3 wks,Cet

22、uximab 400 mg/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 ver

23、sus Iressa,Property C225 Iressa 靶点 EGFR EGFR 或variable MOA/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, 250

24、mg/m2/周,29例EGFR阳性PR 2例SD 5例G3/4 皮疹,疲乏N/V,Lynch 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BACIdeal 2 250mg 500mg TotalMen 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,G

25、2/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,EGFR受体突变与Iressa疗效,Science, N ENG J MED 2004EGFR mutant- 15/58 unselected tumor from Japan and 1/61 from USA.Adenocarcinoma: 15/70, other 1/49Female 9/45; Male 7/74Japan women 8/14

26、,COX-2,Angiogenesis Apoptosis disturbance Proliferation Immuno-escape,Cox-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/F43/10 PS0/1/2=31/20/2 腺/非

27、腺: 30/23 一线含铂方案,2.3% CR, 23.3% PR 41.9% SD TTP 4, MST 7 G3/4 中性粒减少 4/2 G3神经/疲乏/贫血=3/1/1,泰素80mg/m2 /w*6w Celecoxib 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1.5 Primary endpoint: RR, overall

28、survivalTTP, toxicities,Nugent FW, et al. P ASCO 2003; A2697,Results,RR: 13.3%( CR 1例,PR3例),53.3% SD TTP 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 angiogenesis,Tumour,4. Appearance of new tumour vasculature,1. Secretion of angiogenic f

29、actors,3. Endothelial cell proliferation and migration,2. Proteolytic destruction of extracellular matrix,Sprouting capillary,Avastin plus chemo in NSCLC: Phase II trial,NSCLC Tax/CBP(200mg/m2/AUC 6) Stage IIIB/IV Tax/CBP+Avastin 7.5mg/kg No prior chemo Tax/CBP+Avastin 15mg/kg1st endpoint: TTP,OR,Sa

30、fety 2nd: 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 32 RR(%) 19% 28% 31.5% 死亡 20 23 21 MST 14.9月 11.6月 17.7月,Avastiss Efficacy in non-squamous Carcinoma,对照组 7.5mg 15mg N 25 22 32 RR 12% 31% 31% TTP 3.9m 4.4m 7.4m MST 12.3m

31、 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 0-2G (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/鳞癌12/518例含铂，16例含紫杉醇 中位周期2PR 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,