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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,EGFR Iressa, 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 disea
4、se 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 1 INTACT 2 Expanded Access Programme Post-marketing use in Japan Other sales Other N
5、SCLC 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
6、once 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
7、 or 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,Obj
8、ective 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,Ch
9、aracterisation 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
10、 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,Randomise,Continue gefitinib or placebo until disease progression,aGemcitabine/cisplatin (INTACT 1 n=1093) or paclitaxel/carboplatin (INTACT 2 n=1037),Eligibility c
11、riteria 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
12、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,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 A708
13、1， 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 ge
14、fitinib 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: BA
15、C 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/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 IIIB/IV期， PS0-3，1-3个方案 中位年龄 61y;
