《晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙与特罗凯的比较课件》由会员分享，可在线阅读，更多相关《晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙与特罗凯的比较课件（53页珍藏版）》请在金锄头文库上搜索。
1、NSCLC,Progress in the treatment,晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙与特罗凯的比较,蔡 俊 明台北榮民總醫院 胸腔部 胸腔腫瘤科陽明大學 醫學院 內科學系,三十年来晚期非小细胞肺癌的治疗成果,Tumour cell proliferation,PI3K,MAPK,Tumour cell survival,Akt,mTOR,STAT 3/5,Grb-2,Ras,Raf,MEK,ATP,Anti-EGFR Abs Cetuximab, Panitumumab, Matuzumab, h-R3, MDX-447Anti-HER1,HER2,HE
2、R4 TKIs Gefitinib, Erlotinib, BIBW-2992, PKI-166, GW-572016, CI-1033, AEE788RAS farnesyltransferase inhibitors MMS214662, R115777, SCH66336RAF inhibitors Sorafenib, L-779450MEK inhibitors CI-1040, U-0126mTOR inhibitors Temsirolimus, RAD001,ATP,SOS,Small molecule tyrosine kinase inhibitors,表皮生长因子受体讯息
3、传递的生物标记与抑制剂,肺腺癌的表皮生长因子受体突变,Response Rate vs. Clinical Background,Clinical Background vs. EGFR Mutations,EGFR mutation (%),RR (%),Asian,Non-Asian,Female,Male,Never,Ever,Adeno,Non-Adeno,Asian,Non-Asian,Female,Male,Never,Ever,Adeno,Non-Adeno,Mitsudomi, IJCO, 2006,T854A,E884K,L747S,D761Y,敏感性突变,Sharma, e
4、t al. Nat Rev Cancer 2007,生长因子受体易瑞沙与特罗凯的敏感性突变,抗药性突变,428,100 55 125 288 283 TAX317 TAX320 JMEI,19,30,29,32,30,BSC,Docetaxel,Docetaxel,Pemetrexed,4.6,7.9,7,5.7,8.3,1-yr Survival (%) MS (m) DCR (%),47.3,63.4,46.6,53.1,54.1,9.1,8.8,6.7,5.8,Docetaxel,117,60,27,10,40,428,非小细胞肺癌的救援性治疗 Comparison of Docetax
5、el, Pemetrexed & EGFR-TKIs,Gefitinib,BR.21 versus ISEL 以安慰剂为对照组的研究,Favours EGFR TKI,Favours placebo,HR,0.40,0.60,0.80,1.00,1.20,特罗凯 Erlotinib (BR.21)1 30% reduction in risk of death p=0.001,易瑞沙 Gefitinib (ISEL)2 11% reduction in risk of death Not significant,1Shepherd FA, et al. N Engl J Med 2005;35
6、3:12332 2Thatcher N, et al. Lancet 2005;366:152737,何以易瑞沙失败 ? BR21 vs ISEL,病人选择与纳入条件,Criteria for inclusion in ISEL and BR21 clinical trials,ISEL: development of progressive disease within 90 days of the preceding round of chemotherapy (early relapse)BR21: no selection for early relapse,428,100 55 12
7、5 288 283 TAX317 TAX320 JMEI,19,30,29,32,30,BSC,Docetaxel,Docetaxel,Pemetrexed,4.6,7.9,7,5.7,8.3,1-yr Survival (%) MS (m) DCR (%),47.3,63.4,46.6,53.1,54.1,9.1,8.8,6.7,5.8,Docetaxel,Gefitinib,117,60,27,10,40,428,非小细胞肺癌的救援性治疗 Comparison of Docetaxel, Pemetrexed & EGFR-TKIs,BR.21 and ISEL对照组群的存活曲线显示它们是
8、相似的组群,Proportion surviving,1.0 0.8 0.6 0.4 0.2 0,0 2 4 6 8 10 12 14 16 18 20 22 24 26 28,Time (months),1Shepherd FA, et al. N Engl J Med 2005;353:12332 2Thatcher N, et al. Lancet 2005;366:152737,药物剂量,何以易瑞沙失败 ? BR21 vs ISEL,易瑞沙 与 特罗凯 结构相似，活性不同?,易瑞沙与特罗凯结构上的差异使得两者在血浆、肿瘤和正常组织中分布浓度不同，其代谢作用、活体外活性也不同，使得药物所
9、产生的临床效果和毒性不同。,特罗凯,易瑞莎,cLogP = 3.30,cLogP = 3.87,易瑞沙之亲脂性约比特罗凯高三倍,易瑞莎较易被代谢、由胆汁排出、易与蛋白质结合、血浆中药物浓度较低。,特罗凯,易瑞莎,主要代谢产物的活性不同,Li J, et al. Clin Cancer Res 2007;13:37317 McKillop D, et al. Xenobiotica 2006;36:2939,Gefitinib,CI,F,N,O,NH,N,O,O,NH,O,O,N,H,Desmethyl-gefitinib,Erlotinib,O,O,O,O,NH,N,N,OSI-420,H,M
10、W 429.2,MW 446.9,特罗凯,易瑞莎,Dose-proportional Cmax and AUC Repeated daily dosing does not result in drug accumulation High plasma exposure at 150mg/day p.o.,Hidalgo M, et al. J Clin Oncol 2001;19:326779 Ranson M, et al. J Clin Oncol 2002;20:224050,Cmax (ng/mL),AUC024 (nghour/L),Erlotinib 150mg/day,Gefi
11、tinib 225mg/day,Gefitinib 525mg/day,Gefitinib 700mg/day,2,500 2,000 1,500 1,000 500 0,45,000 40,000 35,000 30,000 25,000 20,000 15,000 10,000 5,000 0,药物动力学比较 (每日剂量 ),Paez, Science 2004,Gefitinib induces apoptosis in the H3255,表皮生长因子受体 L858R突变对 EGFR-TKI 较野生型敏感,* A: adenocarcinoma; AS: adenosquamous c
12、arcinoma; BAC: bronchioloalveolar cell carcinoma; LC: large cell carcinoma; S: squamous cell carcinoma * Mitsudomi, et al. Oncogene 1991.,非小细胞肺癌细胞株的生物特性,非小细胞肺癌细胞株：EGFR 基因突变与药物敏感性,侵犯脑膜对特罗凯具有抗性之肺癌细胞对易瑞沙敏感 EGFR突变之角色,70 y/o Japanese-American woman, never smoked Stage IV adenocarcinoma, RML with rib meta
13、stases2002/02 Mediastinoscopic LN biopsy 2002/04 TRIBUTE trial (TXL+Ca+erlotinib) 42% 2003/11 WBRT due to brain mets 2004/08 Hemiparesis, diplopia, incontinence (bowel & bladder), wheelchair boundBrain & spine MRI: leptomengeal carcinomatosis 2004/10 Could not tolerated temozolomide+CPT-11in progres
14、sion. ECOG PS 4 2004/10 On gefitinibSymptoms: significantly improved in 3 wks 2005/02 Ambulating independently with a walker 2005/04 ECOG PS 2 2005/06 Aspiration pneumonia and died.,Prior to gefitinib 2 ms,Choong NW, Nature CP Oncol 3:50, 2006,Prior to gefitinib 2 ms 4.5 Ms,EGFR突变对上皮生长因子受体嗜酪酸塩抑制剂之敏感性与抗药性的影响 (一),Choong NW, Nature CP Oncol 3:50, 2006,Costa, JCO, 26:1182, 2008,EGFR突变对上皮生长因子受体嗜酪酸塩抑制剂之敏感性与抗药性的影响 (二),Costa, JCO, 26:1182, 2008,EGFR突变对上皮生长因子受体嗜酪酸塩抑制剂之敏感性与抗药性的影响 (二),Screen 47 known kinase inhibitors for ability to inhibit H1975 proliferation 85% inhibition at 2 M,
