《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-447 Anti-HER1,HER2
2、,HER4 TKIs Gefitinib, Erlotinib, BIBW-2992, PKI-166, GW-572016, CI-1033, AEE788 RAS farnesyltransferase inhibitors MMS214662, R115777, SCH66336 RAF inhibitors Sorafenib, L-779450 MEK inhibitors CI-1040, U-0126 mTOR inhibitors Temsirolimus, RAD001,ATP,SOS,Small molecule tyrosine kinase inhibitors,表皮生
3、长因子受体讯息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,Sh
4、arma, et 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
5、Docetaxel, Pemetrexed 353:12332 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 ea
6、rly relapse,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,Gefitinib,117,60,27,10,40,428,非小细胞肺癌的救援性治疗 Comparison of Docetaxel, Pemetrexed 353:12332 2That
7、cher 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;13:37
8、317McKillop 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,MW 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.,Hida
9、lgo M, et al. J Clin Oncol 2001;19:326779Ranson M, et al. J Clin Oncol 2002;20:224050,Cmax (ng/mL),AUC024 (nghour/L),Erlotinib 150mg/day,Gefitinib 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 (
10、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 carcinoma; 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
11、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 metastases 2002/02Mediastinoscopic LN biopsy 2002/04TRIBUTE trial (TXL+Ca+erlotinib) 42% 2003/11WBRT due to brain mets 2004/08Hemiparesis, diplopia, incontinence (
12、bowel EKB-569; CI-1033,Determine IC50,Measure EGFR Autophos inhibition,Ambit Biosciences,Compound IC50 (M) CI-10330.023 EKB-569 0.033 CL-387,7850.051 SU-114640.450 ZD64741.900 GW5720163.500 Gefitinib6.600 PKI-1667.700 Erlotinib10.000 Inhibition of H1975 cell proliferation,克服T790M抗药性药物之研究,易瑞沙与特罗凯：副作用
13、表列,易瑞沙与特罗凯做为晚期非小细胞肺癌 后线治疗的比较 逆溯性配对研究,Sungkyunkwan University, School of Medicine Samsung Medical Center,Myung-Ju Ahn, M.D.,Gfitinib: 2002-2005; Erlotinib: 2006-2008 Gefitinib: 316 vs Erlotinib: 257 (Matched Age, Sex, PS, Smoking, No of PriorTx),Ahn et al, Unpublished data,病患基本资料,36% 72% 50-56%,肿瘤反应,
14、Ahn et al, Unpublished data,Total OS; Median 10.7 months,(B) Gefitinib OS; Median 10.0 months Erlotinib OS; Median 12.4 months (p=0.07),Ahn et al, Unpublished data,A) 整体存活曲线 B) 分別接受易瑞沙与特罗凯治疗病患之存活曲线,研究图示 Statistics Target N =48 for each group Simons optimal two-stage design P0=10%, P1=25%, -error 5%,
15、 -error 20%, 10% drop-out rates 1st stage: responders 2/18 2nd stage: additional 25 pts,方 法,RANDOMI ZAT ION,Gefitinib 250mg/d Q4wKs,Erlotinib 150mg/d Q4wks,REEVALUAT ION,REEVALUAT ION,Until Disease progression or Intolerable toxicities,4 weeks,8 weeks,At least 2 of 3 Adenoca. Female Never smoker or EGFR mutant,病患基本资料,Numbers of treatment cycles : median 5 (range, 0.5-20), total 605 cycles Gefitinib group: median 6 (range, 0.5-19), total 331 cycles Erlotinib group: median
