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.ppt

BR.21 and ISEL对照组群的存活曲线显示它们是相似的组群 论文搜集策略摘要 资料搜集策略摘要 个别研究之疾病无恶化期 90% accuracy intervals (any line of therapy) 表皮生长因子受体突变阳性各种治疗疗效 SATURN 研究設計 Stratification factors: EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS (0 vs 1) CT regimen (cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never) Region 非鳞状细胞癌 SATURN - OS 全 部 WJTOG0203: 整体存活－依临床特质之亚群分析 0.4 0.6 0.8 1.0 1.2 Favourserlotinib Favoursplacebo HR Male Female Caucasian Asian Adenocarcinoma Squamous-cell Never smoker Former smoker Current smoker HR (95% CI) n 0.88 (0.74–1.05) 659 0.64 (0.46–0.91) 230 0.86 (0.73–1.01) 746 0.66 (0.42–1.05) 131 0.77 (0.61–0.97) 403 0.86 (0.68–1.10) 360 0.69 (0.45–1.05) 152 0.75 (0.56–1.00) 244 0.88 (0.72–1.08) 493 All 0.81 (0.70–0.95) 889 SATURN: 整体存活－依临床特质之亚群分析 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) Placebo (BR.21)1 Placebo (ISEL)2 1Shepherd FA, et al. N Engl J Med 2005;353:123–32 2Thatcher N, et al. Lancet 2005;366:1527–37 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。 Erlotinib Gefitinib O O O O NH N N CI F N O NH N O O NH O O N MW 429.2 MW 446.9 特罗凯 易瑞莎 cLogP = 3.30 cLogP = 3.87 Erlotinib Gefitinib O O O O NH N N CI F N O NH N O O NH O O N MW 429.2 MW 446.9 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;13:3731–7McKillop D, et al. Xenobiotica 2006;36:29–39 OSI-420 Desmethyl-gefitinib Activity in cells = Erlotinib ≈ 10% of gefitinib Activity in xenograft models = Erlotinib Minimal 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. Hidalgo M, et al. J Clin Oncol 2001;19:3267–79Ranson M, et al. J Clin Oncol 2002;20:2240–50