NSCLC靶向药物治疗选择课件.ppt

NSCLC靶向药物治疗选择,广东省人民医院东病区呼吸科高兴林,Schiller, et al. NEJM 2002,1.00.80.60.40.20,051015202530,Time (months),Cisplatin/paclitaxelCisplatin/gemcitabineCisplatin/docetaxelCarboplatin/paclitaxel,Probability of survival,Therapeutic plateau: overall survival 12 months,NSCLC = non-small cell lung cancer,Pemetrexed (n=283),Docetaxel (n=288),Survival Distribution Function,Months,0.00,0.25,0.50,0.75,1.00,0.0,2.5,5.0,7.5,10.0,12.5,15.0,17.5,20.0,22.5,MST 8.3 mos1-yr OS: 29.7%,HR 0.99 95% CI of HR (0.82, 1.20),MST 7.9 mos1-yr OS: 29.7%,靶向药物EGFR-TKI带来了希望,EGFR-TKI,特罗凯 易瑞沙,两个药物的三大不同点:临床数据，药代动力学和分子结构,临床数据,药代动力学,分子结构,EGFR = epidermal growth factor receptorTKI = tyrosine-kinase inhibitor,1、分子结构不同,EGFR选择性酪氨酸激酶抑制剂 特罗凯(厄洛替尼),EGFR酪氨酸激酶抑制剂 易瑞沙(吉非替尼),黄色部分为可变结构，调控多种因素，包括药物与酪氨酸激酶活性位点结合的亲和力、溶解性及其代谢率制药公司设计药物的化学组分，使之具有独特的活性和结构，从而生产最佳的酪氨酸激酶抑制剂,相同的喹唑啉环结构,*IC50=0.02M2,*IC50=0.002M1,特罗凯是活性更强的EGFR抑制剂,Gefitinib,1Moyer JD, et al. Cancer Res 1997;57:4838482Woodburn JR, et al. Br J Cancer 1996;74:1824,IC50 of Tarceva is an order of magnitude lower than that of gefitinib,*versus purified EGFR,CI,F,N,O,NH,N,O,O,NH,O,O,N,Tarceva,O,O,O,O,NH,N,N,两者主要代谢产物活性不同,Li J, et al. Clin Cancer Res 2007;13:37317McKillop D, et al. Xenobiotica 2006;36:2939,Gefitinib,CI,F,N,O,NH,N,O,O,NH,O,O,N,H,Desmethyl-gefitinib,Tarceva,O,O,O,O,NH,N,N,OSI-420,H,体内模型特罗凯和吉非替尼对野生型EGFR的抑制作用,F. Hoffmann-La Roche data on file,体外试验特罗凯对突变型EGFR的抑制作用比吉非替尼更强,Costa DB, et al. J Clin Oncol 2008;26:11824,L858R,L858R-L747S,2、药代动力学水平不同,标准剂量下特罗凯的血浆暴露浓度是吉非替尼的7倍,特罗凯给药为最大耐受剂量吉非替尼如需达到特罗凯相同药物浓度，需要3倍常规剂量,Cmax = maximum plasma concentrationAUC = area under the curve,1Hidalgo M, et al. J Clin Oncol 2001;19:3267792Ranson M, et al. J Clin Oncol 2002;20:224050,吉非替尼剂量无法抑制野生型EGFR和所有突变型EGFR,Li J, et al. J Natl Cancer Inst 2006;98:171423,100101,Unbound gefitinib (ng/mL),Time (days),051015202530,IC50mutantEGFR,IC50wild-typeEGFR,Plasma concentrations versus time in 13 cancer patients,following gefitinib 250mg/day,BR.21研究：在推荐剂量下，特罗凯血浆药物暴露浓度能充分抑制野生型和突变型EGFR,PK data from BR.21 study and plasma protein binding study OSI-774-TILL-01; Cellular inhibition of kinase activity IC50 values. Carey K, et al. Cancer Res 2006;66:816371,Trough plasma concentrations versus time in patients with NSCLC,following Tarceva 150mg/day (BR.21 study),28,56,84,112,140,168,1,000100100,Time (days),Tarceva-free drug concentration (ng/mL),IC50 wild-typeEGFR,IC50 mutant EGFR,3、临床疗效不同,吉非替尼肺癌治疗生存评估 (ISEL): 研究设计,首要终点为总生存期以及腺癌患者总生存期,III期临床n=1692局部进展或转移性 NSCLC既往使用过12种方案化疗对多数化疗耐药或治疗后复发,吉非替尼 250mg/d 加 BSC(n=1129),安慰剂 加 BSC(n=563),随机分组,2,ISEL: 总生存期,HR=0.89 (0.771.02),p=0.087,总人群 (n=1,692),腺癌人群(n=812),HR=0.84 (0.681.03),p=0.089,Proportion surviving,1.00.80.60.40.20,0246810121416,Time (months),1.00.80.60.40.20,0246810121416,Time (months),Thatcher N, et al. Lancet 2005;366:152737,HR = hazard ratio,吉非替尼在总人群和腺癌人群中中未能证明其较安慰剂的生存期收益,之前化疗反应不同患者吉非替尼治疗获益相似,Thatcher N, et al. Lancet 2005;366:152737,之前化疗达PD的患者和达SD或CR/PR的患者相比，吉非替尼治疗获益无显著差异：表明ISEL研究的失败和基线中化疗耐药患者比例较高无关,Previous chemotherapy response CR/PRPrevious chemotherapy response SDPrevious chemotherapy response PD/NE,0.2,0.3,0.4,0.6,0.8,1.0,1.5,HR,Favours gefitinib,Favours placebo,CR = complete response; PR = partial response SD = stable disease; PD = progressive diseaseNE = not evaluable,BR.21：研究设计,Shepherd FA et al, N Engl J Med 2005; 353:123-132.,BR.21: 特罗凯治疗显著延长生存,Shepherd F, et al. N Engl J Med 2005;353:12332Tarceva Summary of Product Characteristics, F. Hoffmann-La Roche Ltd,Survival probability (%),Survival time (months),1007550250,051015202530,Tarceva,(n=488),Placebo,(n=,243,),BR.21和ISEL研究安慰剂组的OS保持一致表明：两个研究入组人群基线条件相似,Proportion surviving,1.00.80.60.40.20,0246810121416182022242628,Time (months),1Shepherd FA, et al. N Engl J Med 2005;353:123322Thatcher N, et al. Lancet 2005;366:152737,特罗凯和吉非替尼临床获益的对比,Favours EGFR TKI,Favours placebo,HR,0.40,0.60,0.80,1.00,1.20,特罗凯 (BR.21)1降低了27%的死亡风险p=0.001,吉非替尼 (ISEL)2降低了11%的死亡风险（无统计学差异）,1Shepherd FA, et al. N Engl J Med 2005;353:123322Thatcher N, et al. Lancet 2005;366:152737,特罗凯和吉非替尼比较: 小结,相似点结构相似，同属喹唑啉类都属于小分子酪氨酸激酶抑制剂,不同点药物活性 (特罗凯吉非替尼)物理化学特性不同代谢产物活性不同药代动力学水平不同Cmax 和AUC暴露浓度特罗凯是吉非替尼的7倍两个药物临床获益完全不同,分子学和药代动力学特性不同可以部分解释为什么两个药物临床效果的差异,EGFR-TKI药物的副作用皮疹意味着什么？,皮疹的分级1，2，3/4度,Lynch TJ, et al. Oncologist 2007;12:61021,皮疹是临床获益的信号 RR/DCR,Wacker B et al, Clin Cancer Res 2007;13 :3913-3921.,1,2,3,3,皮疹级别：,与无皮疹相比：p=0.048p=0.017p0.001,BR21：皮疹是生存获益的信号 PFS,Wacker B et al, Clin Cancer Res 2007;13 :3913-3921.,BR21：皮疹是生存获益的信号 OS,Wacker B et al, Clin Cancer Res 2007;13 :3913-3921.,不包括在入组28日内死亡的患者多变量分析中含协同关系,医生和患者应将皮疹视为更大临床获益可能的积极事件,皮疹的发生可能与药物在血浆中的暴露浓度相关,1Hidalgo, et al. JCO 20012Ranson, et al. JCO 2002F. Hoffmann-La Roche data on file; Thatcher et al, 2005;Shepherd et al, 2005; Blackhall et al, 2006,特罗凯给药为最大耐受剂量吉非替尼如需达到特罗凯相同药物浓度，需要3倍常规剂量,吉非替尼治疗NSCLC的疗效和皮疹严重程度相关,1.000.750.500.250,02.55.07.510.012.515.017.520.0,Time (months),Survival distribution function,Mohamed M, et al. J Clin Oncol 2004;22(Suppl. 14):637 (Abs. 7097),Median OS (months)Rash11No rash4.5,Log-rank p0.0001,目前世界范围内特罗凯与吉非替尼的应用情况,特罗凯已在全球超过80个国家得到许可，用于二/三线治疗晚期 NSCLC吉非替尼在美国被严格限制于既往/目前使用吉非替尼且有效的患者 (仅三线治疗)在欧洲国家未获许可在亚太地区一些国家中获许用于晚期NSCLC患者的二/三线治疗,谢 谢！,