特罗凯临床研究汇总.ppt

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level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Power to add,more time,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Power to add,more time,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,LC-1012-IR-0085,有效期至,2011,年,12,月,31,日,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,LC-1012-IR-0085,有效期至,2011,年,12,月,31,日,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,LC-1012-IR-0085,有效期至,2011,年,12,月,31,日,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,LC-1012-IR-0085,有效期至,2011,年,12,月,31,日,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,Power to add,more time,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Power to add,more time,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Power to add,more time,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,目 录,二线治疗：,BR.21,Trust,TITAN,HORG,台湾研究，,Tailor,Delta,维持治疗：,SATURN,一线突变：,EURTAC,Optimal,一线交替：,FASTACT II,突变治疗：,Pooled Analysis,唯一经全球、多中心、大样本、前瞻性、随机双盲的临床研究证明能显著延长晚期,NSCLC,患者总生存的,EGFR TKI,Shepherd FA,et al.N Engl J Med 2005;353:123-132.,BR.21,2005,2006,2008,2007,BR.21,原文,(NEJM),分子与临床,预测因素,(NEJM),亚组分析,-,吸烟与生存,(Clinical Lung Cancer),亚组分析,-,生活质量,(JCO),皮疹与预后分析,(CCR),亚组分析,-,老年与年轻,(JCO),临床预后因子,(JTO),预测与预后因子,(Mol Oncol),KRAS,与生存,(JCO),迄今,BR.21,研究在全球已有,9,篇文献,Br.21:,特罗凯延长腺癌患者生存,特罗凯,(n=246),安慰剂,(n=119),1.00,0.75,0.50,0.25,0,生存概率,月,HR=0.7,p=0.008,BR.21,（腺癌）,051015202530,1.Gary M.Clark Molecular Oncology 2008;1:406-412,P=0.008,10,8,6,4,2,0,特罗凯,1,对照组,1,7.8,个月,5.4,个月,BR.21,（腺癌）,OS,BR.21,研究：各亚组,OS,均延长,Shepherd F,et al.N Engl J Med 2005;353:123132.,HR,95%,可信区间,HR,因素,(,特罗凯,/,安慰剂,)95%CI,特罗凯,安慰剂组,0.70,0.6-0.9,组织学类型腺癌,0.70,0.6-0.9,其它,0.80,0.6-1.0,性别,男性,0.80,0.6-0.9,女性,0.80,0.6-1.1,种族亚裔,0.60,0.4-1.0,其它,0.80,0.7-0.9,吸烟无吸烟史,0.40,0.3-0.6,目前或曾吸烟,0.90,0.7-1.0,PS0-1,0.7,0.6-0.9,2,0.8,0.5-1.1,3,0.8,0.4-1.3,0.000.50,1.00,1.50,特罗凯,更好,安慰剂更好,HR,BR.21,研究特罗凯显著延缓,NSCLC,相关症状的恶化时间,延缓患者咳嗽，呼吸困难和疼痛症状的恶化时间,咳嗽,呼吸困难,疼痛,100,80,60,40,20,0,比率,100,80,60,40,20,0,比率,100,80,60,40,20,0,比率,Median(months),Tarceva4.9,Placebo3.7,0369121518,Time(months),0369121518,Time(months),0369121518,Time(months),p=0.04*,*,Adjusted log rank,Median(months),Tarceva2.8,Placebo1.9,p=0.02*,*,Adjusted log rank,Median(months),Tarceva4.7,Placebo2.9,p=0.01*,*,Adjusted log rank,Bezjak,et al.JCO 2006,患者改善比率,*(%),40,30,20,10,0,特罗凯,安慰剂,Bezjak,et al.JCO 2006,*,任何时间超过基线改变,10,点,(,临床有意义,),总体,体力,角色,认知,情感,社会,p0.01,p0.01,p0.01,BR.21,研究特罗凯二线治疗显著改善患者生活质量,BR.21,研究,不良事件,Shepherd FA,et al.N Engl J Med 2005;353:123-132.,BR.21,研究小结,特罗凯对各亚组均有生存获益,特罗凯改善患者生活质量,特罗凯不良反应轻，安全性好，患者耐受性佳,通过建立预后模型,可以发现不同风险级别获益趋势不同,TRUST,研究,T,a,r,ceva L,u,ng Cancer,S,urvival,T,reatment,52,个,国家,/,地区,545,个中心,7,040,例,2004-2013,Groen H et al,J Clin Oncol,2008;26(Suppl.):abstr 19000.,基于,BR.21,研究令人鼓舞的结果，更大规模的,期临床试验,TRUST,研究在全球多个研究中心展开,IIIB/IV,期,NSCLC,既往一线或二线放化疗失败或不适合进行化疗或放疗,厄洛替尼,150 mg/d,疾病进展或者,不可耐受毒副反应,主要目标,为既往至少一次标准方案放化疗后疾病进展和不适宜进行化放疗的晚期,NSCLC,患者提供厄洛替尼治疗,次要目标,缓解率,(RR),疾病进展时间,(TTP),生存期,(OS),安全性,(Safety),Groen H et al,J Clin Oncol,2008;26(Suppl.):abstr 19000.,TRUST,研究设计,TRUST,研究,:,验证,BR.21,研究结果,*,不同研究终点的样本量不同,DCR=CR+PR+SD,1,Shepherd,et al.NEJM 2005,2,Tarceva SmPC;,3,Roche,data on file,BR.21(N=488),TRUST(N=6580),月,8,7,6,5,4,3,2,1,0,80,70,60,50,40,30,20,10,0,PFS,OS,疾病控制率,DCR,1,年生存率,%,2.2,3.25,6.7,7.9,45%,69%,31%,38%,1.00,0.75,0.50,0.25,0,01020304050,TRUST,研究,:,亚裔和中国患者,OS,获益更多,OS,概率,月,1,Shepherd,et al.NEJM 2005,；,2,Reck,et al.JTO 2010;,3,Mok,et al.JTO 2010,；,4,Wu YL et al.WCLC 2011.,7.9,TRUST G,lobal,2,6,580,14.7,TRUST E/SE Asia,3,1,242,TRUST China,4,15.,68,519,例数,OS,TITAN,研究设计,:,与化疗头对头，快速进展的患者,主要终点,:OS,次要终点,:PFS,RR,QoL(FACT-L),与临床结果相关的生物标志物分析,未接受过化疗,IIIb/IV NSCLC,PD,4,个周期的一线含铂双药化疗,SATURN,Non-PD,培美曲塞,or,多西他赛,PD,Off study,肿瘤标本,特罗凯,150mg/day,PD,Off study,Ciuleanu T,et al.Chicago Multidisciplinary Symposium in Thoracic Oncology,Dec 2010(Abs.LBOA5),TITAN,研究,:,主要终点,-OS,1.0,0.8,0.6,0.4,0.2,0,03691215182124273033363942454851,No at risk,特罗凯,203120765238292218151088543320,化疗,2211448963402220149776432200,特罗凯,(n=203),化疗,(n=221),5.3,5.5,HR=0.96(0.781.19),Log-rank p=0.7299,时间,(,月,),OS,概率,月,TITAN:,接受培美曲塞二线治疗患者,(,非鳞癌,)OS,*Excludes 30 patients with squamous histology who received pemetrexed,厄洛替尼,(n=203),化疗,(n=191)*,HR=0.93(0.751.17),p=0.5455,OS,概率,1.0,0.8,0.6,0.4,0.2,0,03691215182124273033363942454851,5.3,5.3,Ciuleanu T,et al.Chicago Multidisciplinary Symposium in Thoracic Oncology,Dec 2010(Abs.LBOA5),HORG:,厄洛替尼,vs,培美曲塞,III,期临床研究,(,二线,),主要终点,:TTP,次要终点,:RR,OS,安全性,厄洛替尼,150mg/d(n=166),培美曲塞,(n=166),R,IIIB/IV,期,NSCLC,既往,1-2,个,化疗方案,ECOG PS 02,(n=332),HORG=Hellenic Oncology Research Group;,Vamvakas,et al.ASCO 2010(Abs.7519),HORG:TTP,和,OS,概率,1.0,0.8,0.6,0.4,0.2,0,051015202530354045,月,月,1.0,0.8,0.6,0.4,0.2,0,1,年生存率,(%),厄洛替尼,(n=166),35.7%,培美曲塞,(n=166),38.5%,p=0.916,厄洛替尼,(n=163),培美曲塞,(n=161),p=0.299,TTP,OS,051015202530354045,Vamvakas,et al.ASCO 2010(Abs.7519),概率,特罗凯,和吉非替尼用于,晚期非小细胞肺癌患者的不同疗效,:,来自台湾的回顾性多中心研究,Fan W-C,Yu C-J,Tsai C-M,et al.,J Thorac Oncol 2011;6:14855,*,回顾性分析了,2004,年,1,月,-2008,年,12,月间，台湾,5,个三级临床中心接受特罗凯,和吉非替尼治疗的,NSCLC,患者临床数据,概率,5.1,7.2,1.0,0.8,0.6,0.4,0.2,0,时间,(,月,),010203040,特罗凯,(n=119),吉非替尼,(n=410),p,0.001,台湾研究：,不吸烟,/,少吸烟腺癌亚组特罗凯,PFS,更长,中位,PFS(,月,),7.2,5.1,65.8%,58.9%,72.8%,64.3%,全组,腺癌亚组,80,60,40,20,0,DCR (%),特罗凯,吉非替尼,台湾研究：,腺癌亚组特罗凯,DCR,更高,P,=0.025,P,=0.02,R,TAILOR,：,比较厄洛替尼与多西他赛二线治疗,EGFR,野生型,NSCLC,患者的,3,期研究（,Italy,）,（,ASCO 2012,）,多西他赛,75 mg/m2 iv day 1,21 or,35 mg/m2 iv day 1,8,15,28,厄洛替尼,150 mg po,daily,晚期,/,复发,接受过含铂双药治疗,EGFR,野生型,KRAS,状态明确,PS,评分,0-2,分,分层因素,中心,复发,/,进展,化疗方案（,pem vs gem vs vnb,）,PS,评分,(0 vs 1 vs 2),1,：,1,随机分组,N=174,不允许,交叉用药,Marina Chiara Garassino,et,al,2012,ASCO,oral abstract session,7501#,主要终点：,OS,；,次要终点：,PFS,无进展生存率,0,1,2,3,4,5,6,7,0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,月,HR 0.69(95%CI 0.52-0.93)p=0.014,T,AILOR,研究：,ITT,人群的,PFS,Marina Chiara Garassino,et,al,2012,ASCO,oral abstract session,7501#,特罗凯仅在很少部分,(2.2%),野生型患者中获得肿瘤应答，更多的是使患者获得疾病稳定,(20.6%),尽管在研究设计和实施方面存在缺陷，但,TAILOR,研究还是给我们带来了思考,-,TAILOR,研究带来的思考,？,二线状态未知,NSCLC,该如何选择治疗,比较厄洛替尼与多西他赛二、三线治疗EGFR野生型或突变型晚期NSCLC的随机III期研究：DELTA研究设计,（,ASCO 2013,）,开放，多中心,III,期临床研究，,41,家中心、,301,例患者参与,主要终点：,PFS,计划目标样本量,280,例，基于以下假设,厄洛替尼,PFS,优于多西他赛,(,中位,PFS,：,3.5m vs.2.5m;HR 0.714;,=0.05,双侧,;,=0.80),次要终点：,OS,、,ORR,、安全性、,EGFR,野生型或突变型分析,N=301,病理学,证实的,IIIB/IV,期,NSCLC,*,接受过,1,种或,2,种化疗方案，且至少一种为含铂方案,可评估,/,可测量病灶,ECOG PS 0-2,厄洛替尼：,150mg/d,N=150,多西他赛,60mg/m,2,q3w,N=151,1:1,Okano,Y,et al.2013 ASCO Abstract 8006.,*,AJCC,第,6,版,DELTA,=,D,ocetaxel and,E,rlotinib,L,ung Cancer,T,ri,A,l,PFS,OS,二线野生型治疗：,DELTA,研究,化疗胜出？,化疗比,TKI,中位,PFS,仅长,1,个多月,且,OS,无统计学差异,生活质量？,目 录,二线治疗：,BR.21,Trust,TITAN,HORG,台湾研究，,Tailor,Delta,维持治疗：,SATURN,一线治疗：,EURTAC,Optimal,一线交替：,FASTACT II,突变治疗：,Pooled Analysis,1:1,既往未化疗IIIB/IV期NSCLC N=1949,无进展,CR,PR,SD,N=889,4,个疗程,含铂两药,一线化疗*,安慰剂,PD,厄洛替尼,150mg/day,PD,肿瘤取样,(,强制性,),次要终点,:,所有患者与,EGFR IHC+,患者,OS;EGFR IHC,者,OS,与,PFS;,生物标记分析,;,安全性,;,症状进展时间,;QoL,*,顺铂,/,吉西他滨,;,顺铂,/,多西他赛,;,顺铂,/,长春瑞滨,;,卡铂,/,吉西他滨,;,卡铂,/,多西他赛,;,IHC=,免疫组织化学,Co-,主要终点,:,所有患者,PFS,EGFR IHC+,患者,PFS,Capuzzo et al Lancet Oncol 2010,SATURN,研究,:,试验设计,SATURN,：,特罗凯维持治疗,PFS,和,OS,均显著获益,PFS,概率,时间,(,周,),081624324048566472808896,时间,(,周,),081624324048566472808896,HR=0.71(0.620.82),Log-rank p0.0001,HR=0.81(0.700.95),Log-rank p=0.0088,1.0,0.8,0.6,0.4,0.2,0,1.0,0.8,0.6,0.4,0.2,0,OS,PFS,特罗凯,(n=437),安慰剂,(n=447),特罗凯,(n=438),安慰剂,(n=451),OS prob