特罗凯产品介绍.ppt

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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,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,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,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,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,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,Fourth level,Fifth level,*,内 容,特罗凯,关键性临床研究,特罗凯,概况,特罗凯,概况,分子结构与药代动力学特征,特罗凯,产品信息,作用机理,特罗凯,药物成分,通用名：厄洛替尼,化学结构属于喹唑啉类,EGFR,选择性酪氨酸激酶抑制剂,分子式：,C,22,H,23,N,3,O,4,.HCI,分子量：,429.90,IC,50,=0.002,M,Moyer JD,et al.Cancer Res 1997;57:483848,O,N,N,HCI,HN,O,O,O,特罗凯,概况,分子结构与药代动力学特征,特罗凯,产品信息,作用机理,EGFR,信号通路,配体与,EGFR,结合,形成二聚体,酪氨酸激酶结构域改变,13,细胞内信号传导通路被激活,4,5,特定的配体与细胞外的,EGFR,结合,受体结构的改变形成了二聚体,细胞内酪氨酸激酶结构域,磷酸化,细胞增殖，迁移，黏附等,P,P,ATP,ATP=adenosinetriphosphate,P,P,1.Cohen S,et al.J Biol Chem 1980;255:483442;2.Soderquist AM,et al.Fed Proc 1983;42:261520,3.Chinkers M,et al.Nature 1981;290:5169;4.Carey et al.Cancer Res 2006;66:816371,5.Wells A.Int J Biochem Cell Biol 1999;31:63743,酪氨酸激酶结构域改变,13,EGFR,失活,细胞内酪氨酸激酶结构域磷酸化，下游信号通路激活，肿瘤细胞发生增殖，迁移，黏附等,特罗凯,与,ATP,竞争性结合,在酪氨酸酶结构域，抑制磷酸化，从而阻断细胞内信号通路的传导,P,P,ATP,1.Cohen S,et al.J Biol Chem 1980;255:483442;2.Soderquist AM,et al.Fed Proc 1983;42:261520,3.Chinkers M,et al.Nature 1981;290:5169;4.Carey et al.Cancer Res 2006;66:816371,5.Wells A.Int J Biochem Cell Biol 1999;31:63743,EGFR,信号通路,特罗凯,概况,分子结构与药代动力学特征,特罗凯,产品信息,作用机理,特罗凯的研发历史,Pre-,1996,发现和临床前研发,Tarceva,TM,Q2 1999 I,期数据,;,开始,II,期试验,Q1 2001OSIP,Genentech,和,Roche,签署协议 共同研发,Tarceva,TM,Q2 2001II,期数据,Q3/4 2001III,期临床开始,(NSCLC,和胰腺癌,),Q3/4 2002III,期临床完成入组,Q1 2003,超过,30,个,phase II and III,临床在进行中,Q4 2003III,期临床联合化疗,(TRIBUTE/TALENT),未达到临床终点,Q2 2004 III,期临床,BR.21,（,NSCLC,）达到临床终点,Q3 2004 III,期临床,PA.3,(,胰腺癌,),显示,Tarceva,TM,联合健择延长生存,Q4 2004 FDA,批准,Tarceva,TM,二、三线治疗局部进展或者转移性,NSCLC,Q32005 EMEA,批准特罗凯二、三线治疗局部进展或者转移性,NSCLC,Q42006 SFDA,批准特罗凯二、三线治疗局部进展或者转移性,NSCLC,2008 FDA,批准特罗凯联合吉西他滨一线治疗晚期胰腺癌,Q22010 EMEA,、,FDA,批准特罗凯一线维持治疗局部进展或者转移性,NSCLC,11,月,9,月,2009,2010,2011,2013,2012,特罗凯,上市历程,2009,中国获批,二线,适应症,2006,中国获批,三线,适应症,2011,中国获批,维持治疗,适应症,2013,计划中国获批,一线突变,适应症,2005,欧洲获批,二线,/,三线,治疗适应症,2010,欧洲美国获批,一线,维持适应症,欧洲、美国获得,一线突变,适应症,OPTIMAL,研究结果发表,2004,FDA,批准,二线,/,三线,适应症,药物相互作用,与可诱导,CYP3A4,的药物合用可降低厄洛替尼的疗效，同样，,C,YP3A4,抑制剂可导致不良反应增加。,与,CYP3A4,抑制剂酮康唑合用可增加,厄洛替尼,A,UC,达,86%,。因此与酮康唑或其余,CYP3A4,强抑制剂同时使用时应注意特罗凯,的剂量。,与,CYP3A4,诱导集利福平合用可降低,厄洛替尼,A,UC,达,69%,。应考虑使用无,CYP3A4,诱导作用的其他替代治疗。,与,CYP3A4,底物或调节剂合用时需要注意调整剂量。,Tarceva,(erlotinib)summary of product characteristics,F.Hoffmann-La Roche Ltd.,2005.,注意事项及剂量调整策略,注意事项,1,育龄妇女用药期间应避免妊娠。,因吸烟可减少血中药物浓度，应推荐戒烟。,剂量调整策略,1,必要时可按每,50mg,一级的梯度减药。,6%,患者因皮疹需要减量，,1%,患者因腹泻而需减药。,在特罗凯,关键性临床试验中详细说明了难以控制的,3,级以上皮疹或腹泻患者的剂量调整指南,2,3,暂时停药直至症状,1,级,2,减量,50mg,1,1.,Tarceva,(erlotinib)summary of product characteristics,F.Hoffmann-La Roche Ltd.,2005.,2.,Shepherd FA et al.,N Engl J Med.,2005;353:123-132.,3.,Data on file,OSI Pharmaceuticals,Inc.,特罗凯,用法、用量,特罗凯,的推荐剂量为每日,150mg,特罗凯,应在餐前,1,小时或餐后,2,小时服用,特罗凯,规格有两种：,150mg,100mg,特罗凯,关键性临床研究,特罗凯,延长,NSCLC,患者生存期,改善患者的生活质量,安全性好，不良反应仅为轻至中度皮疹,Shepherd F,et al.N Engl J Med 2005;353:123132.,BR.21,研究设计,特罗凯,组,n=488,特罗凯,150mg/d,安慰剂组,n=243,分组,双盲,随机,2:1,临床试验终点：,总生存期,无进展生存期,肿瘤有效率,症状改善,731,例,NSCLC,IIIB/V,期,PS,评分,0-3,1,次化疗失败,BR.21,研究首次证实：特罗凯,显著延长,OS,中位,OS,一年生存率,特罗凯,(n=488),6.7,月,31.2%,安慰剂,(n=243),4.7,月,21.5%,HR=0.73(0.61-0.86),P0.001,1.0,0.8,0.6,0.4,0.2,0.0,0612182430,概率,4.7,6.7,月,1,年生存率提高,45%,中位,OS,提高,42.5%,27%,死亡风险下降,Shepherd F,et al.N Engl J Med 2005;353:123132.,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,TRUST,研究,设计,疾病进展,或,不可耐受毒副作用,IIIB/IV,期晚期肺癌,既往化疗失败,不适合进一步化疗或者放疗,特罗凯,150mg/d,IV,期大规模临床研究，,2004,年,11,月至,2007,年,6,月，全球,51,国家,513,中心，共计,6665,名非小细胞肺癌患者入组,。,主要目的：,给,NSCLC,患者特罗凯,治疗。,次要目的：,有效率、疾病进展时间、总生存期和安全性。,Martin Reck,et al.J Thoracic Oncology 2010;5(10):1616-1622.,TRUST,研究,进一步验证：,特罗凯,治疗临床获益，中国患者,OS,更长,1.0,0.8,0.6,0.4,0.2,0.0,01020304050,概率,月,7.9,14.7,15.37,中位,OS,TRUST,全球,1,(n=6,580),7.9,月,TRUST,亚裔,2,(n=1,242),14.7,月,TRUST,中国,3,(n=519),15.37,月,1.Martin Reck,et al.J Thoracic Oncology 2010;5(10):1616-1622.,2.,Tony Mok,et al.,J Thorac Oncol.,2010;5.,Optimal,研究背景,EGFR-TKIs,在,EGFR,活化,突变,患者,中获益的证据,前瞻性、随机,性,研究以比较,EGFR-TKI,与化疗一线,治疗疗效,评价,EGFR,活化,突变作为预后与预测因子的价值,前瞻性筛选允许更少的病例数,Optimal,研究设计,特罗凯,150mg/,天直至进展,未经化疗,IIIB/IV,期,NSCLC,EGFR,基因突变,(,外显子,19,或,L858R),ECOG PS 02,N=165,含铂双药化疗,R,1:1,分层因子,突变类型,组织学,吸烟状态,Act Mut+=activating,突变,s;ECOG=Eastern Cooperative Oncology,组,;PS=performance status HRQoL=health-related quality of life;FACT-L=Functional Assessment of Cancer Therapy-Lung;LCSS=lung cancer symptom scale,主要终点：,无进展生存,(PFS),次要终点：,总生存,(OS),客观有效率,(ORR),疾病进展时间,有效持续时间，,HRQoL,(FACT-L,LCSS),生物标记分析,疗效评价,每,6,周,Zhou,et al.ESMO 2010,OPTIMAL,PFS(ITT),HR=0.16(0.100.26),Log-rank p0.0001,Gem/carbo(n=72),特罗凯,(n=82),13.7,4.6,PFS,概率,1.0,0.8,0.6,0.4,0.2,0,05101520,风险患者,特罗凯,827051202,Gem/carbo7226400,时间,(,月,),Zhou,et al.ESMO 2010,截止日期,2010-8-16,PFS,亚组分析,:,OPTIMAL,总体,分期,IV,分期,IIIB,女,男,年龄,65,年龄,65,PS 01,PS 2,从不吸烟,目前,/,从前吸烟,腺癌,非腺癌,00.51.01.5,0.16(0.100.26)154,0.18(0.110.28)138,0.27(0.061.16)16,0.13(0.070.24)91,0.26(0.140.50)63,0.17(0.070.43)38,0.19(0.110.31)116,0.16(0.100.26)144,0.21(0.041.28)10,0.14(0.080.25)109,0.21(0.090.49)45,0.17(0.110.28)134,0.22(0.060.73)20,HR(95%Cl)n,HR,特罗凯,更好,gem/carbo,更好,Zhou,et al.ESMO 2010,最佳肿瘤应答,:,OPTIMAL,20,40,60,80,100,患者,(%),CR/PR,CR/PR,83%,特罗凯,(n=82),Gem/carbo(n=72),36%,0,p0.0001,RR,特罗凯,组,96%,的 患者 疾病控制,(CR,PR,或,SD),Zhou,et al.ESMO 2010,总结,:,OPTIMAL,对于,EGFR,活化,突变,的,NSCLC,患者，特罗凯是高效一线治疗药物,中位,PFS,延长,三倍,(13.7,月,vs 4.6,月,),特罗凯,治疗疾病进展和死亡风险降低,84%,(HR 0.16),各亚组（组织学,、,吸烟史、,年龄、性别、疾病分期,）特罗凯一线治疗,均有获益,除了皮疹,(,大部分为轻到中度,),，特罗凯严重,不良反应,较化疗少,特罗凯,治疗,NSCLC,疗效明确,特罗凯,延长,NSCLC,患者生存期,改善患者的生活质量,安全性好，不良反应仅为轻至中度皮疹,BR.21,研究证实：特罗凯,延缓患者相关症状的恶化时间,1.Shepherd FA,et al.N Engl J Med 2005;353(2):123-132.,2.Bezjak A,et al.J Clin Oncol 2006;24:3831-3837.,特罗凯,n=298,对照组,n=153,特罗凯,n=353,对照组,n=179,特罗凯,n=348,对照组,n=179,咳嗽,P=0.04,呼吸困难,P=0.0,1,疼痛,P=0.0,2,4.9,3.7,4.,7,2.9,2.8,1.9,32%,62%,47%,至症状恶化中位时间,(,月,),0246,BR.21,研究证实：,特罗凯,显著改善患者生活质量,特罗凯,安慰剂,患者改善比率,(%),总体,体力,角色,认知,情感,社会,40,30,20,10,0,p0.01,p0.01,p0.01,Bezjak,et al.JCO 2006,特罗凯,延长,NSCLC,患者生存期,改善患者的生活质量,安全性好，不良反应仅为轻至中度皮疹,特罗凯,治疗,NSCLC,疗效明确,特罗凯,安全性好,，,主要不良反应为轻,/,中度皮疹,1.,Shepherd F,et al.N Engl J Med 2005;353:123132.,2.,吴一龙等,.,中华肿瘤杂志,2010,年 第,32,卷 第,2,期,148,页,-151,页,TRUST,中国研究,2,n=519,皮疹分级,患者数,发生率,所有患者,436,84.0%,1-2,度,414,79.8%,3-4,度,22,4.2%,BR.21,研究,1,特罗凯,(n=485),安慰剂,(n=242),p,值,不良反应,(%),所有,3,度,所有,3,度,所有,3,度,皮疹,76,9,17,0,0.001,0.001,腹泻,55,6,19,1,0.001,0.001,食欲不振,69,9,56,5,0.001,0.06,恶心,40,3,34,1,0.12,0.07,呕吐,25,3,23,2,0.52,0.45,口腔黏膜炎,19,1,3,0,0.001,0.31,脱水,7,4,6,3,0.64,0.67,眼部毒反应,28,1,9,1,0.001,0.67,疲劳,79,19,74,23,0.22,0.33,感染,34,2,21,5,0.001,0.03,皮疹,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,级别,HR,95%CI,p,值,2+vs 0,0.29,0.22-0.38,0.001,1 vs 0,0.41,0.31-0.55,0.001,2+vs 1,0.70,0.54-0.90,0.005,2+,度,(n=223),中位,:,11.1,个月,1,度,(n=135),中位,:,7.1,个月,0,度,(n=86),中位,:,3.3,个月,生存率,1.0,0.75,0.50,0.25,0,061218243036,生存期,(,月,),医生和患者应将皮疹视为更大临床获益可能的积极事件,特罗凯,相关皮疹处理,多西霉素或米诺环素,100mg bid;,泼尼松、甲强龙,30mg qd(30,日内逐渐减量,),Lynch TJ,et al.Oncologist 2007;12:610-21,无需治疗,或,1%,或,2.5%,氢化可的松软膏,以及,/,或,抗生素软膏,轻 度,1,级,中 度,2,级,重 度,3,级以上,考虑减量或推迟治疗,依据皮疹治疗共识处理皮疹,确保服药方法正确：餐前,1,小时或餐后,2,小时口服,预防处理,从治疗开始，即一天二次全身使用不含酒精的润肤乳液。减少日晒时间，外露的肌肤使用防晒用品,按中度皮疹方案治疗,以及,系统性的应用皮质激素,以及,考虑减量,轻 度,中 度,重 度,每,2,周评估,合成四环素*,以及,2.5%,氢化可的松软膏,以及,/,或,抗生素软膏,总 结,特罗凯,具有更强的药代动力学特征，血药浓度可以同时抑制,EGFR,突变及野生型,特罗凯,安全性好，主要不良反应为轻至中度皮疹,特罗凯,治疗,NSCLC,疗效肯定,特罗凯,是选择性,EGFR,酪氨酸激酶抑制剂，是超越化疗的靶向治疗选择,