《肺癌的靶向治疗》ppt课件

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,第四级,第五级,肺癌的靶向治疗,*,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,第四级,第五级,肺癌的靶向治疗,*,Slide Title,Body Text,Second Level,Third Level,Fourth Level,Titelmasterformat durch Klicken bearbeiten,Textmasterformate durch Klicken bearbeiten,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,第四级,第五级,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,第四级,第五级,Click to edit Master title style Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Body Text,Second Level,Third Level,Fourth Level,肺癌的靶向治疗,*,Slide Title,Body Text,Second Level,Third Level,Fourth Level,肺癌的靶向治疗,*,Slide Title,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,第四级,第五级,肺癌的靶向治疗,*,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,第四级,第五级,肺癌的靶向治疗,*,肺癌的靶向治疗,北京协和医院呼吸内科,李龙芸,肺癌的靶向治疗,中国肺癌流行病学回顾,26.9%,38.4%,30.5%,2000,和,2005,年肺癌患者数,Yang et al, 2005,患者数,晚期肺癌的化学治疗已达平台,化学治疗是肺癌的主要治疗方法,一线中位生存期,810,个月,一年存活率,30%40%,二线中位生存期,57,个月,肺癌的靶向治疗,21,世纪分子靶向治疗,飞越进展,为肺癌病人带来了新生的希望,肺癌的靶向治疗,新的靶向治疗药物,肺癌的靶向治疗,肿瘤细胞靶的选择,毒性小,药物生物活性高,治疗后能提高生活质量,经选择性的病人能获得很好的疗效,Targeted Cancer Therapies,肺癌的靶向治疗,Targeting Tumor & Its microenvironment,Endothelial Cell,Cancer Cell,Growth factor signaling,Microtubule dynamics,Histone,acetylation/deacetylation,DNA replication, transcription, repair,Metastasis,1,1,4,3,2,1,1,4,2,5,Tumor Cell Growth / Replication,Angiogenesis,肺癌的靶向治疗,Targets of Cancer Therapy,Cell Growth Motility Survival Proliferation Angiogenesis,P,P,P,P,PDK1,2,Growth Factor Signaling,Gene Transcription,DNA Replication and Repair,1,6,3,5,8,9,10,11,2,Plasma Membrane,Nuclear Membrane,12,7,4,7,7,1.Growth factors,2.Growth factor receptors,3.Adaptor proteins,4.Docking proteins/binding proteins,5.Guanine nucleotide exchange factors,6.Phosphatases and phospholipases,7.Signaling kinases,8.Ribosomes,9.Transcription factors,10.Histones,11.DNA,12.Microtubules,Microtubule Dynamics,RNA Translation,肺癌的靶向治疗,Cell Growth, Proliferation, Survival, Transformation,Proliferation,Migration,Grb2,Glycogen,Synthesis,Survival,Akt/PKB,MEK,ERK,PI3-K,RAF,PI(4,5)P2,PI(3,4,5)P3,PTEN,P,P,P,P,EGF, TGF-,EGFR,HER2,PDK1,2,PDK1,2,RAS-GTP,SOS,GTP,P,RAS-GDP,TKI,Growth Factor Signaling Through EGFR/HER2,肺癌的靶向治疗,Receptor Tyrosine Kinase (RTK) Families and Their Activation,IGF-1R,P,P,P,P,HER2,HER3,HER4,EGFR,TGF-,a,EGF,Heregulin,Epiregulin,Heregulin,Epiregulin,None,HER (erbB) Family,VEGFR-2,VEGFR-3,VEGFR-1,VEGF-A,VEGF-B,VEGF-C,VEGF-D,VEGFR Family,Flt-3,PDGFR,KIT,FL,PDGF,SCF,PDGFR Family,P,P,P,P,VEGFRs, PDGFR, KIT, Flt-3,Mutant Flt-3,P,P,P,P,EGFR/HER2,P,P,P,P,Receptor Dimerization and Activation,VEGF-A,VEGF-C,VEGF-D,IGF-1 IGF-2,肺癌的靶向治疗,目前的靶向治疗药物,-1,EGFR,抑制剂,EGFR,Erlotinib (,厄罗替尼,),(),Gefitinib,(,吉非替尼,、,ZD 1839),(),Cetuximab,(Erbitux MoAbs,西妥昔单抗,),Her-2,Trastuzumab,(,曲妥珠单抗,)(),EGFR+Her-2,BIBW2992 (TOVOK),肺癌的靶向治疗,目前的靶向治疗药物,-2,血管生长,抑制剂,VEGF,bevacizumab,（贝伐单抗） （,）,thalidomide,（沙利度胺） （,）,Vandetanib,(,范得他尼,、,ZD6474,、,ZACTIMA,),（,）,Cediranib(Recentin, AZD2171),（,）,Axitinib(,艾斯替尼,、,AG-013736),（,）,MMP,(,基质性金属蛋白酶抑制剂,),Prinomastat,(,司立马司他,),（,）,Unclear,Endostatin,(,血管内皮抑制素,),（,）,肺癌的靶向治疗,目前的靶向治疗药物,-3,诱导细胞凋亡,Bc1-2,oblimerser (G3139,、奥利默森纳,),(),XIAP,AEG35156,(),Survivin,ISIS23722,(),其它,Farnesyltransferase,Lonafarnib (,),Proteosome,bortezomib (,),B-raf,sorafenib,（索拉非尼、,BAY43-9006,）,(),Sunitinib,（舒坦、,SU11248,、,SUTENT,）,(),m-TOR,Temsirolimus,（,CCI-779,、,Torisel,）,(),RXR,bexarotene,(,),Vaccine,L-BLP25 (,),MoAb-toxin fusion,TLK 286,（,谷胱甘肽类似物,）,(,),Retinoids,（,视黄类似物,）,Bexarotene (,、,),胰岛素样,生长因子,1,受体,（,IGF-IR,）,CP751871 (),肺癌的靶向治疗,表皮生长因子受体酪氨酸激酶抑制剂,吉非替尼,肺癌的靶向治疗,IDEAL,易瑞沙,250,mg/,天组总结,提高治疗受益,50,%,的患者获得疾病控制,68,%的患者一个月内达到客观缓解,改善症状,40.3%,以上的患者出现疾病相关的症状改善,中位症状改善时间为8天,症状改善与,客观缓解,延长生存时间,35%,的患者用易瑞沙治疗后生存达到一年,不良事件较轻,最常见的药物不良事件是皮肤反应和腹泻,通常较轻,(,为,1,2,级,),3级不良事件患者比例少于10%,安全性较好,易瑞沙未见有意义的血液学指标改变事件，如骨髓抑制,Fukuoka et al 2003,客观缓解、生存期与症状改善之间均有相关性,55%,患者治疗一周后症状缓解,预计27%的患者用易瑞沙治疗后生存超过一年,中位生存时间,7,个月左右,无论既往接受过几次化疗，均有不同程度的客观缓解,IDEL1,IDEL2,Kris et al 2003,肺癌的靶向治疗,东方人,(N=342),HR=0.66 (0.48, 0.91),非东方人,(N=1350),HR=0.93 (0.81, 1.08),Survival time (months),Percent surviving,Survival time (months),0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,IRESSA,-,Placebo,Gefitinib,Placebo,Proportion surviving,0,2,4,6,8,10,12,14,16,0.0,1.0,0.8,0.6,0.4,0.2,Time (months),0,2,4,6,8,10,12,14,16,HR=0.92 (p=0.242),Median: 5.0 vs 4.9 months,不吸烟者,(n=375),吸烟者,(n=1317),HR=0.67 (p=0.012),Median: 8.9 vs 6.1 months,ISEL,研究,肺癌的靶向治疗,INTEREST,研究概述,第1个,EGFR-TKI,直接对照标准二线化疗(多西他赛)的随机、,开放、平行组、国际多中心的,III,期临床研究,比较,易瑞沙,与多西他赛治疗既往接受过含铂化疗的局部晚期或复发或转移,NSCLC,的疗效，以证明两组总生存期在临床上是相似的,研究主要终点为总生存期，并采用非劣效性设计,总共入组1466例，亚裔323例，中国5,家研究中心,中国医学科学院肿瘤医院,北京协和医院,复旦大学附属肿瘤医院,交通大学附属上海胸科医院,广东省人民医院,Douillard et al; Data presented at WCLC 2007 in Seoul, Korea,肺癌的靶向治疗,INTEREST,研究设计,吉非替尼,250,mg/day,多西他赛,75,mg/m,2,每三周方案,1:1,随机分组,入组病例,年龄,18,岁,生存预期,8,周,既往化疗进展或复发,可继续接受多西他赛治疗,既往1或2次化疗,(,至少1次含铂方案),体力评分,PS 0-2,主要终点,总生存期,协同分析,所有人群非劣效,EGFR,基因复制高表达(,FISH,阳性)人群优效性,次要终点,无疾病进展生存期,客观有效率,生活质量改善率,疾病相关症状,安全性和耐受性,探索性终点,生物标记物,研究终点,Douillard et al; Data presented at WCLC 2007 in Seoul, Korea,肺癌的靶向治疗,INTEREST,主要终点,Overall Survival,(,PP,人群),预设,HR,可信区间上限 =,1.154,723,593 (82.0%),710,576 (81.1%),N,Events,Primary Cox analysis without covariates,HR (96% CI) =,1.020,(0.,905,1.150,),Median OS (months),1-year,survival,7.6,32%,8.0,34%,Gefitinib,Docetaxel,Conclude non-inferiorityin the overall PP population,723,336,225,131,83,50,31,14,0,0,710,339,228,139,89,46,24,7,0,0,518,503,0,4,8,12,16,20,24,28,32,36,40,0.0,0.2,0.4,0.6,0.8,1.0,Months,Probabilityof survival,At risk :,Gefitinib,Docetaxel,Douillard et al; Data presented at WCLC 2007 in Seoul, Korea,肺癌的靶向治疗,INTEREST,意义,第1个,在,NSCLC,二线治疗中开展的,EGFR-TKI,与标准化疗的全球,III,期临床研究,第1次,证明,NSCLC,二线治疗在,未经选择,的,患者中,EGFR-TKI,的总生存期与标准化疗相当,但更加安全、生活质量更高,易瑞沙,是晚期,NSCLC,二线的标准治疗方案,肺癌的靶向治疗,ISTANA,韩国二线随机对照,III,期研究,2008,年7月,肺癌的靶向治疗,患者,18,岁,预计生存期,12,周,化疗后进展或复发,可耐受进一步多西他,赛治疗,至少接受过一次含铂,两联化疗,WHO PS 0-2,随机分组,1:1,易瑞沙,250 mg/day,多西他赛,75 mg/m,2,每3周,主要终点,PFS,次要终点,客观缓解率,总生存,生活质量,安全性和耐受性,WHO, World Health Organization; PS, performance status,ISTANA,研究设计,韩国,III,期研究,肺癌的靶向治疗,事件数,中位,PFS(,月,),6,个月无进展率,易瑞沙,(n=82),61(74.4%),3.3,32%,多西他赛,(n=79),59(74.7%),3.4,13%,HR(90% CI)=0.729 (0.533-0.998),单侧检验,P,0.0441,1.00,0.75,0.50,0.25,0.00,0.0 2.5 5.0 7.5 10.0 12.5 15.0,无进展的比例,时间（月）,无协变量的主要分析,HR,1,意味着易瑞沙的进展危险更低,CI:,可信区间；,PFS：,无进展生存；,HR：,风险比；,ITT：,意向治疗,易瑞沙,多西他赛,ISTANA,研究的,PFS(,ITT,人群,),肺癌的靶向治疗,比值比（,OR）,（,95,CI,）,4.74(1.81,，,12.41); p=0.0007(,双侧,),28.1%,7.6%,30,25,20,15,10,5,0,患者,(%),易瑞沙,(n=82),多西他赛,(n=79),ISTANA,研究的客观缓解率,(,RECIST),肺癌的靶向治疗,结 论,对于接受过含铂方案的晚期,NSCLC,的韩裔患者，吉非替尼疗效更好，耐受良好，可以代替多西他赛作为二线治疗,肺癌的靶向治疗,靶向药物的维持治疗,靶向药物可能是维持治疗更为理想的选择,单药用于2-3线有效,耐受性好,使用方便,与细胞毒药物不同的作用机制,肺癌的靶向治疗,NSCLC,初治,IIIb/IV,期,PS 0-1,随机,标准两药联合化疗,3-6,周期,观察直到进展,进展后治疗不限,标准两药联合化疗,3,周期,而后吉非替尼治疗直至进展,进展后治疗不限,主要终点,:,总生存,2003,年,2,月至,2005,年,5,月已入组约,600,例患者,随访期：计划,2,年,预计,2008 ASCO,报告初步结果,WJTOG 0203,研究,(,日本,),肺癌的靶向治疗,Overall Survival -Adeno,(n=467),0 10 20 30 40 50 60,20,40,60,80,100,0,HR= 0.79; 95%CI, 0.65-0.98,p= 0.03,Chemotherapy followed by gefitinib,(MST= 15.42 mo),Arm B,Chemotherapy alone,(MST= 14.33 mo),Arm A,Time from randomization (months),Overall survival (%),肺癌的靶向治疗,Progression-Free Survival,20,80,100,0,10,20,30,40,50,60,40,60,0,Time from randomization (months),Progression-free survival (%),HR= 0.68; 95%CI, 0.57-0.80,p 0.001,Chemotherapy followed by gefitinib,(PFS= 4.60 mo),Arm B,Chemotherapy alone,(PFS= 4.27 mo),Arm A,肺癌的靶向治疗,结 果,含铂两药一线化疗后，使用吉非替尼维持,治疗，可以显著延长,PFS,总体人群并未达到生存的显著性差异，但在预设亚组中，腺癌患者的生存显著延长。,含铂两药一线化疗后使用吉非替尼维持治疗，可以给腺癌患者带来显著的临床获益,肺癌的靶向治疗,主要终点,:,总生存,预计入组,400,例,2004,年启动，预计,2009,年完成,EORTC 08021,研究,(,欧洲,),CR,PR,SD,吉非替尼,250mg/,日,直至进展或不能耐受,安慰剂,每日一片,直至进展或不能耐受,NSCLC,患者,IIIB,或,IV,期,EGFR,阳性,含铂两药方案一线2-6周期后,未用过,TKI,治疗,1:1,www.eortc.org,肺癌的靶向治疗,中国患者的回顾性对照研究研究设计,入组条件,年龄,18,岁,书面知情同意,组织学,/,细胞学,证实,NSCLC,IIIb,或,IV,期,均接受过化疗,距离上次化疗,21,天以上,末次化疗,是否复发,N=173,维持治疗组,N=62,复发治疗组,N=111,吉非替尼,250mg/d,直至出现,不能耐受,的毒性,疾病进展,死亡,AII 037, CCO 2006 ACOS/CSCO,年会专刊,2002.10-2006.4,北京协和医院回顾性研究,肺癌的靶向治疗,维持/复治总体疗效,分组,例数,MST (,月,),P,值,PFS (,月,),P,值,维持组,62,25.0,0.0004,16.5,0.0000,复治组,111,12.5,9.2,药物不良反应通常轻微,(1-2,度,),且可逆,维持组生存与吸烟状态,组织学类型,肝转移及吉非替尼疗效显著相关,客观有效率与年龄,吸烟状态,组织学类型,呼吸短促改变和皮疹出现无显著相关性,作者结论：,吉非替尼耐受性性良好,吉非替尼可用于化疗后维持治疗能延长生存期,AII 037, CCO 2006 ACOS/CSCO,年会专刊,肺癌的靶向治疗,研究设计,(,中国即将进行,),吉非替尼,250mg,每日一次口服,安慰剂,每日一次口服,IIIB/IV,期,NSCLC,患者,含铂一线两药化疗,4,周期,达到,CR,PR,或,SD,1:1,随机,治疗至进展,中国15-20家中心参与,约需入选300例患者,预计年内开始,肺癌的靶向治疗,吉非替尼 病例介绍,董,XX，,女，42岁,右上肺中分化腺鳞癌,右上肺切除术后半年复发,rT4N2M1,2003,年1月开始易瑞沙治疗,吉非替尼,-,病例介绍,2,女性，,57,岁，既往不吸烟，,2003,年,4,月,27,日,右肺上中叶切除术，诊断为高分化腺癌,IV,期,化疗,2,个周期后出现,PD,2003,年,11,月,26,日起开始口服吉非替尼。,1,个月后达到,PR,，之后继续服药,肺癌的靶向治疗,2004,年,12,月,2,日发现,PD(,一年,3,个月,),泰索帝,+,卡铂*,2,疗效达,SD,再次服用吉非替尼，,CT,提示双侧肺部小结节明显吸收,疗效达,PR,肺癌的靶向治疗,2006,年,12,月再次,PD (1,年,),2007,年,5,月,28,日,Alimta,，疗效,SD,肺癌的靶向治疗,2007,年,12,月,(,泰素帝,+,贝伐单抗,) MR,2008,年,3,月,(,吉非替尼*,2,月,)MR,已存活,4,年,8,个月,肺癌的靶向治疗,厄罗替尼,肺癌的靶向治疗,特罗凯,显著延长总生存期,1,2,shepherd FA, Pereira J, Ciuleanu T, et al. N Engl J Med 2005; 353(2): 123-132,中位生存期,：,42.5%,HR 0.73,死亡风险,27%,( 95%,CI=0.60-0.87; P=0.001 ),( 6.7个月,vs4.7,个月 ),特罗凯,(N=488),对照组,(,N=243),0 6 12 18 24,月,一年生存率：,45%,( 31.2%,vs 21.5% ),生存概率,1.000.75,0.50,0.25,肺癌的靶向治疗,Tarceva Lung Cancer Survival Treatment TRUST study,肺癌的靶向治疗,TRUST,试验设计,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,150 mg/d,疾病进展或者不可耐受毒副反应,主要目标：为既往至少经一疗程标准方案化疗,/,放疗后疾病进展以及,不适宜进行化,/,放疗的晚期,NSCLC,患者提供特罗凯治疗,次要目标：,缓解率,(RR),疾病进展时间,(TTP),生存期,(OS),安全性,肺癌的靶向治疗,TRUST,全球研究概况,研究涉及,59,个国家的,12, 000,多,非小细胞肺癌患者,截止,2007,年,10,月,25,日, 7039,位,患者数据分析结果,S.G. Allan ASCO 2008 Abstract 8081,肺癌的靶向治疗,疾病控制率,亚组分析,女性,不吸烟,非鳞癌,男性,不吸烟,非鳞癌,男性,吸烟,鳞癌,男性,吸烟,非鳞癌,女性,吸烟,鳞癌,男性,不吸烟,鳞癌,N = 1178,N = 411,N = 960,N = 1785,N = 162,N = 78,S.G. Allan ASCO 2008 Abstract 8081,肺癌的靶向治疗,TRUST,全球数据,总结,总生存,女性,吸烟 鳞癌,vs,男性,吸烟 鳞癌 无差异性,无进展生存 女性 吸烟 鳞癌亚组,二线,vs,三线特,PFS,分别,12.7,周、,8.9,周,),疾病控制率,非鳞癌 不吸烟 疗效较高,女性,80%,男性,75%,吸烟 鳞癌用特罗凯治疗可能获益,肺癌的靶向治疗,TRUST,亚洲数据,(,东亚,/,东南亚,),7,个亚洲国家共,1223,例患者,T.S. Mok ASCO 2008 Abstract 19001,中国,台湾,韩国,香港,泰国,/,印度尼西亚,/,马来西亚,肺癌的靶向治疗,无进展生存,25.1,周,(PFS),N = 1222,N=1222,95% CI 23.9-28.9,亚洲,全球,T.S. Mok ASCO 2008 Abstract 19001,肺癌的靶向治疗,亚洲中期分析报告,*,患者数,1%,24%,52%,20%,2%,总体疾病控制率,= 77%,*,N=1046,中国,/,台湾,/,香港,/,泰国,/,韩国,0,100,200,300,400,500,600,CR,PR,SD,PD,无法评估,TRUST,亚洲数据总结,疾病控制率,78% (N = 1097),中位无进展生存,25.1,周,(N=1222),PS 0/1,比较,PS 2,有更长,PFS,26.3,周,VS. 20.7,周,一年生存率目前为,60%,总生存数据尚未公布,肺癌的靶向治疗,TRUST,研究中国中期报告：,总结,疗效数据令人振奋,疾病控制率达,79,PFS,为,5.65,个月,厄洛替尼对各亚组患者均有良好疾病控制率及,PFS,中期分析结果证实了以往临床试验中厄洛替尼的良好耐受性,皮疹和腹泻是最常见的,AEs，,但大多数病例都易于处理,厄洛替尼相关,SAEs,发生率很低,厄洛替尼是延长晚期,NSCLC,患者生存并有良好耐受的药物,2008 ASCO,特罗凯信息,肺癌的靶向治疗,FAST-ACT:,F,ist-line,A,sian,S,equential,T,arceva,A,nd,C,hemotherapy,T,rial,研究设计,安慰剂,特罗凯,150mg/day,既往未治疗的,IIIb/IV,期,NSCLC (n=150),R,1,1,进展,健泽,+,顺铂 或,卡铂,6,程,+,安慰剂,健泽,+,顺铂 或卡铂,6,程,+,特罗凯,进展,分层：,中心,分期,组织学类型,吸烟状态,治疗,后期治疗,筛选,Post-study,健泽,1250mg/m,2,(d1,8);,顺铂,75mg/m,2,或卡铂,5AUC (d1); Tarceva 150mg/day (d1528),主要终点,:,无进展率,(CR+PR+SD*),Week 8,次要终点：,PFS,无进展率,(CR+PR+SD*),Week 16,ORR, TTP, OS,NCI, Seoul, South Korea,Lung Cancer Research Group (LCRG) in Asia,J.S.Lee ASCO 2008. Abstract 8031,肺癌的靶向治疗,主要临床终点 无进展率,(,第,8,周,),80.3%,N=76,N=78,J.S.Lee ASCO 2008. Abstract 8031,肺癌的靶向治疗,FAST-ACT,次要临床终点,无进展生存,（,PFS) 7.2,月,N=76,N=78,J.S.Lee ASCO 2008. Abstract 8031,肺癌的靶向治疗,FAST-ACT,次要临床终点,缓解率,（,ORR),*,Response rate (%),36.8%,24.4%,*All partial response,GC-Erlotinib,GC-Placebo,50,40,30,20,10,0,12.4%,Odds ratio 1.85(95% CI: 0.913.76; p=0.089),36.8%,24.4%,肺癌的靶向治疗,FAST-ACT,其他分析,中位总生存尚未达到,生物标记物的分析尚在进行中,J.S.Lee ASCO 2008. Abstract 8031,肺癌的靶向治疗,FAST-ACT,安全性,治疗相关性非血液性毒性,*,*Reported in 10% of patients in at least one treatment arm; includes AEs due tochemotherapy;,includes gemcitabine- and erlotinib-associated rash,Percentage of patients,GC-Erlotinib,Grade 1/2,Grade 3/4,GC-Placebo,Grade 1/2,Grade 3/4,100,80,60,40,20,0,Rash,Nausea,Anorexia,Fatigue,Alopecia,Vomiting,Constipation,Dry skin,Pruritus,Diarrhea,肺癌的靶向治疗,FAST-ACT,总结,特罗凯和化疗序贯一线治疗组比较单用化疗组,延长无进展生存,（,7.2,月,vs. 5.5,月,; P = 0.005),提高肿瘤缓解率,(36.8% vs. 24.4%),第,8,周无进展生存率明显提高,(80.3% vs. 76.9%),无未预期的毒副反应,分子生物学的进一步研究可能可以进一步的,解释研究结果,随机,III,期研究正在计划中,肺癌的靶向治疗,厄洛替尼,病例介绍,女性，,49,岁，,ECOG 2,分,无吸烟史,纤支镜诊断为高分化腺癌,NC *4,周期后疾病进展,2006-6-8,开始服用单药厄洛替尼治疗,西妥昔单抗（爱必妥,）用于非小细胞肺癌的治疗,肺癌的靶向治疗,作用机制,(2),EGFR,靶向单克隆抗体联合放化疗治疗，在多种动物模型及离体实验中显示出了,协助或协同抗,肿瘤效应,。,Courtesy of Jos Baselga (modified),Erbitux: NSCLC,一线治疗,Regimen,RR(%),PFS(months),OS,(months),Rosell et al.,(LUCAS),Cis/vino +,Erbitux,35,5,8.3,Cis/vino,28,4.6,7.3,Butts et al.,Platinum/gem +,E,rbitux,28,5.1,12,Platinum/gem,18,4.2,9.3,Lynch et al.,Carbo/taxane +,Erbitux,26,4.4,(IRRC),4.3,(Invest),n. a.,Carbo/taxane,17,4.2,(IRRC),3.8,(Invest),FLEX,Cis/vino +,E,rbitux,Primary endpoint of superior survival met,Cis/vino,Rosell R, et al.,Ann Oncol 2008;19:362369,Butts C, et al. J Clin Oncol 2007;25:57775785,Lynch T, et al. J Thorac Oncol 2007;2(Suppl. 4):S340S341. Updated information presented at WCLC 2007,FLEX press release, September 2007,肺癌的靶向治疗,肺癌的靶向治疗,FLEX:,F,irst-line in,L,ung cancer with,E,rbitu,X,肺癌的靶向治疗,肺癌的靶向治疗,肺癌的靶向治疗,FLEX,研究目的,晚期,NSCLC,的一线治疗,西妥昔单抗与化疗联合方案,vs,单化疗方案,生存获益,？,肺癌的靶向治疗,FLEX EGFR,评定,肺癌的靶向治疗,FLEX,病人基线特征,肺癌的靶向治疗,FLEX,临床试验后抗肿瘤治疗,肺癌的靶向治疗,FLEX,预先设定的亚组分析,主要亚组分析均有生存获益,ECOG PS,吸烟状态,组织学类型,性别,年龄,分期,肺癌的靶向治疗,肺癌的靶向治疗,FLEX,种族差异,预后因素,腺癌,女性,非吸烟者,ECOG PS 0/1,临床试验后治疗,EGFR TKIs,中位生存,95% CI,高加索人群 亚洲人群,肺癌的靶向治疗,FLEX,亚洲人群亚组（,n=121,）,小样本,(,总人群的,10%)CT,组腺癌多临床试验后接受靶向治疗,不足以在该人群中给予明确结论,基线预后因素,腺癌,临床试验后治疗,EGFR TKIs,肺癌的靶向治疗,高加索人群,肺癌的靶向治疗,高加索人群,肺癌的靶向治疗,FLEX,总结,西妥昔单抗联合顺铂,/,长春瑞滨一线,化疗治疗,NSCLC VS,单化疗,显示,了更佳的生存获益,鳞癌和非鳞癌均能获益,痤疮样皮疹,是西妥昔单抗的主要副,反应，可预见、同时可以控制,注意入组者肿瘤组织均有,EGFR,表达,肺癌的靶向治疗,西妥昔单抗,+,顺铂,+,健 择,西妥昔单抗,+,顺铂,+,长春瑞滨,西妥昔单抗,+,顺铂,+,紫杉醇,用于晚期,NSCLC,一线治疗,肺癌的靶向治疗,Challenges of detecting EGFR T790M in gefitinib/erlotinib-resistant tumours,Lung Cancer (2008) 60 (supplement 2), 53-59,肺癌的靶向治疗,晚期,NSCLC,应用吉非替尼及特罗凯,长期治疗后，可发生获得性耐药,两个耐药机制已被确定,EGFR,基因,T790M(exonzo),继发突变,MET Porto-oncogen,扩增,第二代的,TKIS,可克服,T790m,的抵抗,肺癌的靶向治疗,第二代,EGFR,抑制剂,BIBW 2992(EGFR+Her2,抑制剂,),肺癌的靶向治疗,BIBW 2992 (Tovok)*A novel, potent and irreversible dual inhibitor of EGFR and HER2*,*This compound is an investigational agent. Its efficacy and safety have not been established,肺癌的靶向治疗,Dual targeting of EGFR and HER2 broadens the reach of erbB kinase receptor family inhibition,肺癌的靶向治疗,BIBW 2992 blocks all cancer-relevantEGFR and HER2 dimers,肺癌的靶向治疗,BIBW 2992 is an irreversible dual EGFR/HER2 inhibitor,Dual EGFR and HER2 inhibitory activity is expected to,13,Maximize inhibition of signaling by erbB receptors,Result in improved efficacy across more cancer types,Irreversible binding,13,Provides a sustained blockade of receptors and may improve inhibition of tumour cell proliferation,Provides activity against receptors that are resistant to first-generation inhibitors (e.g.,EGFR,L858R/T790M,mutants),1. Eskens FALM et al. Br J Cancer 2008; 98:8085. 2.,Solca F,et al.,AACR-NCI-EORTC Proceedings, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. 2005;118 (Abstract A244),. 3,. Solca F,et al,. AACR-NCI-EORTC Proceedings, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.,2005;118 (Abstract A242),肺癌的靶向治疗,BIBW 2992 has a good safety profile,Tolerability,BIBW 2992 was well tolerated and comparable with other agents in this class in terms of dose-limiting toxicities such as rash and diarrhoea,1,2,No non-mechanism-related toxicities are evident to date,18,1. Eskens FALM et al. Br J Cancer 2008; 98:8085. 2.,Plummer R et al,.,Eur J Cancer Suppl 2006;4(12):173174. 3. Agus DB et al. J Clin Oncol 2006:24(18S);2074. 4. Mom CH et al. J Clin Oncol 2006;24(18S):3025. 5. Shaw H et al. J Clin Oncol 2006;24(18S): 3027. 6.,Eskens FA et al. Proceedings, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. November 2005. 116 (Abstract A235). 7.,Plummer R et al. Proceedings, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. November 2005. 8182 (Abstract A105). 8. Marshall JL et al. Proceedings, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. November 2005. 168 (Abstract B161),肺癌的靶向治疗,BIBW 2992 shows,in vivo,efficacy in xenograft models (ovarian and gastric cancer models),Solca F,et al.,Pr,esented at,AACR-NCI-EORTC International Conference on Molecular Targets,and Cancer Therapeutics, Philadelphia, 1418 Nov 2005,EGFR-driven,0,250,500,750,1000,1250,1500,0,5,10,15,20,25,30,35,Days,Tumour Volume mm,control,100 mg/kg gefitinib,20 mg/kg BIBW 2992,Treatment,Ovarian cancer,SKOV-3,HER2-driven,0,250,500,750,1000,1250,0,10,20,30,40,control,20 mg/kg trastuzumab,10 mg/kg trastuzumab,15 mg/kg BIBW2992,Treatment,Tumour Volume mm,Gastric cancer,NCI-N87,Days,肺癌的靶向治疗,BIBW 2992 induces apoptosis,in vitro,Results from nucleosome assays (nucleosome,formation is a hallmark of apoptosis),Nucleosome assay,-0.10,0.10,0.30,0.50,0.70,0.90,1.10,1.30,1.50,2 h,5 h,7 h,13 h,18 h,24 h,OD 405 nm,250 nM BIBW 2992,Untreated cells,Blank,Solca F,et al.,Pr,esented at,AACR-NCI-EORTC International Conference on Molecular Targets,and Cancer Therapeutics, Philadelphia, 1418 Nov 2005,肺癌的靶向治疗,BIBW 2992 induces apoptosis,in vivo,Control,BIBW 2992,20 mg/kg,24h,48h,72h,96h,CY,5.5,- Annexin V imaging,Low,High,0,250,500,750,1000,1250,0,10,20,30,40,Days,Tumour Volume (mm),3,control,20 mg/kg BIBW 2992,Treatment,Gastric Cancer,NCI,-,N87,0,50,100,150,200,24,48,72,96,Hours,Photon CPS (1x1E6),Control,BIBW 2992,N=5/group,*P4000,EGFR,Reversible,Erlotinib,110,40,4000,EGFR,Reversible,Lapatinib,534,63,4000,EGFR/HER2,Reversible,CP 714,