NSCLC维持治疗..ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,3/11/2012,#,晚期,NSCLC,的维持治疗,-,从疗效确证到个体化选择,NSCLC,的传统治疗及其局限性,100,例,接受一线含铂,两药化疗,75,例,临床获益,(CR/PR/SD),“观察并等待”,38,例,2-3,个月,接受二线治疗,“能接受后续治疗的患者才,最有可能从治疗中获得生存,的益处,.”,Stinchcombe,and,Socinski,2009,很多患者由于症状及体,力状态的快速恶化而不,能接受更多的治疗,Stinchcombe,TE,et,al.,J,Thoracic,Oncol,2009;4:243-250.,0,2,5,50,75,100,二线治疗患者的丢失引人关注,多项研究显示，约,50%,的患者一线治疗进展后，不能接受二线治疗,维持治疗是否可在目前治疗模式基础上改善患者,OS,？,Socinski,et,al.,2002,1,Belani,et,al.,2003,2,Brodowicz,et,al.,2006,3,von,Plessen,et,al.,2006,4,Barata,et,al.,2007,5,Park,et,al.,2007,6,Ciuleanu,et,al.,2008,7,Pirker,et,al.,2008,8,Scagliotti,et,al.,2008,9,Fidias,et,al.,2009,10,接受二线治疗的患者比例,(%),维持治疗带来希望,一线治疗,含铂两药化疗,(46,周期,),观察并等待,二线或后续治疗,确诊,确诊,PD,PD,二线治疗,直到PD,PD,PD,一线治疗,含铂两药化疗,(4,6周期),CR/PR/SD,维持治疗,CR/PR/SD,Pfister,DG,et,al.,J,Clin,Oncol,2004;22:33053,维持治疗的理论基础,Goldie,和,Coldman,1,提出：早期使用非交叉耐药,的药物可以在耐药性产生前杀死更多的肿瘤细胞,1986,年,Roger,S.Day,2,提出：最有效的药物应该,用于巩固治疗以期达到最大治疗效果,1.Goldie,JH,et,al.,Cancer,Treat,Rep,1982,Mar;66(3):439-49.,2.Roger,S.Day.,Cancer,Res,1986;46:3876-3885.,1.,诱导化疗阶段可以看作为一种体内药物敏感试验，从中选出的肿瘤缓,解或疾病稳定的患者，更有可能从诱导化疗中的一种敏感药物的维持/,巩固治疗中获益,2.,诱导化疗通常采用两药联合的方案，因此对NSCLC患者，选择性地采,用一种具有单药疗效的药物进行维持化疗，理论上有可能延缓PFS,改,善疾病相关症状，并且副作用相对最小,维持治疗的种类,连续性维持治疗,(Continuation,maintenance),通常指使用一线方案中的药物维持治疗（,同药维持,）,转换性维持治疗,(Switch,maintenance),通常指使用一线方案以外的药物维持治疗（,换药维持,）,维持治疗的早期探索,一线治疗最佳持续时间的探讨,研究者,III期,Park,2007,N=314,III期,Socinski,2002,N=230,一线治疗,持续时间,PC,4,vs,6周期,PC4周期,vs,PC直至PD,ORR,(CR+PR),42.4,vs,42.6,22.3,vs,24,PFS,月,6.2,vs,4.6,P=0.001,NR,OS,月,14.9,vs15.9,P=0.461,6.6,vs,8.5,P=0.63,毒性,相似,外周神,经病变,维持治,疗组较,长,QoL,无显著性差异,延长治疗有获益趋势；,研究在亚洲进行，50%,的入组患者后续接受吉,非替尼解救治疗,无显著性差异,残留外周神经病变限制,两组中大部分患者使用,紫杉醇,ASCO,指南,NCCN,指南,推荐,4-6,周期,4-6,周期联合化疗后继续延长治疗，未显著改善生存却导致毒性累积,试验,一线,治疗,维持,治疗,ORR(%),(CR+PR),PFS,月,OS,(,月,),维持治疗阶段,3/4,毒性,反,应及其患者比例,(%),Belani,N=390,周疗Pac+月疗C；,周疗Pac+周疗C；,3/4w,X,4,周疗Pac+周疗C；,6/8w,X,2,Pac*,vs,Ob,32:,24:,18,8.9,vs,6.8,17.5,vs,14.0,至少一次毒副作用(86),3/4级毒副作用(45),Westeel,MIC,Vin,vs,BSC,Vin,53,5,vs,3,P=0.11,12.3,vs,12.3,P=0.65,白细胞减少(46)，感染,(13)贫血(9)神经病变(7),三代化疗药物的单药维持治疗,Belani,CP,et,al.,J,Clin,Oncol,2003;,21:29332939.,Westeel,V,et,al.,J,Natl,Cancer,Inst.,2005;97:499-506.,紫杉醇、长春瑞滨未显著改善,PFS,、,OS,，且毒性有所增加,*,Pac,70mg/m2,3,of,4,weeks,n=65,吉西他滨,1250,mg/m,2,D1,、,D8,；,q3w,顺铂,80,mg/m,2,2:1,吉西他滨单药维持,吉西他滨,1250,mg/m,2,D1,8,；,3,周方案,+BSC,(n=138),D1,；,q3w,诱导化疗阶段,N=352,BSC,(n=68),维持化疗阶段,N=206,TTP,RR,SD,次要终点,缓解率、缓解持续时间、总体生存期、毒性反应和症状控制,Broodowicz,T,et,al,Lung,Cancer,2006;,52:155-163.,吉西他,BSC,组,滨组,TTP,6.6,月,5.0,月,P,0.001,吉西他,BSC,组,滨组,TTP,3.6,月,2.0,月,P,80,患者的,OS,KPS80:,n=99,KPS80:,n=107,7,12.2,10,10.8,8.3,7.8,5,0,15,10,20,30,25,80,80,80,安慰剂组,HR=0,8,(95%,CI:,0.51.3),HR=0,8,(95%,CI:,0.51.3),全程,(,始于诱导,),HR=2.1,(95%,CI:1.23.8),25.3,维持,(,始于维持,),HR=2.1,(95%,CI:1.23.8),22.9,多西紫杉醇单药维持,早二线,vs.晚二线,IIIB/IV,期,既往未化疗,ECOG,PS,0-2,允许,CNS,转移,主要终点：OS,次要终点：,RR,PFS,QoL,安全性,立即组,(n=142),多西他赛,75mg/m,2,D1,q3w,，直到,PD,或最多,6,周期,延迟组,(n=91),BSC,，,PD,后多西他赛,75,mg/m,2,D1,q3w,直到,PD,或最多,6,个周期,*,CR,PR,SD,R,N=307,I:,153,D:,154,吉西他滨1000mg/m,2,，D1、8,卡铂,AUC,5，D1,q3w,x,4周期,(N=552),入组,*,每,3,个月评估肿瘤情况,Fidias,PM,et,al.,J,Clin,Oncol,2009;,27(4):591-8,立即组延迟组,PFS,5.7,月,2.7,月,P,0.0001,多西紫杉醇单药维持：显著延长,PFS,Fidias,PM,et,al.,J,Clin,Oncol,2009;,27(4):591-8,立即组延迟组,1YS,51.1%,43.5%,OS,12.3,月,9.7,月,P,0.0853,多西紫杉醇单药维持：未显著延长,OS,Fidias,PM,et,al.,J,Clin,Oncol,2009;,27(4):591-8,三代化疗药物单药维持的提示,吉西他滨、多西紫杉醇同为三代化疗药物中的较强者,且毒性较低,一个为同药维持，一个为换药维持,均获得,PFS/TTP,的延长，但未显著改善,OS,似乎两种维持策略都能行得通,但需要维持药物更有效且低毒,并希望能看到总生存期的延长,2:1,随机,使用下列一种方案诱导化疗,4,周期后达到,CR,PR,or,SD,JMEN,：培美曲塞的换药维持,培美曲塞,500,mg/m,2,+,BSC*,(d1,q21d),直至疾病进展,(N=441),*,两组患者均接受叶酸，维,生素,B,12,和地塞米松预处理,安慰剂,+,BSC*,(d1,q21d),直至疾病进展,(N=222),吉西他滨,+,铂类,紫杉醇,+,铂类,多西他赛,+,铂类,随机化因素：,性别,PS,(0/1),分期,(IIIB/IV),诱导化疗后最佳肿瘤疗效,非铂类诱导化疗药物,脑转移,Ciuleanu,T,et,al.,Lancet,.,2009;374:1432-1440.,Induction,(4,cycles),培美曲塞,+,BSC,(n=387),安慰剂,+,BSC,(n=194),4.0,2.0,中位生存期,(月),HR,(95%,CI),p-,值,0.60,(0.49-0.73),0.0001,JMEN,：培美曲塞维持显著延长,PFS,(,独立评审,),*,82,名患者因为影像学数据不充足而没有参与独立评审,Ciuleanu,T,et,al.,Lancet,.,2009;374:1432-1440.,Induction,(4,cycles),(n=441),(n=222),13.4,10.6,中位生存期,(月),HR,(95%,CI),p-,值,0.79,(0.65-0.95),0.012,JMEN,：培美曲塞维持显著延长,OS,培美曲塞,+,BSC,安慰剂,+,BSC,Ciuleanu,T,et,al.,Lancet,.,2009;374:1432-1440.,Progression-free,Probability,JMEN,对组织学类型的探讨,培美曲塞维持显著延长非鳞癌的,PFS,0,3,6,9,12,15,18,21,24,0.6,0.5,0.4,0.3,0.2,0.1,0.0,1.0,0.9,0.8,0.7,0,3,6,9,12,15,18,21,24,0.6,0.5,0.4,0.3,0.2,0.1,0.0,1.0,0.9,0.8,0.7,培美曲塞,4.4,月,安慰剂,1.8,月,培美曲塞,2.4,月,安慰剂,2.5,月,Time,(months),非,鳞,癌,培美曲塞,安慰剂,PFS(,月,),HR,P,值,4.4,1.8,0.47,(,0.37-0.6,),0.00001,鳞,癌,培美曲塞,安慰剂,PFS(月),HR,P值,2.4,2.5,1.03,(0.77-1.5),0.896,Time,(months),Ciuleanu,T,et,al.,Lancet,.,2009;374:1432-1440.,Survival,Probability,0,3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,0.5,0.4,0.3,0.2,0.1,0.0,0.7,0.6,1.0,0.9,0.8,0,3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,0.5,0.4,0.3,0.2,0.1,0.0,0.7,0.6,1.0,0.9,0.8,培美曲塞,15.5,月,培美曲塞,9.9,月,安慰剂,10.3,月,安慰剂,10.8,月,Time,(months),JMEN,对组织学类型的探讨,培美曲塞维持显著延长非鳞癌的,OS,非,鳞,癌,培美曲塞,安慰剂,OS(,月,),HR,P,值,15.5,10.3,0.70,(0.56-0.88),0.002,鳞,癌,培美曲塞,安慰剂,OS(月),HR,P值,9.9,10.8,1.,07,(,0.490.73,),0.,678,Time,(months),Ciuleanu,T,et,al.,Lancet,.,2009;374:1432-1440.,级,AEs,(%),培美曲塞,n=,441,安慰剂,n,=,222,中性粒细胞减少,贫血,白细胞减少,乏力,食欲不振,感染,腹泻,恶心,呕吐,感觉神经病变,粘膜炎,/,口腔炎,3,3,2,5,2,1,1,1,1,1,1,0,1,1,1,0,0,0,1,0,0,0,JMEN,：培美曲塞维持耐受性良好,P0.05,for,grade,3/4,rates,of,neutropenia,and,fatigue,Ciuleanu,T,et,al.,Lancet,.,2009;374:1432-1440.,2011,ASCO,PARAMOUNT,：培美曲塞的同药维持,研究的治疗阶段,疾病进展,21,to,42,天,*,CR,PR,SD,培美曲塞单药维持治疗,(,直到,PD),500,mg/m,2,培美曲塞,+,BSC,d1,q21d,2:1,随机,安慰剂,+,BSC,d1,q21d,培美曲塞,+,顺铂一线治疗,(4,个周期,),患者入组条件,:,非鳞癌的,NSCLC,既往无肺癌的系统治疗,ECOG,PS,0/1,500,mg/m,2,培美曲塞,+,75,mg/m,2,顺铂,d1,q21d,随机，双盲，安慰剂对照的,III,期研究,两组均予以叶酸和,vitamin,B12,分层因素:,PS,(0,vs,1),诱导前疾病分期(IIIB,vs,IV),诱导治疗后的疾病缓解情况(CR/PR,vs,SD),PD,主要研究终点：,PFS,次要研究终点：,OS,、,RR,、,EQ-5D,、,Aes,等,Paz-Ares,LG,et,al.,2011ASCO,Abstract,No:,CRA7510,*,维持治疗必须在第4周期诱导化疗d1之后21-42天之内开始,400,例患者未被随机分组,217,例由于疾病进展,62,例由于,AEs,56,例死亡,29,肺癌,15,不良事件,11,药物相关不良事件,1,程序相关不良事件,65,其它原因,PARAMOUNT,研究流程,共,1022,例患者进行了筛查,939,例纳入研究,539,例随机分组,(2:1,Randomization),83,例不符合被剔除,诱导阶段,维持阶段,培美曲塞组,N=359,实验截至日期时有,136,例,(38%),仍在继续接受维持治疗,548,例可以进行维持治疗,8,例患者自己决定不进行维持治疗,1,例医生决定不进行维持治疗,安慰剂组,N=180,实验截至日期时安慰剂组有,43,例,(24%),未出现进展,Paz-Ares,LG,et,al.,2011ASCO,Abstract,No:,CRA7510,Survival,Probability,研究者评估,PFS,(,从诱导阶段开始,),0,3,6,9,12,15,18,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0.0,Pem,+,BSC,Placebo,+,BSC,Pem:,median,=,6.90m,(6.2-7.5),Placebo:,median,=,5.59m,(5.5-6.0),Log,Rank,p0.00001,Unadjusted,HR,:,0.59,(0.47-0.74),Time,(Months),Patients,at,Risk,Pem,+,BSC,Placebo,+,BSC,N=359,N=180,320,157,141,51,59,14,24,5,4,0,0,0,Paz-Ares,LG,et,al.,2011ASCO,Abstract,No:,CRA7510,Survival,Probability,0,3,6,9,12,15,0.6,0.5,0.4,0.3,0.2,0.1,0.0,0.7,0.9,0.8,研究者评估,PFS,(,维持阶段开始,),1.0,Pem,+,BSC,Placebo,+,BSC,Pemetrexed:,median,=,4.1,mos,(3.2-4.6),Placebo:,median,=,2.8,mos,(2.6-3.1),Log-rank,P,=0.00006,Unadjusted,HR:,0.62,(0.49-0.79),Time,(Months),Patients,at,Risk,Pem,+,BSC,Placebo,+,BSC,N=359,N=180,132,52,57,15,21,5,4,0,0,0,Paz-Ares,LG,et,al.,2011ASCO,Abstract,No:,CRA7510,Survival,Probability,Time,(Months),0,3,6,9,12,15,0.6,0.5,0.4,0.3,0.2,0.1,0.0,0.7,1.0,0.9,0.8,Pemetrexed:,median,=,3.9,mos,(3.0-4.2),Placebo:,median,=,2.6,mos,(2.2-2.9),Log-rank,P,=0.0002,Unadjusted,HR:,0.64,(0.51-0.81),Pem,+,BSC,Placebo,+,BSC,独立评审评估,PFS,(,维持阶段开始,),88%,(472/539)的患者接受独立评审评估,Patients,at,Risk,Pem,+,BSC,Placebo,+,BSC,N=316,N=156,128,44,56,13,16,7,4,0,0,0,Paz-Ares,LG,et,al.,2011ASCO,Abstract,No:,CRA7510,PFS,的亚组分析,Favors,Pemetrexed,Favors,Placebo,Treatment,Hazard,Ratio,(95%,CI),0.0,0.2,0.4,0.6,0.8,1.0,1.2,1.4,1.6,1.8,2.0,0.62,0.62,0.55,0.48,0.74,0.67,0.53,0.41,0.70,0.74,0.49,0.69,0.34,0.70,0.50,0.64,0.39,0.62,All,Randomized,Patients,(N=539),Stage,IV,(n=489),Stage,IIIB,(n=50),Induction,Response,CR/PR,(n=242),Induction,Response,SD,(n=280),Pre-randomization,PS,1,(n=366),Pre-randomization,PS,0,(n=170),Non-smoker,(n=116),Smoker,(n=419),Male,(n=313),Female,(n=226),Age,70,(n=447),Age,70,(n=92),Age,65,(n=189),Other,Histologic,Diagnosis,(n=32),Large,Cell,Carcinoma,(n=36),Adenocarcinoma,(n=471),PFS,结果内部保持一致，各亚组均可见培美曲塞组获益,Paz-Ares,LG,et,al.,2011ASCO,Abstract,No:,CRA7510,CTCAEs,3/4,级药物相关毒性,(,随机后患者,),培美曲塞组,安慰剂组,3/4级不良事件,疲劳,*,贫血,*,中性粒细胞减少,*,白细胞减少,厌食,恶心,感觉性神经病,粘膜炎/口腔炎,ALT,(SGPT),N=359,(%),4.2,4.5,3.6,1.7,0.3,0.3,0.3,0.3,0.3,N=180,(%),0.6,0.6,0,0,0,0,0.6,0,0,*,组间有统计学显著性差异,(Fishers精确检验,P0.05),Paz-Ares,LG,et,al.,2011ASCO,Abstract,No:,CRA7510,研究结论,PARAMOUNT,研究达到了主要研究终点,培美曲塞同药维持显著延长,PFS,OS,数据将会在成熟后进行报告,第一个,证实,换药,维持和,同药,维持,同样,有效的化疗药物,同药维持治疗可最大限度的利用有效的一线药物,同药维持不存在所谓的“早二线”与“晚二线”之争,Paz-Ares,LG,et,al.,2011ASCO,Abstract,No:,CRA7510,1,Multidisciplinary,Oncology,and,Therapeutic,Innovations,Department,&,Centre,Investigation,Clinique,Aix,Marseille,Univ-Assistance,Publique,Hpitaux,de,Marseille,Marseille,France,2,Medical,Oncology,Service,La,Paz,University,Hospital,Madrid,Spain,3,SIHS,Irkutsk,Regional,Oncology,Center,Irkutsk,Russia,4,Yonsei,Cancer,Center,Yonsei,University,College,of,Medicine,Seoul,Korea,，,5,Medical,Oncology,Hospital,SS,Annunziata,Sassari,Italy,6,Lungenfachklinik,Immenhausen,Immenhausen,Germany,7,Department,of,Pulmonary,Medicine,The,University,Hospital,Linkoping,Sweden,8,Global,Medical,Affairs,F.,Hoffmann-La,Roche,Ltd.,Basel,Switzerland,9,N.N.,Blokhin,Cancer,Research,Center,of,Russia,Moscow,Russia.,Barlesi,F,et,al.,2011,ECCOAbstract,34LBA.,NSCLC,的维持治疗,AVAPERL,(MO22089):,晚期非鳞癌,NSCLC,患者一线贝伐单抗,-,顺铂联合培美曲塞,治疗后随机接受贝伐单抗或贝伐单抗联合培美曲塞,继续维持治疗的最终疗效结果,F.Barlesi,1,J.,de,Castro,2,V.,Dvornichenko,3,J-H.,Kim,4,A.,Pazzola,5,A.,Rittmeyer,6,A.,Vikstrm,7,L.,Mitchell,8,E.K.,Wong,8,V.,Gorbunova,9,AVAPERL,：研究设计,既往未治疗的,B,组,:,贝伐单抗,+,培美曲塞,a,随机、开放、,III,期研究,b,贝伐单抗剂量,=,7.5,mg/kg,培美曲塞剂量,=,500,mg/m,2,顺铂剂量,=,75,mg/m,2,贝伐单抗,b,CR/PR/SD,一线诱导,4,个周期,q3w,R,继续维持治疗,q3w,直至,PD,A,组,:,贝伐单抗,+,培美曲塞,b,+,顺铂,b,PD,随访,IIIB-IV,期,非鳞癌,NSCLC,分层因素,:,性别,吸烟状态,随机时的疗效,Barlesi,F,et,al.,2011,ECCOAbstract,34LBA.,AVAPERL:,研究终点,主要终点：,无进展生存期,(PFS),次要终点：,总生存期,(OS),客观缓解率,(ORR),(RECIST,1.0),疾病控制率,(DCR),缓解持续时间,疾病控制持续时间,安全性,(NCI,CTC,3.0),生活质量,(QLQ-C30,与,QLQ-LC13),Barlesi,F,et,al.,2011,ECCOAbstract,34LBA.,无进展生存期,(,患者,%),贝伐单抗,+,培美曲塞,10.2,个月,(81,个事件,),100,0,128,125,3,126,122,6,103,73,9,时间,(,月,),66,38,12,25,12,15,4,2,18,0,0,处危险患者,贝伐单抗,+,培美曲塞,贝伐单抗,贝伐单抗,6.6,个月,(104,个事件,),HR,0.50,(0.370.69);,P,.001,贝伐单抗,+,培美曲塞继续维持,(n=128),贝伐单抗继续维持,(n=125),50,0,a,随机患者，意向治疗人群,Barlesi,F,et,al.,2011,ECCOAbstract,34LBA.,AVAPERL:,自诱导阶段的,PFS,a,自随机之日起的无进展生存期,(,患者,%),AVAPERL:,自随机时的,PFS,a,a,ITT,人群的中位随访时间,(,排除诱导,):8.28,个月,(,贝伐单抗珠,+,培美曲塞组,),7.95,个月,(,贝伐单抗组,),贝伐单抗,+,培美曲塞,7.4,个月,(81,个事件,),贝伐单抗,3.7,个月,(104,个事件,),时间,(,月,),0,128,125,3,104,73,6,67,36,9,25,13,12,4,2,15,0,0,处危险患者,贝伐单抗,+,培美曲塞,贝伐单抗,HR,0.48,(0.350.66);,P,.001,贝伐单抗,+,培美曲塞继续维持,(n=128),贝伐单抗继续维持,(n=125),100,50,0,Barlesi,F,et,al.,2011,ECCOAbstract,34LBA.,总生存,(,患者,%),AVAPERL:,自诱导阶段的,OS,a,0,128,125,3,127,123,6,120,110,9,103,96,15,20,17,18,3,2,21,0,0,12,时间,(,月,),56,45,贝伐单抗,+,培美曲塞,贝伐单抗,未达到,(34,个事件,),15.7,月,(42,个事件,),处危险患者,贝伐单抗,+,培美曲塞,贝伐单抗,中位随访时间,:,11,个月,(,排除诱导阶段为,8,个月,).,总生存分析时出现了,30%,的事件,贝伐单抗,+,培美曲塞继续维持,(n=128),贝伐单抗继续维持,(n=125),100,HR,0.75,(0.471.20);,P,=0.23,50,a,随机患者，意向治疗人群,0,Barlesi,F,et,al.,2011,ECCOAbstract,34LBA.,维持阶段,3-5,级不良事件发生率,(%),0,0,2.5,1.7,1.7,1.7,2.5,5.6,3.2,4.8,2.4,5.6,2.4,0.8,0,AVAPERL:,维持阶段不良事件汇总,*,20,贝伐珠单抗,(n=120),贝伐珠单抗,+,培美曲塞,(n=125),Barlesi,F,et,al.,2011,ECCOAbstract,34LBA.,Barlesi,F,et,al.,2011,ECCOAbstract,34LBA.,AVAPERL:,结论,AVAPERL,研究达到了主要终点,在未经选择的非鳞癌,NSCLC,患者及所有不同亚组中，一,线顺铂,-,培美曲塞,-,贝伐单抗后以贝伐单抗,+,培美曲塞继续,维持治疗得到了,史无前例的,PFS,获益,(,10.2,月,;,HR,0.50;,P,.001),两种方案均耐受良好，但贝伐单抗,+,培美曲塞组不良事件,发生率更高,OS,数据对贝伐单抗,+,培美曲塞组有利但仍不成熟,总体上，,AVAPERL,的结果强烈地支持了贝伐单抗,+,培美曲,塞继续维持治疗非鳞癌,NSCLC,患者,非鳞癌,NSCLC,维持治疗,PFS,小结,研究,E4599,PARAMOUNT,AVAPERL,PFS,(,月,),4.5,6.2,5.6,6.9,6.6,10.2,改进方式,三代化疗药的一线,(CP),贝伐单抗的同药维持,(BCP),培美曲塞的一线,培美曲塞的同药维持,培美曲塞,+,贝伐单抗一线及贝伐同药维持,培美曲塞,+,贝伐单抗的一线及双药同药维持,提示：由于化疗药物的改进和抗血管生成药物的应用使得,PFS,提高一倍以上,非鳞癌NSCLC维持治疗策略,PFS,演进,增加培美曲塞,同药维持,6.9,月,增加贝伐单抗,一线及两药维持,10.2,月,增加贝伐单抗,一线及,贝伐,维持,6.6,月,E4599,对照组,PARAMOUNT,对照组,AVAPERL,试验组,AVAPERL,试验组,PARAMOUNT,试验组,三代化疗药物,4.5,月,培美曲塞一线,5.6,月,毒性有所增加,毒性有所增加,非鳞癌,IV,期,NSCLC,PS,0-1,脑转移患者可入组,紫杉醇,200,mg/m,2,卡铂,AUC=6,贝伐单抗,15,mg/kg,4,cycles,q3w,贝伐单抗,培美曲塞,N=1282,贝伐单抗,/,培美曲塞,随,机,化,期待中,-,-,-,（换药维持能否大幅度提高生存期？）,ECOG,5508:,培美曲塞,vs,贝伐单抗,vs,培美曲塞+贝伐单抗,入组条件,初治的晚期,NSCLC,N=1949,4,周期一线,含铂两药化疗,未,PD,N=889,150mg/D,N=438,安慰剂,N=451,PD,PD,患者必须接受,肿瘤标本检测,分层因素,EGFR,IHC,分期,ECOG,PS,CT,治疗方案,吸烟史,地域,SATURN,：厄洛替尼的维持治疗,厄洛替尼,主要终点,所有患者的,PFS,EGFR,IHC+,患者的,PFS,次要终点,所有患者的,OS,，,EGFR,IHC+,患者的,OS,，,EGFR,IHC-,患者的,OS,和,PFS,，生,物学指标，安全性，症状恶化时间，生,活质量,Cappuzzo,F,et,al.,Lancet,Oncol,2010;,11:,52129,无进展概率,厄洛替尼,安慰剂,PFS(周),12.3,11.1,HR,P,值,(,月,),SATURN,：显著延长,PFS,(ITT),0.71,(0.620.82),0.0001,（,延长,8.4,天,）,厄洛替尼,(n=437),安慰剂,(n=447),Cappuzzo,F,et,al.,Lancet,Oncol,2010;,11:,52129,生存概率,SATURN,：显著延长,OS,(ITT),厄洛替尼,(n=438),安慰剂,(n=451),(,月,),Cappuzzo,F,et,al.,Lancet,Oncol,2010;,11:,52129,厄洛替尼,安慰剂,OS,(月),12.0,11.0,HR,P,值,0.81,(0.700.95),0.0088,无进展概率,EGFR,基因突变,厄洛替尼,(n=22),安慰剂,(n=27),HR,(95%,CI),=,0.10,(0.04,0.25),Log-rank,p0.0001,(,周,),EGFR,基因野生型,厄洛替尼,(n=199),安慰剂,(n=189),HR,(95%,CI),=,0.78,(0.63,0.96),Log-rank,p=0.0185,(,周,),组间交互检验，,p70%,，不吸烟,50%,（,IPASS,人群,OS,为,18.8:17.4,，,P=0.109,）,EORTC,08021-ILCP,01/03,吉非替尼在非选择人群的维持治疗,吉非替尼,250mg/d,直至进展或毒性,不能耐受,4,个周期铂类为基础,的化疗后未进展的,晚期,NSCLC,患者,随,机,分,组,安慰剂,首要终点：,OS,次要终点：,PFS,和毒性,该研究计划入组,598,例患者，,入组,173,例后因,获益低,而提前停止入组,ASCO,2010,R.,M.,Gaafar,et,al.,Abstract,#,7518,ASCO,2010,R.,M.,Gaafar,et,al.,Abstract,#,7518.,吉非替尼组,N=87,安慰剂组,N=86,HR,95%CI,P,值,0.83,(0.60-1.15),0.61,(0.45-0.83),0.2,0.0015,mOS(,月,),mPFS(,月,),不良反应,皮疹,(%),腹泻,(%),10.9,4.1,38.5%,47,34,9.4,2.9,35.7%,13,13,EORTC,08021-ILCP,01/03,：,欧洲非选择人群的,OS,EGFR,突变状态,在维持治疗和总生存期中的作用,不同人群中疗效迥异,突变人群,优势人群（亚洲）,非选择人群（欧美）,27.7个月(NEJ,002),18.7个月(INFORM),10.9个月(EORTC),10个月(SATURN),维持治疗数据对比,说明,KPS80,OS:,25.3:12.2,试验,GEM,维持,DOC,维持,维持策略,GEM,同药维持,DOC,换药维持,患者,例数,206,307,PFS/TTP,(月),3.6:,2.0,5.7:,2.7,P值,0.001,0.0001,OS,(月),13:11,12.3:,9.7,P值,0.195,0.0853,PARAMOUNT,Alimta,同药维持,539,4.1:,2.8,0.00006,不成熟,?,非鳞癌,JMEN,Alimta,换药维持,663,4.4:,1.8,0.00001,15.5:,10.3,0.002,非鳞癌,AVAPERL,SATURN,INFORM,NEJ,002,A和B双药维持,Tarceva,换药维持,Iressa,换药维持,Iressa,同药维持,253,889,296,230,7.4:3.7,2.87:,2.59,4.8:,2.6,*10.8:5.4,0.001,0.0001,0.0001,0.001,未达,:15.7,12.0:,11.0,18.7:16.9,27.7:,26.6,0.23,0.0088,0.2608,0.483,非鳞癌,非选择人群,亚洲人群,优势人群？,突变人群,*,始于诱导治疗；,GEM,，吉西他滨；,DOC,，多西紫杉,醇,.,Ciuleanu,T,et,al.,Lancet,.,2009;374:1432-1440.,Cappuzzo,F,et,al.,Lancet,Oncol,2010;,11:,52129.,Zhang,L,et,al.,2011ASCO,Abstract,No:,LBA7511.,Broodowicz,T,et,al,Lung,Cancer,2006;,52:155-163.,Fidias,PM,et,al.,J,Clin,Oncol,2009;,27(4):591-8.,Paz-Ares,LG,et,al.,2011ASCO,Abstract,No:,CRA7510.,维持治疗可使更多患者接受有效治疗,总生存的改善获得认可，正在改变现行治疗模式,需要精确定位不同药物的优势人群以进一步改善疗效,个体化剂量调整可降低毒性，有望使难治性患者获益,总,结,法国著名雕塑家,罗丹代表作，,雕,塑界里程碑式的,作品,-,思想者,肿瘤治疗演进史是对特异、高效、低毒药物的无尽追求,而维持治疗这一新生事物，更需要对疗效,-,毒性平衡的精准,把握和驾驭才能使病人得到最大获益！,是思想与肉,体，力与美,的完美结合,心,Thank,you,