晚期NSCLC经典试验.ppt

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,晚期非小细胞肺癌重要临床研究,晚期非小细胞肺癌过去的治疗模式,(1990s),Good PS,Poor PS,单药化疗,含铂双药化疗,一线化疗结束后,Clinical(PS),疾病进展,观察和等待,二线化疗或,BSC,1L,1LM,2L,观察和等待,非小细胞肺癌治疗领域,重要的临床研究,2009,2010,SATURN,1,线维持：厄洛替尼,vs安慰剂,2005,BR.21,厄洛替尼,vs,安慰剂,2006,2008,JMDB,1,线：,CPem vs CG,IPASS,1,线,EGFR,突变型：吉非替尼,vs CP,2000,化疗,1,E4599,1,线：贝伐,+CP,2011,2012,JMEN,1,线维持：,培美曲塞,vs,安慰剂,OPTIMAL,1,线,EGFR,突变型：厄洛替尼,vs CG,一线,ALK,突变型：,克唑替尼,Paramount,1,线维持：培美曲塞,JMEI 2-3,线：,培美曲塞,vs,多西,AVEPEAL,1,线维持培美曲塞,+,贝伐,一线治疗,维持治疗,2-3,线治疗,NSCLC,一线治疗,非小细胞肺癌发展的迅猛趋势,个体化治疗,Ding,Nature,2008,EGFR TKI,ALK TKI,肺腺癌中，体细胞突变对信号转导通路的影响，已证实为肿瘤发生重要驱动途径和治疗靶点,针对基因靶点的靶向药物已取得惊人疗效并迅速成为相应类型肺癌的标准治疗,取材,基因,检测,应用,相应,靶向,药物,个体化治疗趋势,增殖,侵袭,转移,血管形成,抵抗凋亡,配体,:EGF,TGF-,a,等,细胞核,基因转录,细胞周期进程进展,ATP,ATP,PI3K,Akt,STAT,MEK,EGFR-TK,RAF,RAS,P,PTEN,促进增殖,凋亡逃逸,永生化,TKI,抑制,EGFR,的信号通路,mTOR,ERK,EGFR TKI,IPASS,研究设计,吉非替尼,(250 mg/,天,),卡铂,(AUC 5,或,6)/,紫杉醇,(200,mg/m,2,)3,周,#,1:1,随机入组,*,不吸烟：吸烟数目,1,显示吉非替尼组较,C/P,组缓解率更高,71.2%,47.3%,1.1%,23.5%,有突变,无突变,IPASS,：,EGFR,突变阳性与阴性患者的,PFS,EGFR,突变阳性,EGFR,突变阴性,治疗,-,治疗,交互检验,p0.0001,HR(95%CI)=,0.48,(0.,36,0.64)p0.0001,吉非替尼事件数,97(73.5%)C/P,事件数,111(86.0%),吉非替尼,(n=132),卡铂/紫杉醇,(n=129),ITT,人群,HR(95%CI)=,2.85,(2.05,3.98,)p0.0001,吉非替尼事件数,88(96.7%)C/P,事件数,70(82.4%),132,71,31,11,3,0,129,37,7,2,1,0,108,103,0,4,8,12,16,20,24,吉非替尼,C/P,0.0,0.2,0.4,0.6,0.8,1.0,Probability of progression-free survival,患者数,:,91,4,2,1,0,0,85,14,1,0,0,0,21,58,0,4,8,12,16,20,24,0.0,0.2,0.4,0.6,0.8,1.0,Probability of progression-free survival,吉非替尼,(n=91),卡铂/紫杉醇,(n=85),月,月,Mok NEJM 2009,OPTIMAL:,研究设计,厄洛替尼,150mg/day,未用过化疗,IIIB/IV,期,NSCLC,EGFR,突变,+(19,外显子缺失或,21,外显子,L858R,突变,),ECOG PS 02,(n=165),吉西他滨,(1000 mg/m,2,d1,8),卡铂,(AUC5 d1),q 3 wks,up to 4 cycles,R,ECOG=Eastern Cooperative Oncology Group;PS=performance status;HRQoL=health-related quality of life;FACT-L=Functional Assessment of Cancer Therapy-Lung;LCSS=lung cancer symptom scale,1:1,主要终点,无进展生存期,(PFS),分层因素,突变类型,组织学,吸烟状态,次要终点,总生存,(OS),客观缓解率,至疾病进展时间,缓解期,安全性,HRQoL(FACT-L,LCSS),探索性生物标记物分析,OPTIMAL:,肿瘤最佳缓解率,Erlotinib,n=82,n(%),Gem/carbo,n72,n(%),CR,2(2),0(0),PR,66(81),26(36),SD,11(13),33(46),PD,3(4),12(17),NE,0(0),1(1),ORR,68(83),26(36),p=0.0000,DCR,79(96),59(82),p=0.002,OPTIMAL:,生存期,(Aug.16,th,),PFS probability,1.0,0.8,0.6,0.4,0.2,0,Erlotinib(n=82),Gem/carbo(n=72),HR=0.16(0.100.26),Log-rank p0.0001,Time(months),0510152025,Patients at risk,Erlotinib 8270512020,GC 72264000,13.1,4.6,1-ys 56.9%,1-ys 1.7%,OPTIMAL,:PFS,亚组分析,总体,既往未治疗,IV,期,IIIB,期,女性,男性,65,岁,1600,例，晚期,NSCLC,一线治疗的前瞻性、随机、双盲、全球多中心的,III,期研究,Giorgio,et al.,JCO,.200,8,;,July,:,3543,-55,1,.,随,机,分,组,培美曲塞,(n=862),500 mg/m,2,IV,每,3,周,+,顺铂,75 mg/m,2,第,1,天,吉西他滨,(n=863),1250 mg/m2,第,1,、,8,天,+,顺铂,75 mg/m,2,第,1,天,随机因素,ECOG PS,分期,脑转移史,性别,病理学类型,(,组织学,Vs.,细胞学,),主要终点：,OS,非劣效,OS and PFS,整体人群培美曲塞,/,顺铂的,OS,和,PFS,与吉西他滨,/,顺铂相近,培美曲塞,/,顺铂对非鳞癌患者的疗效更佳,Giorgio,et al.,JCO,.200,8,;,July,:,3543,-55,1,.,培美曲塞,/,顺铂对非鳞癌患者的疗效更佳,贝伐单抗的作用机制,1.Baluk,et al.Curr Opin Genet Dev 2005;2.Willett,et al.Nat Med 2004;3.OConnor,et al.Clin Cancer Res 2009;4.Hurwitz,et al.NEJM 2004;5.Sandler,et al.NEJM 2006 6.Escudier,etal.Lancet 2007;7.Miller,et al.NEJM 2007;8.Mabuchi,et al.Clin Cancer Res 2008;9.Wild,et al.Int J Cancer 2004;10.Gerber,Ferrara.Cancer Res 2005 11.Prager,et al.Mol Oncol 2010;12.Yanagisawa,et al.Anti-Cancer Drugs 2010;13.Dickson,et al.Clin Cancer Res 2007;14.Hu,et al.Am J Pathol 20021,5.Ribeiro,et al.Respirology 2009;16.Watanabe,et al.Hum Gene Ther 2009;17.Mesiano,et al.Am J Pathol 1998;18.Bellati,et al.Invest New Drugs 2010 19.Huynh,et al.JHepatol 2008;20.Ninomiya,et al.J Surg Res2009,肿瘤血管退化,抑制新生血管形成,Consistently increased response rates,47,Continuous control of tumour growth,810,Reduction of ascites and effusions,2,3,11,1420,现存血管通透性正常化,贝伐珠单抗的,III,期临床研究,E4599,主要研究终点,:OS,其他研究终点,:PFS,ORR,耐受性等,Sandler et al.NEJM 2006,*,不允许交叉,未经治疗的复发性,/,IIIb/IV,期 非鳞型,NSCLC(n=878),CP*,6(n=444),贝伐珠单抗,(15mg/kg),每,3,周,+CP,6(n=434),PD,*,PD,贝伐珠单抗维持,15 mg/kg q3w,*CP:,卡铂,AUC=6 mg/ml/min,紫杉醇,200 mg/m,2,d1,q3w,ECOG 4599:,开放性,/,多中心,/,随机对照,/III,期临床研究,(,美国，,2001-2005),Sandler,et al.NEJM 2006,1.0,0.8,0.6,0.4,0.2,0,06121824303642,生存期,(,月,),总生存率,HR=0.79,p=0.003(95%CI:0.67,0.92),10.3,12.3,贝伐珠单抗,+,卡铂,/,紫杉醇,(n=417;305,个事件,),卡铂,/,紫杉醇,(n=433;344,个事件,),E4599,：总体人群,OS,首,次延长至超过一年,Sandler,et al.NEJM 2006,E4599,：总体人群,ORR,显著提高,缓解率提高一倍以上,P0.001,反应率,生存期,(,月,),OS,概率,1.0,0.8,0.6,0.4,0.2,0,0612182430364248,Avastin+CP(n=300),CP(n=302),10.3,14.2,OS,长达,14.2,个月,死亡风险下降达,31%,Sandler,et al.JTO 2008,腺癌亚组,的,OS,为目前最长,贝伐珠单抗化疗或培美曲塞联合顺铂成为,EGFR,突变阴性或未知的患者标准一线治疗选择,总 结,个体化治疗大势所趋，,NCCN,指南强烈推荐厄洛替尼是,EGFR,突变,阳性,患者的一线标准治疗,，克唑替尼是,ALK,突变阳性患者的标准治疗,对,EGFR,突变阴性或未知患者的一线治疗，化疗仍是首选,培美曲塞具有高效低毒的特点，成为新一代的化疗药物。抗血管生成药物，贝伐单抗联合化疗，也是新的标准一线疗法。为基因突变状态未知,/,阴性的患者带来新的生存获益,NSCLC,维持治疗,既往,NSCLC,治疗的模式,由于蓄积毒性，患者只能接受有限的化疗周期,ASCO,指南推荐，对疗效为,SD,或更好的患者进行定期随访直到疾病进展，即采用“观察并等待”的策略,1,确诊,CR/PR/SD,一线治疗,含铂两药化疗,(46,周期,),观察并等待,PD,二线或后续治疗,PD,1,Pfister DG,et al.J Clin Oncol 2004;22:33053,IIIb/IV NSCLC,n=562,Off Study,n=245,Fidias,：多西他赛维持治疗,Randomised,Treated,ORR 29%,Fidias et al,J Clin Oncol 2008,GC phase,n=552,(388 received 4 cycles),SD,PR,CR,n=307,延迟,n=154,延迟多西他赛治疗,n=91,立即多西他赛治疗,n=142,立即,n=153,Fidias,：,多西他赛维持治疗,Fidias,etal.JCO2009,立即多西他,赛,(n=153),延迟多西他,赛,(n=156),1.0,0.8,0.6,0.4,0.2,0,疾病进展率,时间,(,月,),0 6 12 18 24 30 364248,HR=0.71(0.550.92),Log-rank p=0.0001,Immediate,(n=153),Delayed,(n=154),p-Value,Median PFS months,(95%CI),6.5,(4.4,7.2),2.8,(2.6,3.4),0.0001,12-month PFS,%,(95%CI),20%,(13,26),9%,(5,14),如何进行维持治疗,?,Stinchcombe,et al.JTO 2007;,NCCN guidelines v2,2010,有效或疾病稳定的患者,继续,停止铂类,继续治疗,S,witch,换药治疗,维持治疗,46,周期含铂双药一线化疗,2:1,Non-PD,n,=539,培美曲塞,500 mg/m,2,+,顺铂,75 mg/m,2,d1 q3w,x4,个周期,安慰剂,(n=180),PD,培美曲塞,500 mg/m,2,d1 q3w,(n=359),PD,未经过化疗,IIIB/IV NSCLC,非鳞癌,ECOG PS 01,(n=939),PARAMOUNT;S124;NCT00789373,进展性,NSCLC,一线维持治疗,随机、双盲、安慰剂对照,III,期研究,主要终点,PFS,次要终点,OS,ORR,EQ-5D,Resource utilisation,Safety,201,2,年,ASCO,报道,PARAMOUNT,研究,Luis,et,al,2012,ASCO,oral abstract session,7507#,同药维持,PARAMOUNT:Final OS from Induction,Survival Probability,Time from Induction(Months),0 3 6 9 12 15 18 21 24 27 30 33 36,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0.0,Pemetrexed Median OS=16.9 mos(95%CI:15.819.0),Placebo Median OS=14.0 mos(95%CI:12.915.5),Log-rank,P,=0.0191,HR=0.78(95%CI:0.640.96),Luis,et,al,2012,ASCO,oral abstract session,7507#,AVAPERL,“AVAPERL(MO22089):Final efficacy outcomes for patients with advanced nonsquamous nonsmall cell lung cancer randomized to continuation maintenance with bevacizumab or bevacizumab+pemetrexed after first-line bevacizumab-cisplatin+pemetrexed treatment”,Barlesi,et al.EMCC 2011,同药维持,研究设计,主要终点,PFS,次要终点,OS,ORR,缓解持续时间,生活质量,安全性,主要排除标准,肿瘤主体为鳞癌,咯血,(1/2,汤匙 鲜血,),肿瘤侵犯或靠近大血管,抗凝治疗,明确心血管疾病,未控制的高血压,一线治疗,IIIB,或,IV,期,非鳞癌,(n=376),贝伐珠单抗,7.5mg/kg+,培美曲塞,q3w,贝伐珠单抗,7.5mg/kg q3w,贝伐珠单抗,7.5mg/kg q3w+,顺铂,75mg/m,2,+,培美曲塞,500mg/m,2,x4,PD,2009,开始,R,1,1,Barlesi,et al.EMCC 2011,Ahn,et al.EMCC 2011,OS,结果（自诱导治疗开始）,OS estimate,1.0,036912151821,Time(months),贝伐,+,培美,未达到,贝伐,15.7,个月,HR=0.75(0.471.20);p=0.23,贝伐,+,培美 双药维持,(n=128),贝伐 单药维持,(n=125),Barlesi,et al.EMCC 2011,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,15.7,PF,S,结果（自诱导治疗开始）,Barlesi,et al.EMCC 2011,PFS estimate,1.0,0369121518,Time(months),0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,6.6,10.2,贝伐,+,培美,10.2,个月,贝伐,6.6,个月HR=0.50(0.370.69);p2%),Ahn,et al.EMCC 2011,贝伐组,(n=120),贝伐,+,培美组,(n=125),Adverse event(%),任何时间,维持阶段,任何时间,维持阶段,任何不良反应,45.0,21.7,56.0,37.6,中性粒细胞减少,10.0,0,9.6,5.6,高血压,6.7,2.5,16.0,4.8,肺出血,2.5,1.7,1.6,0.8,呼吸困难,2.5,2.5,2.4,1.6,贫血,0.8,0,4.0,3.2,腹泻,0.8,0,2.4,1.6,乏力,2.5,1.7,3.2,2.4,高血糖,1.7,0.8,2.4,1.6,AVAPERL,结论,研究达到了主要终点,贝伐,+,顺铂,+,培美诱导治疗后，贝伐,+,培美维持治疗，,PFS,达到,10.2,个月（对比单贝伐维持,;p0.001,）,两种方案耐受性均良好,不良反应多见于双药维持组，毒性的不同主要来自于化疗药物,1:1,未化疗过的 进展性,NSCLC,n,=,1,949,非,PD,n,=889,4,个疗程含铂两联一线化疗*,安慰剂,PD,厄洛替尼,150mg/day,PD,Mandatory,肿瘤,sampling,次级 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,;QoLCappuzzo,et al.ASCO 2009,*,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-,初级 终点,:,所有患者,PFS,EGFR IHC+,患者,PFS,SATURN,研究设计,换药维持,特罗凯维持治疗,PFS,和,OS,PFS probability,Time(weeks),081624324048566472808896,Time(weeks),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,厄洛替尼,(n=437),安慰剂,(n=447),厄洛替尼,(n=438),安慰剂,(n=451),OS probability,Capuzzo et al Lancet Oncol 2010,SD,患者,生存获益更多,OS probability,1.0,0.8,0.6,0.4,0.2,0,0369121518212427303336,Time(months),9.6,11.9,1.0,0.8,0.6,0.4,0.2,0,0369121518212427303336,Time(months),12.0,12.5,Log-rank p=0.0019,HR=0.72(0.590.89),厄洛替尼,(n=252),安慰剂,(n=235),Log-rank p=0.6181,HR=0.94(0.741.20),厄洛替尼,(n=184),安慰剂,(n=210),SD,CR/PR,OS is measured from time of randomisationinto the maintenance phase,F.Hoffmann-La Roche,data on file,SD,患者无论组织学类型总生存均有获益,鳞癌,10,0.8,0.6,0.4,0.2,0,0369121518212427303336,Time(months),10.6,13.7,HR=0.76(0.591.00),Log-rank p=0.0457,Tarceva(n=155),Placebo(n=142),非鳞癌,HR=0.67(0.480.92),Log-rank p=0.0116,厄洛替尼,(n=97),安慰剂,(n=93),OS probability,1.0,0.8,0.6,0.4,0.2,0,0369121518212427303336,Time(months),8.3,11.3,F.Hoffmann-La Roche,data on file,SD,患者无论突变状态总生存均有获益,Log-rank p=0.2285,22.1,1.0,0.8,0.6,0.4,0.2,0,0369121518212427303336,Time(months),HR=0.48(0.141.62),F.Hoffmann-La Roche,data on file,野生型,OS,突变,OS,OS probability,Time(months),0369121518212427303336,1.0,0.8,0.6,0.4,0.2,0,8.7,12.4,HR=0.65(0.480.87),Log-rank p=0.0041,厄洛替尼,(n97),安慰剂,(n=93),厄洛替尼,(n=97),安慰剂,(n=93),JMEN,：培美曲塞维持,治疗,Stage IIIB/IV NSCLC,PS 0-1,4,周期含铂化疗,CR/PR/SD,随机因素,:,性别,PS,评分,分期,反应率,non-platinum induction drug,脑转移,2:1,R,培美曲塞,500mg/m,2,(,d1,q21d)+BSC(n=441)*,主要终点：,PFS,安慰剂,(,d1,q21d)+BSC(n=222)*,*B,12,folate,and dexamethasone given in both arms,Ciuleanu et al Lancet 2009,换药维持,Non-squamous,Time(months),PFS probability,0 3 6 9 12 15 18 21 24,1.0,0.8,0.6,0.4,0.2,0.0,培美曲塞,安慰剂,HR=0.47(0.37,0.6),Log-rank p0.00001,4.4,1.8,Ciuleanu et al Lancet 2009,JMEN,：培美曲塞维持治疗,两类维持药物治疗的本身差别,细胞毒药物化疗,静注,疾病控制,Qol,改善有限,骨髓抑制,维持治疗,EGFR TKIs,靶向治疗,口服,肿瘤继续缩小,Qol,改善明显,皮疹、腹泻,毒性,NCCN,指南的推荐治疗,NSCLC 2-3,线治疗,Survival probability(%),Time(months),100,75,50,25,0,051015202530,HR=0.73(0.600.87),p=0.001,特罗凯组较安慰剂组相对降低,27,死亡风险,特罗凯组提高了,42.5%,的中位生存率,特罗凯,(n=488),安慰剂,(n=243),Median OS(months),6.7,4.7,BR.21,研究：,OS,Shepherd,et al.NEJM 2005;Tarceva SPC,BR-21:,厄洛替尼,vs,安慰剂,Sheppherd NEJM 2005,Zhu JCO 2008,100,80,60,40,20,0,0612182430,months,Patients(%),No.at Risk,Placebo24310750900,Erlotibib4882551452340,P0.001 by stratified log-rank test,HR,0.70(95%CI,0.58-0.85),安慰剂,厄洛替尼,Overall Survival,100,80,60,40,20,0,0612182430,months,Patients(%),No.at Risk,Placebo243203000,Erlotibib48811527210,P0.001 by stratified log-rank test,HR,0.61(95%CI,0.51-0.74),安慰剂,厄洛替尼,Progression-free Survival,RR 7%,100,80,60,40,20,0,06121824,months,Patients(%),No.of patients,Placebo55221260,Erlotibib115653691,Mdeian95%CI,厄洛替尼,7.9(5.7-10.4),安慰剂,3.3(2.5-6.8),EGFR Wild Type,100,80,60,40,20,0,06121824,months,Patients(%),No.of patients,Placebo1910510,Erlotibib1510711,Exon 19 or 21 Mutations,HR=0.74(0.52-1.05),P=0.0924,Mdeian95%CI,厄洛替尼,10.95.0-inf.,安慰剂,8.3(3.3-11.1),HR=0.55(0.25-1.19),P=0.1217,二线：,JMEI,培美曲塞对照多西他赛的随机,III,期研究,既往接受过化疗的局部晚期或转移性,NSCLC,患者,分层因素,ECOG PS 0/1 vs 2,III,期,vs IV,期,既往化疗最佳疗效,自最后化疗的时间,既往铂类方案,既往紫杉类方案,高半胱氨酸水平,研究中心,主要终点：,OS,随机分组,培美曲塞,500 mg/m,2,IV q21d(n=283),(,叶酸,350-1000 g qd+,维生素,B,12,1000 g q 9wk+,地塞米松,4 mg bid on d-1,d0,d+1),多西他赛,75 mg/m,2,iv q21d(n=288),(,地塞米松,8 mg bid on,d-1,d0,d+1),Hanna et al.J Clin Oncol 2004;22:1589-1597.,JMEI,结果,Hanna N et al.J Clin Oncol 2004,总体人群数据,Pem,Txt,ORR%,9.1,8.8mPFS(m),2.9,2.9,1-ysOS%,（主要终点）,29.7,29.7,MST(m)median survival time,8.3,7.9,随机入组接受治疗的患者,毒性反应,培美曲塞,(n=265),多烯紫杉醇,(n=276),p-value,中性粒细胞减少,5.3,40.2,.001,贫血,血小板减少,肌酐,AST,ALT,7.5,1.9,0,1.1,2.6,6.2,0.7,0,0.4,0.4,0.610,0.277,1.0,0.364,.034,ID:59,Version:,Content Owner:,Modified by:;,Date:,JMEI,的不良反应,NCCN,指南推荐的二线治疗：根据,PS,评分选择治疗,二线治疗：,PS0-2,：多西他赛或培美曲塞或厄洛替尼或化疗,+,贝伐,PS3-4,：厄洛替尼或,BSC,非鳞癌,鳞癌,含铂双药,+,贝伐单抗,含铂双药,含铂双药,一线化疗结束后,CR/PR/SD,贝伐单抗,(+,特罗凯,或 培美曲塞,),特罗凯或培美曲塞,特罗凯,贝伐单抗适用,贝伐单抗不适用,组织学类型,疾病进展,突变型,EGFR TKI,化疗,EGFR,突变检测,1L,1LM,2L,野生型,/,未知,Poor PS,单药化疗,或特罗凯,特罗凯,(,如之前未用过,),特罗凯或培美曲塞或多西他赛（如之前未用过）,Good PS,晚期非小细胞肺癌的目前治疗模式,Adapted from Gandara,et al.Clin Lung Cancer 2009,谢 谢,