NSCLC临床研究功与过.ppt

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1、,徐文2011-08-07张家界,NSCLC临床研究功与过,交流内容,回顾二线治疗细看一线治疗浅析维持治疗,二线NSCLC治疗,2000,化疗,靶向治疗,TAX317多西紫杉醇,TAX320多西紫杉醇,JMEI培美曲塞,ISEL吉非替尼,BR.21特罗凯,TITAN特罗凯,2004,2005,2011,TRUST特罗凯,2009,1997年ASCO对于晚期NSCLC二线治疗指南中的观点,“there is no current evidence that either confirm or refutes that second-line chemotherapy improves survi

2、val inpatients with advanced NSCLC.”,TAX317：多西他赛确立二线治疗地位,1.00.80.60.40.20,036912151821,Shepherd,et al.JCO 2000,*75mg/m2 control group,p=0.01,中位生存期,不良反应,疗效优于BSC，但不良反应严重,概率,时间(月),全组;(3/4组)NA=不提供,JMEI：培美曲塞二线治疗结果与不良反应,Hanna,et al.JCO 2004,1.000.750.500.250,HR=0.99(0.8,1.2),02.55.07.510.012.515.017.520.0

3、22.5,培美曲塞多西他赛,中位生存期,不良反应,OS概率,时间(月),*3/4组NA=不提供,靶向治疗经典研究：BR.21研究与ISEL研究,Thatcher N,et al.Lancet 2005;366:15271537.Shepherd F,et al.N Engl J Med 2005;353:123132.,*,*预先设置腺癌亚组,复治晚期NSCLC的生存比较*,Shepherd,et al.NEJM 2005;OSI and Roche data on fileThatcher,et al.Lancet 2005;Douillard,et al.WCLC 2007Shepherd

4、,et al.JCO 2000;Fossella,et al.JCO 2000Hanna,et al.JCO 2004;Cullen,et al.Ann Oncol 2008,1-year survival rate(%),Tarceva,Docetaxel,Gefitinib,Pemetrexed,Median OS(months),Median OS(minimum reported value),1-year survival rate(minimum reported value),0,1,2,3,4,5,6,7,8,9,0,5,10,15,20,25,30,35,40,Tarceva

5、,Docetaxel,Gefitinib,Pemetrexed,6.7,9,9,9,9,9,5.6,5.7,7.5,29.7%,31%,27%,37%,特罗凯或许比化疗生存改善更具优势,TRUST特罗凯的里程碑,2004,TRUST全球和TRUST亚裔研究报告全球发表,患者入组,2007,2010,全球注册,TRUST德国报告全球发表,2008,2011,ASCO PostWCLC Oral,TRUST研究:亚裔和中国患者0S获益更多,OS概率,月,1Shepherd,et al.NEJM 2005；2Reck,et al.JTO 2010;3Mok,et al.JTO 2010；4Data

6、on File,例数,OS,TITAN研究设计:直接与化疗对照快速进展的患者,Primary endpoint:OSSecondary endpoints:PFS,RR,QoL(FACT-L),correlation of biomarkers with clinical outcome,Chemotherapy nave stage IIIb/IV NSCLC,PD,4 cycles of first-line standard platinum-based doublet,SATURN,Non-PD,Pemetrexed or docetaxel,PD,Off study,Tumour s

7、amples,Erlotinib150mg/day,PD,Off study,Ciuleanu T,et al.Chicago Multidisciplinary Symposium in Thoracic Oncology,Dec 2010(Abs.LBOA5),TITAN研究总生存期和野性型亚组的结果分析,二线治疗总结,虽然没有一个药物能在二线治疗中显示较大优势，但亚裔人群对TKI的敏感程度优于化疗在亚裔人群的作用。毒副作用TKI领先与化疗。特罗凯在二线的地位已经巩固，目前所有新药研究都以当前的最好的药物最比较，从这点可以看出，特罗凯在挽救治疗中疗效领先的作用。,一线治疗,化疗,靶向治疗,

8、Prior to2000,VinorelbineCisplatin Carboplatin,2004,四架马车ECOG1594,2002,突变发现,Aug20,31 2009NEJM,Spain RosellIPASS Mok,2011,OPTIMALEURTAC,*Label does not include NSCLC-specific indication.,First-lineSecond-lineThird-lineNot approved,1970,1980,1990,2000,Medianoverallsurvival,months,12+,8-10,6,2-4,最佳支持治疗,铂

9、类单药化疗,双药联合化疗,化疗靶向治疗,Carboplatin*1989,ErlotinibPemetrexed2004,泰索帝二线1999,PaclitaxelGemcitabine 1998,Vinorelbine1994,泰索帝一线2003,Bevacizumab2006,Gefitinib2003,Food and Drug Administration.Available at http:/.Accessed August 28,2006.;National Comprehensive Cancer Network(NCCN).Practice Guidelines in Oncol

10、ogy.Non-small cell lung cancer v1.2007.Accessed August 15,2007.Schrump et al.Non-small cell lung cancer.In:Cancer:Principles and Practice of Oncology.7th ed.Philadelphia,PA:Lippincott Williams 2005.,晚期非小细胞肺癌治疗史,Cisplatin*1978,1.00.80.60.40.20,051015202530,Months,Cisplatin/paclitaxelCisplatin/gemcita

11、bineCisplatin/docetaxelCarboplatin/paclitaxel,Survival distribution function,Schiller JH,et al.N Engl J Med 2002;346:9284599,一线治疗的随机临床 新药联合铂剂,即便使用了多种第三代联合化疗方案，大多数患者仍处于盲目的“陪绑”化疗状态有效者的生存期不能突破一年,储大同 当代肿瘤内科治疗方案评价第三版,2004 EGFR Mutation Discovery,Lynch NEJM 2004,The height of the hurdle depends onthe meth

12、odology,sequencing only performed in single,highly specialized labshigh turnaround time&cost-intensivePCR as potential alternative,Mutations,available&routine in some,but few,reference labstakes 2-4 dCISH as potential alternative,FISH,IHC,available&routine in all pathology labsquick&inexpensive,临床检测

13、指标,2009年8月两篇新英格兰关于突变的文章,吉非替尼,特罗凯,西班牙研究:带给我们经典的PFS和OS,Median PFS=14 months,1.00.80.60.40.20,Probability,01020304050,Time(months),Median OS=27 months,1.00.80.60.40.20,Probability,01020304050,Time(months),Patients(%),1007550250,SD,PR,CR,PD,DCR90%,Best response,RR70.6%,SLCG=Spanish Lung Cancer GroupRR=r

14、esponse rate;MUT+=mutation positiveCR=complete response;PR=partial responseSD=stable disease;PD=progressive diseaseDCR=CR+PR+SD;TTP=time to progression,Rosell,et al.NEJM 2009,PFS,OS,IPASS研究设计,*不吸烟指100支烟；少吸烟指戒烟15年和吸烟10包年*最大6个周期吉非替尼进展的患者给予卡铂/紫杉醇治疗,IPASS：EGFR突变与无进展生存期,ITT人群含共变量的Cox分析,通过亚组进行治疗的交互检验,p0.0

15、001,HR(95%CI)=0.48(0.36,0.64)p0.0001吉非替尼组事件数,97(73.5%)C/P组事件数,111(86.0%),Mok et al NEJM 361:947 2009,(n=132),缓解率(%),EGFR突变阳性:Odds ratio(95%CI)=2.75(1.65,4.60),p=0.0001EGFR突变阴性:Odds ratio(95%CI)=0.04(0.01,0.27),p=0.0013,(n=129),(n=85),(n=91),突变阳性与阴性患者的缓解率,欧洲：2009年批准易瑞沙用于EGFR TK基因具有敏感突变的局部晚期或转移性NSCLC患

16、者的治疗,吉非替尼现已在全世界60多个国家批准上市,但美国没有上市,次要研究终点OSORR至疾病进展事件(TTP)反应持续时间健康相关QoL(HRQoL)探索性生物标志物分析,特罗凯 150mg/天,卡铂(AUC5 d1)+吉西他滨(1000 mg/m2 d1,8)q3w,最多4个周期,未接受过化疗IIIB/IV期NSCLCEGFR活化型突变(外显子19缺失或外显子21的L858R突变)ECOG PS 02(n=165),R,1:1,OPTIMAL;NCT00874419,分层因素突变类型组织学类型吸烟状态,Zhou C et al.J Clin Oncol 2011;29(suppl):ab

17、stract 7520.Zhou C et al.WCLC 2011.,OPTIMAL研究设计,一线晚期NSCLC治疗III期、随机、开放、阳性对照试验主要研究终点PFS,无进展生存概率,1.00.80.60.40.20,051015202530,事件(月),Patients at risk特罗凯 82705129820G/C722641000,HR=0.164(95%CI:0.1050.256)Log-rank p0.0001,特罗凯G/C,13.7,4.6,OPTIMAL结果：PFS,Zhou C et al.J Clin Oncol 2011;29(suppl):abstract 752

18、0.Zhou C et al.WCLC 2011.,EGFR突变型NSCLC一线治疗研究的PFS,特罗凯,吉非替尼,Median PFS(months),SLCG,CALGB30406,OPTIMAL,IPASS,First-SIGNAL,WJTOG3405,NEJSG002,WJTOG3405:stage IIIB/IV pts(median PFS in overall population=9.2 vs 6.3 mos),EURTAC(26 Jan 11),EURTAC(26 Jan 11),IPASS,First-SIGNAL,WJTOG3405,OPTIMAL,NEJSG002,化疗

19、,FIELT,1614121086420,特罗凯一线突变PFS大致13.5月,Rosell et al.ASCO 2011;De Greve et al.ASCO 2011;Rosell,et al.NEJM 2009;Jnne,et al.ASCO 2010;Zhou,et al.ASCO 2011;Mok,et al.NEJM 2009;Lee,et al.WCLC 2010;Mitsudomi,et al.Lancet Oncol 2010;Maemondo,et al.NEJM 2010,EGFR TKI,chemo+/-贝伐,EGFR mut+ve,EGFR mut ve or un

20、known,晚期 NSCLC,挽救治疗,PR or SD,下一步？,PD,SD=stable disease,贝伐单抗（如果患者使用化疗贝伐单抗）,观察直到进展,维持治疗,TKI维持治疗,化疗维持治疗,浅谈维持治疗,JMEN：培美曲赛维持治疗,Stage IIIB/IV NSCLCPS 0-14 prior cycles of gem,doc,or tax+cis or carb,with CR,PR,or SDRandomisation factors:genderPSstagebest tumour response to inductionnon-platinum induction d

21、rugbrain mets,2:1 Randomisation,Pemetrexed 500mg/m2(d1,q21d)+BSC(n=441)*,Primary Endpoint=PFS,Placebo(d1,q21d)+BSC(n=222)*,*B12,folate,and dexamethasone given in both arms,Ciuleanu et al Lancet 2009,Ciuleanu et al Lancet 2009,JMEN：培美曲赛维持治疗,2:1,Non-PDn=539,Pemetrexed 500 mg/m2+cisplatin 75 mg/m2,d1 q

22、3d,x4 cycles,Placebo,PD,Pemetrexed 500 mg/m2 d1 q3w,PD,ChemonaiveStage IIIB/IV NSCLCNon-squamous histologyECOG PS 01(n=939),PARAMOUNT;S124;NCT00789373,First-line maintenance advanced NSCLC Phase III,randomised,double blind,placebo-controlled Primary endpointPFS,Secondary endpointsOSORREQ-5DResource

23、utilisationSafety,Paz-Ares LG et al.J Clin Oncol 2011;29(suppl):abstract CRA7510.,2011年ASCO最新研究报道PARAMOUNT研究设计,StratificationNSCLC stagePSResponse to induction,PARAMOUNT:Investigator Assessed PFS(from Maintenance),两类维持药物治疗的差别,细胞毒药物化疗静注全身骨髓抑制累积毒性(骨髓抑制,神经毒性,肾毒性),靶向治疗口服和静注 特异性靶向作用于肿瘤细胞无骨髓抑制无累积毒性,由于累积毒性

24、治疗持续时间有限,治疗可持续更长时间 NSCLC治疗有了重新定义的机会,SATURN研究设计,Stratification factors:EGFR IHC(positive vs negativevs indeterminate)Stage(IIIB vs IV)ECOG PS(0 vs 1)CT regimen(cis/gem vs carbo/doc vs others)Smoking history(current vs former vs never)Region,Co-primary endpoints:PFS in all patientsPFS in patients with

25、 EGFR IHC+tumoursSecondary endpoints:OS in all patients and those with EGFR IHC+tumours,OS and PFS in EGFR IHC tumours;biomarker analyses;safety;time to symptom progression;quality of life,1:1,Chemonave advanced NSCLCn=1,949,Non-PDn=889,4 cycles of 1st-line platinum-based doublet*,Placebo,PD,Erlotin

26、ib150mg/day,PD,Mandatory tumour sampling,Capuzzo et al Lancet Oncol 2010,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=0.0088,1.00.80.60.40.20,1.00.80.60.40.20,OS,PFS,Erlotinib(n=4

27、37)Placebo(n=447),Erlotinib(n=438)Placebo(n=451),OS probability,Capuzzo et al Lancet Oncol 2010,无论病例类型，野生型患者特罗凯维持治疗均有获益,Squamous-cell,1.00.80.60.40.20,0369121518212427303336,Time(months),10.6,13.7,HR=0.76(0.591.00)Log-rank p=0.0457,Tarceva(n=155)Placebo(n=142),Non-squamous,HR=0.67(0.480.92)Log-rank

28、p=0.0116,Tarceva(n=97)Placebo(n=93),OS probability,1.00.80.60.40.20,0369121518212427303336,Time(months),8.3,11.3,F.Hoffmann-La Roche,data on file,Zhang L et al.J Clin Oncol 2011;29(suppl):abstract LBA7511.,INFORM;C-TONG 0804;D7913L00071;NCT00770588,INFORM研究设计,1:1,Non-PDn=296,Platinum-based doublet c

29、hemotherapy*q3d,x4 cycles,Placebo,PD,Gefitinib 250md/day,PD,ChemonaveStage IIIB/IV NSCLCWHO PS 02Chinese patients,First-line maintenance advanced NSCLCPhase III,randomised,multicenter,parallel group,placebo-controlledPrimary endpointPFS,Secondary endpointsOSORRDCRHealth-related QoLSafety,*Cisplatin

30、or carboplatin plus either gemcitabine,paclitaxel,docetaxel or vinorelbine,INFORM：PFS(ITT),Zhang L,et al.2011 ASCO Abstract 7511.,100806040200,0 8 16 24 32 40 48 56 64 72 80 88 96 104 112,PFS(%),吉非替尼安慰剂(n=25)(n=24)中位PFS,月2.71.5 事件,n(%)26(100)24(100),HR(95%CI)=0.86(0.48,1.51),EGFR野生型患者的PFS,时间(周),Zhang L,et al,2011,ASCO,Oral abstract,#LBA7511.,特罗凯优于吉非替尼，我反正信了,