FLAURA研究解读.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,二级,三级,四级,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,二级,三级,四级,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,二级,三级,四级,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,二级,三级,四级,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,*,FLAURA研究解读,EGFR-TKI,治疗发展历程,吉非替尼,厄洛替尼,阿法替尼,奥希替尼,2003,吉非替尼,获批,(2L+),2004,厄洛替尼,FDA,获批,(2L+)EGFR,突变敏感性,2005,吉非替尼,中国获批,2L+,适应症,2005,厄洛替尼欧盟获批为,NSCLC,二线治疗,2006,厄洛替尼,中国获批,三线适应症,2009,吉非替尼欧盟获批为,EGFR,突变型,NSCLC,一线治疗,2009,厄洛替尼,中国获批,二线适应症,2011,厄洛替尼欧盟获批为,EGFR,突变型,NSCLC,一线治疗,2011,吉非替尼,中国获批,一线治疗适应症,2011,厄洛替尼,中国获批,维持治疗,适应症,2013,FDA,修改厄洛替尼标签为,EGFR,突变型,NSCLC,一线治疗,2013,阿法替尼，,FDA,获批为,EGFR,突变型,NSCLC,一线治疗,2013,阿法替尼欧盟获批为,EGFR,突变型,NSCLC,一线治疗,2017,阿法替尼,中国获批,一线治疗适应症,2017,奥希替尼中国获批为,EGFR T790M,突变型,NSCLC,二线治疗,2015,奥希替尼欧盟获批为,EGFR,突变型,NSCLC,二线治疗,2017,厄洛替尼,中国获批,一线治疗适应症,2018,奥希替尼,FDA,获为,EGFR,突变型,NSCLC,一线治疗,2018,奥希替尼欧盟获批为,EGFR,突变型,NSCLC,一线治疗,1997,EGFR-TKIs,进入临床发展阶段,2015,吉非替尼再次,FDA,获批为,EGFR,突变,NSCLC,一线治疗,2015,奥希替尼,FDA,获批为EGFR T790M,突变型,NSCLC,二线治疗,2013,2015,2011,2009,2006,2005,2004,2003,1997,2017,2018,Herbst RS,et al.,Nature 2018 01;553(7689):446-454.,2019,2019,奥希替尼中国获批一线治疗适应症,2,EGFR-TKI,已经成为,EGFRm,晚期,NSCLC,的一线标准治疗,Herbst RS,et al.,Nature 2018 01;553(7689):446-454.,Herbst RS,et al.,Nature 2018 01;553(7689):446-454.,3,*According to NCCN Clinical Practice Guidelines In Oncology(NCCN Guidelines,)guidelines,if an EGFR mutation is discovered during first-line therapy,planned systemic and maintenance therapy should be either completed or interrupted followed by NCCN-recommended first-line treatment options;,1,this product is not marketed in Spain.,ESMO=European Society of Medical Oncology;MCBS=ESMO-Magnitude of Clinical Benefit Scale;NCCN=National Comprehensive Cancer Network;NSCLC=non-small cell lung cancer.,1.,Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology(NCCN Guidelines,)for Non-Small Cell Lung Cancer V.7.2019.2019 National Comprehensive Cancer Network,Inc.All rights reserved.The NCCN Guidelines,and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN.To view the most recent and complete version of the NCCN Guidelines,go online to NCCN.org.The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available.,2.Planchard D,et al.,Ann Oncol,2018;29(suppl 4):iv192iv237,.,Progression,Sensitising EGFR mutation*,FIRST-LINE THERAPY,NCCN,1,Subsequent therapy,SUBSEQUENT THERAPY,ESMO,2,NCCN,及,ESMO,指南对,EGFRm,晚期,NSCLC,一线治疗选择推荐,4,IIIb,/IV,期肺腺癌,肿瘤组织,表达,EGFR,突变,(Del19,和,/,或,L858R),#,既往没有治疗晚期,/,转移性疾病,ECOG PS 0-1,分层因素,EGFR,突变类型,(,外显子,19 vs 21),脑转移（有或无）,吉非替尼,250mg PO QD,(N=159),阿法替尼,40mg PO QD,(N=160),主要终点,PFS(,盲态独立评估,),，,TTF,OS,次要终点,O,RR,，至缓解的时间和缓解持续时间，疾病控制的持续时间，肿瘤缩小，,HRQoL,，安全性,R,1:1,N=319,27.3%,16.0%,15.7%,7.3%,0.8,0.6,0.4,0.2,0.0,0,6,12,14,24,30,34,42,48,57,时间,(,月,),OS,率,1.0,51%,40%,20%,28%,48%,61%,LUX-Lung 7,：阿法替尼与吉非替尼相比总生存未见明显获益,Paz-Ares L,et al.Ann Oncol 2017;28:2707,5,ARCHER 1050,：达克替尼与吉非替尼相比总生存有获益,排除,CNS,转移,伴,EGFR,活化突变的晚期,NSCLC,针对晚期,NSCLC,无既往全身治疗,无,CNS转移,无既往,EGFR TKI,或其他,TKI,ECOG PS 0,1,分层因素,人种,(,亚裔,vs,非亚裔,),EGFR,突变类型,(,外显子,19 vs 21),吉非替尼,250mg PO QD,(N=225),达克替尼,45mg PO QD,(N=227),主要终点,PFS(,盲态独立评估,),次要终点,PFS(,研究者评估,),ORR,DCR,TTF,OS,安全性,PROs,R,1:1,N=452,0,6,12,18,24,30,36,42,时间,(,月,),0.0,0.2,0.4,0.6,0.8,1.0,PFS(%),Dacotinib,吉非替尼,OS,0,6,12,18,24,30,36,42,时间,(,月,),0.0,0.2,0.4,0.6,0.8,1.0,OS(%),48,Dacotinib,吉非替尼,PFS,Tony S.Mok et al ASCO 2018 Oral 9004,中位,PFS,延长,5.5,月,中位,OS,延长,7.3,月,6,Dacomitinib,首次减量：,30mg/,日,第二次减量：,15mg/,日,严重的不良反应导致,Dacomitinib,出现较高比例的剂量调整,吉非替尼,250mg:,每日,Abstract 9004 presented by Tony Mok at 2018 ASCO,7,大家应该也有点累了，稍作休息,大家有疑问的，可以询问和交流,8,DacomitinibTKI,未解决的疑问,01,02,03,耐药机制尚未明确,安全性及耐受性较差,Dacomitinib,对已发生,CNS,转移的患者中疗效未知,安全性和耐受性较差，,2/3,患者在使用过程中需要减量（,30mg,或,15mg,），目前尚无初始应用,30mg,可改善生存的有力证据,既往缺乏脑转移的相关数据，,ARCHER 1050,排除了,CNS,转移患者，故,Dacomitinib,在已经发生,CNS,转移的患者中疗效未知；,Dacomitinib,耐药机制尚不明确，是否与阿法替尼相似？,9,FLAURA,研究设计,纳入了稳定性脑转移患者，进展后允许交叉治疗，统计学分析采取序贯多重检验，主要终点,PFS,，,OS,为次要终点,主要终点：,PFS,（研究者评估，,RECIST 1.1),次要终点：,OS,，,ORR,，,DoR,，,DCR,，,DepOR,，安全性,探索性终点：评估奥希替尼对比标准治疗,EGFR-TKI,组的进展后结局,对于进展后由中心确认存在,T790M,突变的,SoC,组患者，后续,允许交叉,使用开放标签的奥希替尼,主要入组标准,18,岁*（日本标准为,20,岁）,WHO PS,评分,0/1,19 Del/L858R,（入组根据当地,a,或中心实验室,b,检测）,既往未经全身抗肿瘤,/EGFR-TKI,治疗,稳定的,CNS,转移,1:1,随机,d,EGFR-TKI SoC,c,;,吉非替尼,250mg p.o.qd,或,厄洛替尼,150mg p.o.qd n=277,奥希替尼,80mg,每日一次口服,n=279,分层：,突变状态,种族,RECIST 1.1,标准每,6,周评估,e,，直至进展,对后续治疗进行随访，每,6,周评估一次,PPO,和,OS,统计学分析,：使用,sequential multiple testing,，检验顺序为,PFS,OS,CNS PFS,，如前一检验无统计学差异，后续终点的显著性检验将不会进行,局晚期或转移性,NSCLC,患者（,n=556,）,Data cut-off:25 June 2019 Soria et al.N Engl J Med 2018;378:113-25,*By investigator assessment if disease progression occurred after the primary analysis data cut-off p.o.,orally;qd,once daily;RECIST 1.1,Response Evaluation Criteria In Solid Tumors version 1.1;WHO,World Health Organization,10,基线特征,Data cut-off:12 June 2017 Soria et al.N Engl J Med 2018;378:113-25,11,FLAURA,研究主要终点：奥希替尼组,PFS,达,18.9,个月,在所有亚组中奥希替尼均有显著,PFS,获益，包括亚裔、,L858R,突变、,CNS,转移亚组患者,Data cut-off:12 June 2017,1.,Soria et al.N Engl J Med 2018;378:113-25,CI,confidence interval;ctDNA,circulating tumour DNA;NC,not calculable;PH,proportional-hazards,12,即使对照组约,1/3,患者接受交叉治疗，,奥希替尼仍显示出总体人群,OS,显著获益,中位,OS,是,FLAURA,研究的次要终点，奥希替尼组达,38.6,个月,，较对照组显著降低,20%,死亡风险,Data cut-off:25 June 2019,*,Time from the date of randomisation to the earlier of the date of anti-cancer therapy start date following study drug discontinuation or death,13,次要终点,OS,的亚组分析,Data cut-off:25 June 2019,14,亚裔和非亚裔患者的,OS,K-M,曲线,亚裔非亚裔,Data cut-off:25 June 2019,0.0,奥希替尼,EGFR-TKI对照组,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0.0,奥希替尼,EGFR-TKI,对照组,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,总体生存的概率,总体生存的概率,15,仍在接受研究治疗药物的患者比例，至第一次后续治疗或死亡时间,Data cut-off:25 June 2019,*,Time from the date of randomisation to the earlier of the date of anti-cancer therapy start date following study drug discontinuation or death,279 271 255 235 212 185 166 157 136 125 112 100 90 79 57 31 90,277 249 222 195 153 123 96 76 58 45 39 35 31 28 18 10 50,0.0,0369 12 15 18 21 24 27 30 33 36 39 42 45 48 51,Time from randomisation(months),第一次后续治疗或死亡的可能性,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,Osimertinib(n=279),Comparator EGFR-TKI(n=277),No.at risk Osimertinib,Comparator,EGFR-TKI,至第一次后续治疗或死亡时间*,16,即使中位暴露时间约为对照组的,2,倍，,奥希替尼组,3,级不良事件发生率仍低于对照组,腹泻,皮疹,指甲影响,皮肤干燥,甲沟炎,口腔炎,厌食,咳嗽,恶心,AST,升高,ALT,升高,奥希替尼组，,n=279,对照组，,n=277,中位暴露时间：奥希替尼组,20.7,个月，,EGFR-TKI,对照组,11.5,个月，奥希替尼组将近对照组,2,倍,可能与治疗相关的,3,级,AEs,：奥希替尼,51,例,(,18%,),；,EGFR-TKI,对比组,79,例,(,29%,),Data cut-off:25 June 2019,*,Time from the date of randomisation to the earlier of the date of anti-cancer therapy start date following study drug discontinuation or death,17,奥希替尼对于初治,EGFRm+,伴脑转移患者的疗效,-PFS,Soria JC.et al.N Engl J Med.2018,Reungwetwattana T,et al.J Clin Oncol.2018,FLAURA,系统性,PFS,：,(,包括颅内进展和颅外进展,),颅内,PFS(iPFS),CNS,全分析集,18,一线使用奥希替尼可以减少或延缓脑转移的发生,J Vansteenkiste et al ESMO Asia 2017,疾病进展主要是由于,CNS,的新发病灶引起的,与标准治疗相比，奥希替尼组的患者，发生,CNS,的进展和,CNS,新发病灶导致的进展更少,CNS PFS CNS,全分析集,CNS全分析集患者进展情况,19,在,NSCLC,中，,EGFR TKI,进行头对头比较，,奥希替尼是获得阳性,OS,结果的,TKI,厄洛替尼,vs,吉非替尼,阿法替尼,vs,吉非替尼,达可替尼,vs,吉非替尼*,奥希替尼,vs,吉非替尼,/,厄洛替尼,Presented by,Pasi A.Jnne,2019 ESMO,20,在其他肿瘤或,NSCLC ALK,通路中，,TKI,间比较未获得阳性结果,CML,：慢性粒细胞性白血病,GIST,：胃肠道间质瘤,Presented by,Pasi A.Jnne,2019 ESMO,21,EGFRm NSCLC:,各研究中,34,级,AEs,对比,a,Grouped term;,b,dermatitis acneiform.,1.Soria JC,et al.,N Engl J Med,.2018;378(2):113,125;2.Park K,et al,Lancet Oncol,.2016;17(5):577589;3.,Wu YL,et al.,Lancet Oncol,.2017;18:14541466;,Most common Grade 3 and 4 AEs in clinical trials,22,一代,/,二代,EGFR TKI,不可避免发生耐药,EGFR T790M,突变,：见于大约,2/3,的经,EGFR-TKIs,厄洛替尼或吉非替尼,治疗进展的晚期,EGFRm,NSCLC,患者,(,范围,51%-68%),1-5,在一项近期入组,24,例患者的研究中，,阿法替尼,耐药肿瘤中,T790M,发生率为,36%,6,EGFR-TKIs,获得性耐药的替代方法包括,7,8,:,旁路通路激活（涉及致癌基因,MET,HER2,BRAF,AXL,等）,小细胞转化,上皮向间充质转化,1.,Cortot AB,Janne PA.Eur Respir Rev.2014;23:356-366.2.Yu HA,et al.ClinCancer Res.2013;19:2240-2247.3.Oxnard GR,et al.Clin Cancer Res.2011;17:1616-1622 4.SunJM,et al.LungCancer.2013;82:294-298.5.Arcila ME,et al.Clin Cancer Res.2011;17:1169-1180.6.CampoM,et al.J Thorac Oncol.2016;11:2022-2026.7.Gerber DE,et al.AmSoc ClinOncol Educ Book.2014:e353-65.8.Wu YL,et al.ELCC2015.Poster 241.,一代,EGFR-TKIs,获得性耐药机制,阿法替尼获得性耐药机制,一代,EGFR-TKI,耐药机制明确，二代,TKI,耐药机制尚需探索,23,AURA,系列研究奠定奥希替尼作为,EGFR-T790M+,标准治疗,AURA,AURA 17,AURA 3,1.Yang JCH,et al.ELCC 2016.Abstract LBA2_PR.,2.Mok TS,et,al.,ASCO,2017.Oral 9005.,3.Zhou CC,et al.ESMO 2017.Post 1331/1353/1354.6.Vassiliki A Papadimitrakopoulou,Yi-Long Wu,et,al.2016 wclc,24,But,临床真实的后线治疗情况并不乐观,25,FLAURA,研究首次进展后允许交叉用药：,奥希替尼组以化疗为主；对照组以奥希替尼为主，交叉治疗患者约占,1/3,患者分布,接受第一次后续,(,二线,),抗肿瘤治疗,无后续抗肿瘤治疗,仍在研究治疗阶段,第一次后续,(,二线,),抗肿瘤治疗,其它,*,细胞毒药物治疗,奥希替尼,包括,EGFR-TKI,在内的治疗，不是奥希替尼,奥希替尼 (n=279),22%,31%,47%,EGFR-TKI,对照组(n=277),接受 FST,(n=133),接受 FST,(n=180),5%,30%,65%,29%,68%,3%,22%,4%,患者(%),100,90,80,70,60,50,40,30,20,10,0,47%,27%,化疗,奥希,替尼,Data cut-off:25 June 2019,*Refers to those patients who did not receive either chemotherapy or an EGFR-TKI;,The majority of patients who received cytotoxic chemotherapy received a platinum-based chemotherapy regimen,FST,first subsequent treatment,180,例,EGFR-TKI,对照组患者接受了第一次后续治疗,85,例患者,(47%),交叉到,奥希替尼组,(,占所有随机入组到,EGFR-TKI,对照组患者的,31%,),26,Yu,et al.CCR 2013;Kobayashi JTO 2018,ARCHER 1050,研究中,dacomitinib,的耐药机制及后续治疗,接受二线治疗的患者中，一代和二代药物分别仅有,11.1%,和,9.7%,的患者，接受了奥希替尼的治疗,27,五大真实世界研究：二线奥希替尼治疗比例,6%-36%,Roeper J et al.,Pneumologie,.2019,73(suppl 01).,Seto,T et al.Oncol,Ther,2018;6:203-215.,Chiang AC et al.Presented at:,iASLC,19th WCLC;September 23-26,2018;Toronto,Canada,Chua B et al.Ann Oncol,29(suppl 9):ix150-ix169.Abs 523P,Grohe C et al.Presented at:DGHO Annual Meeting 2018 September 28-october 2 2018.Vena Austria,一线接受一,/,二代,EGFR-TKI,治疗的患者比例,不能接受二线治疗的患者比例,没有接受检测、没有,T790M,突变、没有接受奥希替尼治疗的患者比例,患者,%,100%,A,30%,B,-42%,C,二线,奥希替尼,100%,A,-69%,C,二线,奥希替尼,二线,奥希替尼,二线,奥希替尼,二线,奥希替尼,-7%,100%,A,-62%,B,-35%,C,100%,A,-39%,B,-25%,C,100%,A,-53%,B,-34%,C,B,27%,24%,6%,36%,13%,美国仅有,6%,、亚洲和欧洲约,13%-36%,的患者，二线有机会接受奥希替尼治疗,28,