肺癌免疫治疗进展.pptx

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容,免疫治疗的原理,抗,PD-L1/PD-1,抑制剂的作用机理,抗,PD-L1/PD-1,抑制剂区别,免疫治疗在晚期,NSCLC,中的应用,二线治疗,一线单药治疗,一线联合治疗,免疫治疗的安全性,总结,内 容,免疫治疗的原理,抗,PD-L1/PD-1,抑制剂的作用机理,抗,PD-L1/PD-1,抑制剂区别,免疫治疗在晚期,NSCLC,中的应用,二线治疗,一线单药治疗,一线联合治疗,免疫治疗的安全性,总结,肿瘤的显著特征,Hanahan D,Weinberg RA.Cell 2011;144(5):646-74.,“十大特征”,2011,基因组不稳定,和突变,肿瘤促进的炎症,逃避免疫攻击,异常细胞能量,“六大特征”,2000,抵抗细胞死亡,诱导血管生成,持续的增殖信号,无限的复制能力,激活浸润和转移,逃避生长抑制,对肿瘤的认识：,“逃避免疫攻击”,在“十大特征”时才更新,4,T,细胞免疫检查点和共刺激通路,刺激,刺激,刺激刺激,抑制,抑制,抑制,抑制,这些通路经免疫制剂可被,激活,，对抗肿瘤介导的免疫抑制,这些通路经免疫制剂可被,阻断,，对抗肿瘤介导的免疫抑制,P,ardoll DM,.,Nat Rev Cancer,.2012;12:252264.,5,抗,PD1,抑制剂与抗,PD-L1,抑制剂的区别,-,同一通路，不同靶点,1.Herbst,et al.Nature 2014;2.Chen,et al.Clin Cancer Res 2012;3.Brown,et al.J Immunol 20034.Akbari,et al.Mucosal Immunol 2010;,5.Latchman,et al.Nat Immunol 2001;6.Matsumoto,et al.Biochem Biophys Res Commun 2008.,PD-1,PD-1,B7.1,X,PD-L1,PD-L2,肿瘤细胞,PD-L1,T,细胞,X,B7.1,巨噬细胞,PD-1,PD-1,B7.1,X,PD-L1,PD-L2,肿瘤细胞,PD-L1,T,细胞,X,B7.1,巨噬细胞,靶向抑制,PD-L1,，能够阻断肿瘤细胞和,PD-1/B7.1,的协同抑制信号，从而防止其下调,T,细胞活性,1,2,3,保留,PD-L2/PD-1,交互作用，最小限度保持免疫稳态，这种交互可能有助于预防自身免疫性反应，尤其是在肺部,1,阻断,PD-L2/PD-1,交互作用会影响免疫稳态，有增加自身免疫反应的潜在可能,1,4,靶向抑制,PD-1,，能够阻断肿瘤细胞与,PD-1,之间的抑制信号，但仍保留肿瘤细胞与,B7.1,之间的交互作用,1,2,3,Anti-PDL1,Anti-PD1,6,内 容,免疫治疗的原理,抗,PD-L1/PD-1,抑制剂的作用机理,抗,PD-L1/PD-1,抑制剂区别,免疫治疗在晚期,NSCLC,中的应用,二线治疗,一线单药治疗,一线联合治疗,免疫治疗的安全性,总结,7,现有,PD-L1,/PD-1,抑制剂二线治疗,NSCLC,的,III,期研究,1.,Felip E,et al.ESMO 2017,;2.Herbst,et al.ESMO 2016;3.Barlesi,et al.ESMO 2016,CheckMate 017,1,CheckMate 057,1,KEYNOTE-010,2,OAK,3,研究组别,Nivolumab vs,多西他赛,Nivolumab vs,多西他赛,Pembrolizumab 2,mg,或,10mg/kg,vs,多西他赛,Atezolizumab vs,多西他赛,研究分期,III,III,II/III,III,PD-L1,选择,未选择,未选择,选择,(TPS 1%),未选择,病例数，,n,272(135 vs 137),582(292 vs 290),1033(344 vs 346 vs 343),最初入组,850(425 vs 425),病理类型，,%,非鳞癌,鳞癌,其他,/,未知,0,100,-,100,0,-,70,21,8,74,26,-,治疗线数，,%,2L,3L,3L,其他,/,未知,100,0,0,0,88,11,1,0,69,20,9,1,75,25,0,0,最新数据最少随访时间,36,月,36,月,19,月,19,月,Nivolumab,二线治疗,NSCLC,的,III,期研究结果：,CheckMate 017,和,CheckMate 057,总人群,OS,Felip E,et al.ESMO 2017,Nivolunmab,2015.3.4FDA,批准用于非鳞癌二线治疗：,All comer,2015.10.9 FDA,批准用于鳞癌二线治疗：,All comer,PD-L1,表达亚组分析：阴性人群免疫治疗是否获益？,Borghaei,et al.N Engl J Med 2015,PD-L1,expression,Interactionp,value,OS,1%,0.06,1%,5%,0.001,5%,10%,0.001,10%,NE,PFS,1%,0.02,1%,5%,0.001,5%,10%,0.001,10%,NE,1.0,0.5,2.0,0.25,Nivolumab,Docetaxel,PD-L1,possitive,PD-L1,negative,PD-L1,not evaluable,PD-L1 expression,Interactionp,value,OS,1%,1%,0.56,5%,5%,0.47,10%,10%,0.41,NE,PFS,1%,1%,0.70,5%,5%,0.16,1%,）,主要研究终点：,ITT,人群,OS,*,ITT,人群及,TC1/2/3,或,IC1/2/3,为分层,HR,；其他亚组为未分层,HR,TC,：肿瘤细胞，,IC,：肿瘤浸润免疫细胞,Gadgeel,et al.WCLC 2016(abstract PL04a.02),Atezolizumab,多西他赛,中位,9.6,个月,(95%CI,8.6,11.2),中位,13.8,个月,(95%CI,11.8,15.7),Overall Survival(%),Months,HR,0.73*,(95%CI,0.62,0.87),P,=0.0003,至少随访,19,个月,A,tezolizumab,二线治疗,NSCLC,的,III,期,OAK,研究：,Atezolizumab,2016.10.18 FDA,批准用于,NSCLC,二线治疗：,All comer,*,未分层,HR,，,P,值仅用于表述目的,组织学类型信息来自,eCRF,Gadgeel,et al.WCLC 2016(abstract PL04a.02),HR,0.73*,(95%CI,0.60,0.89),P,=0.0015,中位,11.2,个月,(95%CI,9.3,12.6),中位,15.6,个月,(95%CI,13.3,17.6),中位,7.7,个月,(95%CI,6.3,8.9),中位,8.9,个月,(95%CI,7.4,12.8),至少随访,19,个月,HR,0.73*,(95%CI,0.54,0.98),P,=0.0383,非鳞癌,鳞癌,Overall Survival(%),Months,Overall Survival(%),Months,至少随访,19,个月,中位,DoR:,16.7,个月,vs,6.2,个月,Atezo(N=45)vs,多西 他赛,(N=48),中位,DoR:,9.7,个月,vs,6.9,个月,Atezo(N=13)vs,多西他赛,(N=9),OAK,研究：组织学类型亚组,OS,和,DoR,Atezolizumab,多西他赛,PD-L1,亚组分析：,阴性人群免疫治疗是否获益？,中位,OS,OS HR,n(%),96(15%),628(100%),188(30%),333(53%),290(46%),77(35%),130(59%),89(40%),222(100%),非鳞癌,TC3,或,IC3,TC2/3,或,IC2/3,TC1/2/3,或,IC1/2/3,TC0,和,IC0,所有非鳞癌,TC2/3,或,IC2/3,TC1/2/3,或,IC1/2/3,TC0,和,IC0,所有鳞癌,0.61,0.35,0.72,0.75,0.73,0.76,0.57,0.71,0.82,0.73,0.21 2,多西他赛更佳,Hazard Ratio,Atezolizumab,更佳,Atezolizumab,多西他赛,OS HR,0,41(18%),鳞癌,TC3,或,IC3,Gadgeel,et al.WCLC 2016(Abstr PL04a.02),10,20,30,40,时间,(,月,),OS,获益可见于,PD-L1,阴性患者，无需进行,PD-L1,检测,CheckMate 017,1,ITT,人群,(n=272),CheckMate 057,1,ITT,人群,(n=582),KEYNOTE-010,2,ITT,人群*,(n=1033),OAK,3,ITT,人群,(n=850),病理类型,鳞癌,非鳞癌,所有病理类型,所有病理类型,PD-L1,选择,未选择,未选择,选择,(TPS 1%),未选择,ORR,%,Nivo 20%vs doc 9%,Nivo 19%vs doc 12%,Pembro,2mg/kg,19%,vs doc 10%,Atezo 14%vs doc 13%,随访时间,至少,36,个月,至少,36,个月,中位,19.2,个月,至少,19,个月,抗,PD-L1/PD-1,二线治疗,NSCLC,的,OS,（,ITT,人群）,*III,期研究剂量：,2mg/kg q3w,和,10mg/kg q3w,1.,Felip E,et al.ESMO 2017,(Abstr,1301PD)2.Herbst,et al.ESMO 2016(Abstr LBA48)3.Barlesi,et al.ESMO 2016(Abstr LBA44),HR 0.62,HR 0.75,HR 0.73,HR 0.72,Nivo,Doc,Nivo,Doc,Atezo,Doc,Pembro2mg/kg,Doc,13.8,9.6,9.2,6.0,9.5,12.2,10.5,8.6,Nivolumab,、,Pembrolizumab,和,Atezolizumab,三药均已被,FDA,批准用于晚期,NSCLC,二线治疗,Pembrolizumab,仅批准用于,PD-L1,表达阳性（,TPS1%,）的患者，使用必须进行,PD-L1,伴随诊断,Atezolizumab,无论,PD-L1,表达水平与组织类型，,OS,均有显著获益，,mOS,长达,13.8,个月，使用无需,PD-L1,检测。,二线治疗小结：,内 容,免疫治疗的原理,抗,PD-L1/PD-1,抑制剂的作用机理,抗,PD-L1/PD-1,抑制剂区别,免疫治疗在晚期,NSCLC,中的应用,二线治疗,一线单药治疗,一线联合治疗,免疫治疗的安全性,总结,KEYNOTE-024&CheckMate 026,研究设计,晚期或转移性，未治疗的,NSCLC,PD-L1,50%,无,EGFR,敏感突变和,ALK,阳性,ECOG PS 1,N=305,Pembrolizumab,200 mg Q3W,治疗至疾病进展，不能耐受的毒性，研究者决定，或者完成,35,个周期的治疗,R,研究者决定的含铂化疗,46,个周期,在疾病进展后可交叉（可选）,主要研究终点：,PFS,次要研究终点：,ORR,OS,安全性,耐受性,主要研究终点：,PFS(,5%,PD-L1+),随机分层因素：,PD-L1,表达,(5%vs 5%),组织学类型,(,鳞癌,vs,非鳞癌,),Nivolumab,3 mg/kg IV Q2W,n=271,IV,期或复发性,NSCLC,未经过系统性治疗,无能用靶向治疗的,EGFR,突变,/ALK,阳性,1%,PD-L1,a,如果脑转移在随机前至少,2,周前经过治疗，允许入组,含铂双药化疗,(,根据组织类型选择,),6,个周期,n=270,PD,或不能耐受的毒性,PD,前,48,周,每,6,周,进行影像学评估，之后每,12,周进行评估,交叉至,nivolumab,c,(,可选的,),R1:1,次要研究终点：,PFS(1%PD-L1+),OS(1%PD-L1+and 5%PD-L1+),ORR(5%PD-L1+),KEYNOTE-024,CheckMate 026,18,KEYNOTE-024,主要终点：,PFS,（独立评审）,事件,n,中位,月,HR(95%CI),P,Pembro,组,73,10.3,0.500.37-0.68),0.001,化疗组,116,6.0,62%,50%,0,3,6,9,12,15,18,0,10,20,30,40,50,60,70,80,90,100,时间（月）,P,F,S,%,风险人数,154,104,89,44,22,3,1,151,99,70,18,9,1,0,48%,15%,根据,RECIST v1.1,评估，独立审评（盲法）,Martin Reck,et al.ESMO 2016,成功。被,NCCN 2017 v2.0,推荐,19,CheckMate 026,主要终点：,PFS,（,PD-L1,5%,人群，独立评审,）,风险人数：,Nivolumab,211104,71,49,35,24,6,3,1,0,化疗组,212,144,74,47,28,21,8,1,0,0,Nivolumab,组,n=211,化疗组,n=212,中位,PFS,，月,(95%CI),4.2,(3.0,5.6),5.9,(5.4,6.9),1,年,PFS,率，,%,23.6,23.2,Nivolumab,化疗,月,PFS(%),24,21,18,15,12,9,6,3,27,100,80,60,40,0,20,0,所有随机人群,(1%PD-L1+):HR=1.17,(95%CI:0.95,1.43),HR=1.15,(95%CI:0.91,1.45),P,=0.2511,Mark Socinski,et al.ESMO 2016,失败。可能原因在于人群的选择,20,BIRCH,研究一线治疗队列：疗效结果,C,arcereny E,et al.WCLC 2017(Abstr OA 17.02),TC2/3,或,IC2/3(n=138),TC3,或,IC3(n=65),ORR,%,更新分析结果,中位随访,34.3,个月,ORR(,研究者评估,),中位生存,月,OS,PFS,35%,26%,24.0,7.3,7.6,26.9,mDoR,14.5,月,mDoR,16.5,月,数据截止日期：,2017.8.7,BIRCH,研究：,Atezolizumab,一线治疗,OSNCT02031458,C,arcereny E,et al.WCLC 2017(Abstr OA 17.02),数据截止日期：,2017.8.7,Overall Survival(%),Months,Overall Survival(%),Months,Overall Survival(%),Months,Median OS=24.0 mo,(95%CI 18.1,30.8),Median OS=26.9 mo,(95%CI,12.0,NE,),Median OS=23.5 mo,(95%CI,18.1,29.5,),24-mo OS rate=,50%,(95%CI,41.5,59.2,),24-mo OS rate=,52%,(95%CI,39.3,65.2,),24-mo OS rate=,49%,(95%CI,37.0,61.1,),TC2/3 or IC2/3,n=138,TC3 or IC3,n=65,TC2 or IC2,n=73,中位随访,34.3,个月,所有,PD-L1,亚组均获得持久生存,BIRCH,研究：不同,EGFR,，,KRAS,突变与,ORR,、,DOR,、,PFS,和,OS,Endpoint,EGFR mutant,a,n=13,EGFR wild-type,n=103,KRAS mutant,n=32,KRAS wild-type,n=67,INV ORR TC2/3 or IC2/3,n(%),4(31%),24(23%),10(31%),16(24%),mDOR,mo(95%CI),10.4 mo,(5.5,17.5),13.1 mo,(7.8,NE),15.8 mo,(7.2,NE),11.2 mo,(7.8,16.5),mPFS,mo(95%CI),7.6 mo,(1.4,13.6),7.7 mo,(4.7,9.9),9.8 mo,(4.9,19.8),7.1 mo,(3.9,10.9),mOS(95%CI),28.5 mo(20.1,NE),20.1 mo(15.5,31.1),31.9 mo(20.3,NE),21.3 mo(15.5,31.1),OS events(rate),8(62%),60(58%),15(47%),39(58%),NCT02031458,C,arcereny E,et al.WCLC 2017(Abstr OA 17.02),Atezolizumab,单药对于,EGFR,、,KRAS,野生型和突变型患者都具有良好疗效,其中具有,EGFR,敏感突变的患者均在,EGFR TKI,治疗进展或不能耐受后接受,atezolizumab,治疗,a,不包括,3,例,T790M,突变患者,数据截止日期：,2017.8.7,23,国内抗,PD-L1/PD-1,抑制剂单药一线治疗晚期,NSCLC,的,III,期研究,IV,期,NSCLC,无既往治疗，除外,EGFR/ALK,突变患者接受过的相应,TKI,治疗,IHC,检测,PD-L1,阳性,ECOG PS 0-1,Atezolizumab1200 mg Q3W,直至不再临床获益,1,:1,研究者决定的含铂化疗,46,个周期,既往未接受过系统性化疗的局部晚期或转移性,NSCLC,PD-L1 TPS1%,ECOG PS 0,-1,EGFR,突变,/ALK,基因重排阴性,无癌性脑膜炎及,CNS,转移,Pembrolizumab,200mg IV Q3W,（不超过,35,次,）,含铂双药化疗,（不超过,6,周期）,1:1,初治的,IV,期,NSCLC,PD-L125%,ECOG PS 0,-1,EGFR,敏感突变,/ALK,基因重排阴性,稳定的,CNS,转移且,14,天前已停用激素,Durvalumab,20mg/kg IV Q4W,（,4-6,个周期,）,含铂双药化疗,（,4-6,个周期）,1:1,IMpower 110,IMpower 110:NCT02409342,Keynote 042:NCT02220894 PEARL:NCT03003962,Keynote 042,PEARL,24,Nivolumab,一线单药探索失败,Pembrolizumab,成功批准，成为,PD-L1,高表达（,TPS50%,）晚期,NSCLC,一线治疗的新标准,Atezolizumab,，,II,期,BIRCH,研究显示，单药一线治疗,PD-L1,经选择患者，显示出持久的肿瘤缓解，,mOS,达,24,个月以上，且不论,EGFR,、,KRAS,突变状态，均有治疗活性，三期研究正在进行中。,国内多项,PD1/PD-L1,抑制剂一线单药在,PD-L1,选择人群中的,III,期临床研究正在开展,单药一线治疗小结：,内 容,免疫治疗的原理,抗,PD-L1/PD-1,抑制剂的作用机理,抗,PD-L1/PD-1,抑制剂区别,免疫治疗在晚期,NSCLC,中的应用,二线治疗,一线单药治疗,一线联合治疗,免疫治疗的安全性,总结,肿瘤免疫表型及联合治疗原理,预存免疫,渗透阻止,免疫沙漠,炎性,非炎性,通过联合治疗策略转变成炎性类型,CD8 T,细胞,/IFN,PD-L1,TILs,免疫负荷,激活间质,血管形成,对检查点抑制剂往往有效,MDSCs,Hegde PS et al.,CCR(2016),抗,PD,-,L1/PD-1,联合化疗或双免疫一线治疗,NSCLC,疗效和安全性,1.,Liu SV,et al.ASCO 2017;2.,Papadimitrakopoulou,et al.ASCO 2017;3.Langer,et al.Lancet 2016;4.Rizvi,et al.J Clin Oncol 2016;5.Rizvi,et al.WCLC 2015;6.Hellmann,et al.ASCO 2016,GP28328,1,Ib,期实体瘤,(1L NSCLC),Atezolizumab+,化疗,(n=58),KEYNOTE-021,2,3,I/II,期,1L NSCLC,Cohort G:,化疗,pembrolizumab,(n=123),CheckMate 012,4,I,期,1L NSCLC,N,ivolumab(N)+,化疗,(n=56),CheckMate 012,5,6,I,期,1L NSCLC,Nivolumab(N)+ipilimumab(I),(n=49),Atezo+carbo+pac,Atezo+carbo+,pem,Atezo+carbo,+nab-pac,Carbo+pem,Pembro+carbo+pem,N10+cis+,gem,N10+cis,+pem,N10+carbo+pac,N5+carbo+pac,N1 q3w+I1 q3w,N1 q2w+I1 q6w,N3 q2w+I1 q12w,N3 q2w+I1 q6w,N,25*,25*,26*,63,60,12,15,15,14,31,40,38,39,ORR,%,34,级治疗相关,AEs,69%,23%,37%,45%,29%,35%,37%,33%,71%,54%,85%,25%,47%,73%,29%,36,68,46,30,57,33,47,47,43,13,25,47,39,联合化疗,双免疫联合,*,可评价安全性分别为,n=14,例,n=24,例和,n=20,例,II,期,KEYNOTE-021G,主要终点,:ORR,Papadimitrakopoulou VA,et al.2017 ASCO Abs No.9094;Borghaei H,et al WCLC 2017:Abs No.OA 17.01,Pembro+,化疗,缓解患者,N=33,单纯化疗缓解患者,N=20,DOR,，中位时间（范围）,NR,(1.4+-22.7+),NR,(2.8-23.7+),仍缓解患者，,%,50,40,29,II,期,KEYNOTE-021G,：,PFS&OS,（,BICR,）,Borghaei H,et al WCLC 2017:Abs No.OA 17.01,PC,组,57%,的患者交叉到,pembro,单药组,2017,年,5,月，,FDA,批准,pembrolizumab,联合培美曲塞,/,卡铂用于晚期非鳞,NSCLC,（,all comer,）的一线治疗,30,进行中的抗,PD-L1/PD-1,联合化疗或双免疫治疗,NSCLC,的,III,期研究,研究名,研究描述,化疗,抗,CTLA4,Atezolizumab,IMpower130,Atezolizumab+,含铂双药化疗,(,非鳞癌，,nab-PTX),IMpower131,Atezolizumab+,含铂双药化疗,(,鳞癌，,PTX/nab-PTX,),IMpower132*,Atezolizumab+,含铂双药化疗,(,非鳞癌，,PEM,),IMpower150,Atezolizumab+,含铂双药化疗,贝伐珠单抗,(,非鳞癌,),Pembrolizumab,KEYNOTE-407*,Pembrolizumab+,含铂双药化疗,(,鳞癌,),KEYNOTE-189,Pembrolizumab+,含铂双药化疗,(,非鳞癌,),Nivolumab,CheckMate 227*,Nivolumab,单药或联合,ipilimumab,或联合含铂双药化疗,(,鳞癌和非鳞癌,),Durvalumab,MYSTIC,Durvalumab,单药或联合,tremelimumab,(,鳞癌和非鳞癌,),NEPTUNE*,Durvalumab+tremelimumab(,鳞癌和非鳞癌,),国内参与,免疫联合靶向制剂,-,一代,EGFR TKI,第一阶段：剂量递增,(,安全性评估,),晚期,NSCLC EGFR-TKI,初治,N=8,第二阶段：扩展阶段,(,安全性、疗效评估,),EGFR,突变晚期,NSCLC,，初治或非,EGFR-TKI,经治,N=20,未,PD,患者，每,12,周随访一次至,PD,2016 ESMO Asia 441O;NCT02013219,扩大入组阶段的疗效结果,(n=20),可评价疗效人群的中位随访时间：,14.6,个月,AE,：两阶段共,28,例患者，无肺炎发生报告,ORR,75%,DCR,90%,中位,PFS,11.5,月,Atezolizumab+Erlotinib:,一线治疗,EGFR,突变晚期,NSCLC-Ib,期研究设计,32,Atezolizumab,和,bevacizumab,的互补作用体现在肿瘤免疫循环中的四个方面,：,肿瘤免疫联合的目标，是为了创建一个,更有利的环境,，,最大化,免疫系统清除肿瘤的,潜力,。,免疫检查点抑制剂联合抗血管生成治疗的科学原理,MDSC,myeloid-derived suppressor cell;T,reg,regulatory T cell;VEGF,vascular endothelial growth factor1.Ferrara,et al.Nat Rev Drug Discov 2004;2.Gabrilovich,et al.Nat Med 1996;3.Gabrilovich,et al.Blood 1998;4.Oyama,et al.J Immunol 1998;5.Guermonprez,et al.Annu Rev Immunol 20026.Villadangos and Schnorrer.Nat Rev Immunol 2007;7.Chen and Mellman.Immunity 2013;8.Griffioen,et al.Blood 1996;9.Griffioen,et al.Cancer Res 1996;10.Goel,et al.Physiol Rev 201111.Motz,et al.Nat Med 2014;12.Hodi,et al.Cancer Immunol Res 2014;13.Wallin,et al.Nat Commun 2016;14.Gabrilovich and Nagaraj.Nat Rev Immunol 2009;15.Huang,et al.Cancer Res 200616.Ko,et al.Clin Cancer Res 2009;17.Kusmartsev,et al.J Immunol 2008;18.Herbst,et al.Nature 2014;19.Chen,et al.Clin Cancer Res 2012;20.Zou and Chen.Nat Rev Immunol 2008,Bevacizumab,通过阻断,VEGF,介导的对树突细胞成熟的抑制，使得结合肿瘤抗原的,T,细胞,更有效地启动和活化,（抗原识别）,17,Bevacizumab,，,正常化肿瘤血管结构,，,促进,T,细胞浸润进入肿瘤,（细胞招募）,1,713,Bevacizumab,，,降低髓源性抑制细胞（,MDSCs,）和调节性,T,细胞的（,T,reg,）活性，,重塑肿瘤微环境,，从免疫抑制改变为免疫许可模式,（重塑微环境）,1,7,1417,Atezolizumab,，,通过,T,细胞介导的肿瘤细胞杀伤进而恢复抗肿瘤免疫功能,，因为,Avastin,的,VEGF,介导的免疫调节作用将进一步增强,（免疫功能恢复）,7,1820,已知抗血管生成作用,Bevacizumab,阻止,T,细胞失活，恢复抗肿瘤免疫功能,Atezolizumab,34,a,具有敏感,EGFR,突变或,ALK,易位的患者必须在一个或多个已批准靶向药物治疗疾病进展或不能耐受之后,；,b,Atezolizumab:1200 mg IV q3w,；,c,卡铂：,AUC 6 IV q3w,；,d,紫杉醇：,200 mg/m,2,IV q3w,；,e,贝伐珠单抗：,15 mg/kg IV q3w.,IMpower150,研究设计,:,免疫联合的,III,期研究,A,组,Atezolizumab,b,+,卡铂,c,+,紫杉醇,d,4,或,6,个周期,Atezolizumab,b,C,组（对照组）,卡铂,c,+,紫杉醇,d,+,贝伐珠单抗,b,e,4,或,6,个周期,贝伐珠单抗,e,生存随访,未接受过化疗的,IV,期或复发转移性非鳞,NSCLC,a,具有可供生物标志物检测的肿瘤组织,任何,PD-L1 IHC,状态,分层因素：,性别,PD-L1 IHC,表达,肝转移,N=1202,R1:1:1,B,组,Atezolizumab,b,+,卡铂,c,+,紫杉醇,d,+,贝伐珠单抗,e,4,或,6,个周期,Atezolizumab,b,+,贝伐珠单抗,e,维持治疗（不允行交叉）,Atezolizumab,治疗直至,RECIST v1.1,评价,PD,或不再临床获益,和,/,或,贝伐珠单抗治疗直至,RECIST v1.1,评价,PD,研究目的：评估,C,组加上,atezolizumab,是否具有临床获益（,B,组,vs C,组）,研究者评估,ITT-WT,的,PFS,（,B组,vs C,组,）,35,数据截止日期：,2017,年,9,月,15,日,6.8,月,(95%CI:6.0,7.1),8.3,月,(95%CI:7.7,9.8),HR,0.617(95%CI:0.517,0.737),P,0.0001,至少随访,:9.5,月,中位随访,:15,月,B,组,:atezo+bev+CP,C,组,:bev+CP,35,研究者评估,ITT-WT,的,PFS,（,B,组,vs C,组）,36,数据截止日期：,2017,年,9,月,15,日,18%,37%,56%,67%,B,组,:atezo+bev+CP,C,组,:bev+CP,至少随访,:9.5,月,中位随访,:15,月,36,37,数据截止日期：,2017,年,9,月,15,日,研究者评估,Teff,高表达,-WT,的,PFS,（,B,组,vs C,组）,6.8,月,(95%CI:5.9,7.4),11.3,月,(95%CI:9.1,13.0),HR,0.505(95%CI:0.377,0.675),P,0.0001,至少随访,:9.5,月,里程碑,PFS,%,B,组,:atezo+bev+CP,C,组,:bev+CP,6,个月,72%,57%,12,个月,46%,18%,ITT-WT,人群,PFS,亚组分析,a,ITT-WT,为分层,HR,，其他亚组为未分层,HR,。,数据截止日期：,2017,年9,月,15,日,亚组,n(%),男性,女性,425(61%),267(39%),65,岁,65-74,岁,75-84,岁,375(54%),248(36%),64(9%),ECOG PS 0,ECOG PS 1,282(41%),404(58%),现,/,曾吸烟,从不吸烟,584(84%),108(16%),肝转移,无肝转移,94(14%),598(86%),KRAS,突变型,KRAS,野生型,KRAS,未知,80(12%),124(18%),488(71%),ITT-WT,692(100%),1.0,支持,C,组,:,bev+CP,Hazard Ratio,a,支持,B,组,:,atezo+bev+CP,中位,PFS,月,HR,a,B,组,C,组,0.55,0.73,8.4,8.2,6.8,6.8,0.65,0.52,0.78,8.0,9.7,9.7,6.8,6.9,6.8,0.55,0.64,11.1,7.2,8.0,6.0,0.58,0.80,8.3,8.3,6.8,8.3,0.42,0.63,7.4,8.3,4.9,7.0,0.50,0.47,0.67,8.1,9.7,8.3,5.8,5.8,7.1,0.62,8.3,6.8,38,生物标志物人群的,PFS,a,ITT,、,EGFR/ALK,突变和,ITT-WT,所占,ITT,人群（,n=800,）的百分比,；,Teff为占,ITT-WT,人群（,n=658,）的百分比；,PD-L1,为占,ITT-WT,人群（,n=692,）的百分比；,b,具有敏感,EGFR,突变或,ALK,易位的患者必须在一个或多个已批准靶向药物治疗疾病进展或不能耐受之后,；,c,ITT,、,ITT-WT,和,Teff,高表达,WT,为分层,HR,，其他亚组为未分层,HR,。,.,数据截止日期：,2017,年,9,月,15,日,患者人群,n(%),a,ITT,（包括,EGFR,/,ALK,突变,+,）,800(100%),仅,EGFR,/,ALK,突变,+,b,108(14%),ITT-WT,692(87%),Teff,高表达,(WT)