方勇抗血管生成药物联合TKI治疗晚期非小细胞肺癌方勇

单击此处编辑母版标题样式,单击此处编辑母版标题样式,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,*,Click to edit Master text styles,Second level,Third level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Click to edit Master title style,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,*,抗血管生成药物联合,TKI,治疗,晚期非小细胞肺癌的新进展,-A+T,模式指导晚期肺癌治疗临床应用,方勇,浙江大学医学院附属邵逸夫医院肿瘤内科,肿瘤抗血管生成联合,TKI,应用病例,肿瘤抗血管生成联合,TKI,治疗晚期,NSCLC,研究进展,A+T,模式的未来研究发展,主要内容,患者病史（,1,）,男性，赵,，,53,岁,主诉：“诊断为肺癌近一年，化疗后再次进展” 于,2016-3-30,再次入院,1,年余前因,“,咳嗽痰中带血,7,天,”,就诊于永康市第一人民,医院,。,查,头胸腹部,CT,提示（,2015-4-20,）,：,左肺下叶癌伴左肺门及纵隔多发淋巴结增大，右侧肾上腺转移瘤,考虑,。,颅脑,MRI,增强示“,右侧,额叶低密度灶，转移瘤,考虑,”。,2015-4,行,肺部肿块穿刺活检，病理（,HZ2015036916,）：（左肺下叶）考虑腺癌，免疫组化结果：,P63(+),CgA,（,-,），,TTF-1,（,+,），,CK5/6,（,-,），,CK-7(+),NapsinA,（,+,），符合肺,腺癌,.,分子,病理：,EGFR,野生型,。,并于,2015-05-02,至,2015-07-30,起,永康市中医院,予以,紫杉醇,210mgd1+,顺铂针,40mgd1-3,静滴,q3w,化疗,5,周期。,2015-05-19,在浙江省人民医院行伽马刀治疗，具体方案：患者局麻下头架固定，头颅,MRI,定位，,MR,显示，经,TPS,规划，,50%,剂量曲线包绕，周边剂量,21Gy,，中心剂量,42Gy,，共,11,个靶点。,2015-08-31,起,予,“,贝,伐单抗,400mg,静滴,d1+,奈达铂针,115mg/90mg,静脉滴注,d1+,培美曲塞二钠,(,普来乐,),针,0.8g,静脉滴注,d1,”,方案,化疗,4,次,；,于,予,“,贝,伐珠单抗针,400mg,静滴,d1+,培美曲塞二钠针,0.8g,静脉滴注,d1,”维持,化疗,。,患者病史（,2,）,上腹部,CT,（,2016-3-31,）,What treatment strategy would you next recommend (pre-ASCO 2012)?,1.,免疫治疗,治疗策略您会如何推荐？,Q,：,3,.,放化疗,4,.,TKI,5,.,TKI+AVASTIN,2016-3-31,2016-4-20,2016-5-9,肿瘤抗血管生成联合,TKI,应用病例,肿瘤抗血管生成联合,TKI,治疗晚期,NSCLC,研究进展,A+T,模式的未来研究发展,主要内容,EGFR突变阳性NSCLC的一线治疗,EGFR TKI,单药治疗,目前标准治疗,个月,EGFR TKI,研究,N,PFS(,月,),厄洛替尼,OPTIMAL,82,13.7,EURTAC,86,10.4,ENSURE,110,11.0,JO22903,102,11.8,吉非替尼,NEJ002,114,10.8,WJTOG3405,86,9.2,阿法替尼,LUX-Lung 3,230,11.1,LUX-Lung 6,364,11.0,Chen,et al. Ann Oncol 2013;,Costa,et al,Clin Cancer Res 2014;,Wu,et al.WCLC 2013(abst P1 11-021);,Goto,et al.Lung Cancer 2013;,Maemondo,et al.N Engl J Med 2010;,Mitsudomi,et al.Lancet Oncol 2010;,Sequist,et al.J Clin Oncol 2013;,Wu,et al.Lancet Oncol 2013.,KATO T, et al. 2014 ASCO Abstract,8005.,肿瘤异质性,TKI,治疗的轮回,跷跷板理论,晚期NSCLC的抗血管生成治疗：有望突破化疗瓶颈,单靶点：,靶向,VEGF,信号通路的单克隆抗体,Bevacizumab,（安维汀）：,VEGF-A,Ramucirumab,(,Cyramza,),：,VEGFR-2,多靶点：,靶向,VEGFR/PDGFR/FGFR,的多靶点小分子,TKI,Nintedanib,泛靶点,内皮抑素（恩度）,更安全不易耐药,适合长期维持治疗,Cancer Treat Rev, 2014,40(4):548-57.,1.Sandler, et al. NEJM 2006; 2. Reck, et al. JCO 2009;3.Lucio Crin,et al. Lancet Oncol 2010;4.Fabrice Barlesi,et al.JCO 2013;5. Caicun Z, et al. 2013 WCLC MO06.13.;6.Martin Reck,et al.Lancet Oncol 2014;7. KATO T, et al. 2014 ASCO Abstract 8005;8. Maurice Perol, et al. 2014 ASCO Abstract LBA 8006. 9. JCO (June 1 S), 2005: 7138;10. JCO, 2010 ,28(15): 7598;11。J Thorac Oncol. 2011;6: 11041109；12.,中华肿瘤杂志, 2013,35(8):618-622.,2010,2006,E4599,bevacizumab + CP vs CP,1,2009,AVAiL,bevacizumab + CG vs CG,2,2014,LUME-Lung 1,nintedanib+doc vs doc,6,2013,SAiL,bevacizumab + chemo vs chemo,3,AVAPERL,bevacizumab + pem/cispem+bev,4,vs bev,4,BEYOND,bevacizumab + CP vs CP,5,JO25567,bevacizumab+erlotinib vs erlotinib,7,一线研究,二线研究,REVEL,ramucirumab+doc vs doc,8,抗血管生成治疗在晚期NSCLC的关键研究,2005,ENDO III,endostar+ NP vs NP,9,ENDO IV,endostar+,chemo vs chemo,10,ENDO TC,endostar+ TC vs TC,11,2011,ENDO 2nd,endostar+ doc vs doc,12,一线,/,二线 研究,EGFR突变患者的预后能否进一步提高？,含铂双药化疗,EGFR TKI,治疗,Chen,et al. Ann Oncol 2013;Costa,et al,Clin Cancer Res 2014;Wu,et al.WCLC 2013(abst P1 11-021);Goto,et al.Lung Cancer 2013;,Maemondo,et al.N Engl J Med 2010;Mitsudomi,et al.Lancet Oncol 2010;Sequist,et al.J Clin Oncol 2013;Wu,et al.Lancet Oncol 2013.,联合抗血管生成治疗,mPFS,：,？,贝伐珠单抗的多种作用对疗效提高,(,较传统治疗,),很重要,120,现有肿瘤脉管系统的,消退,13,新血管生长,13,8,抑制,一致提高缓解率,47,持续控制肿瘤生长,810,减少,腹水与积液,2,3,11,1420,存活脉管系统的,抗渗透性,1113,1,.,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 2002; 15. 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.,SAiL：中国患者的OS和TTP好于全球数据,中位,OS,为个月,(95% CI: 16.319.6),中位,TTP,为个月,(95% CI: 8.110.0),1,.,Zhou CC, et al. Clin Transl Oncol 2014; 16:463-468.,2. Crino L, et al. Lancet Oncol 2010; 11(8):733-740.,OS,时间,(,月,),SAiL,中国患者,1,SAiL,总体人群,2,18.5,1,4.6,TTP,时间,(,月,),SAiL,中国患者,1,SAiL,总体人群,2,8.,8,7,.,8,1.0,0.8,0.6,0.4,0.2,0.0,0,6,12,18,24,30,36,1.0,0.8,0.6,0.4,0.2,0.0,0,6,12,18,24,30,36,BEYOND,研究证实：贝伐珠单抗联合卡铂,紫杉醇较单纯化疗,PFS,延长月，,OS,延长月,PFS (,主要终点,),中位,PFS 9.2,月,vs 6.5,月,HR 0.40 (95% CI 0.290.54) p0.001,1.0,0.8,0.6,0.4,0.2,0,6,12,18,24,贝伐珠单抗,+,卡铂紫杉醇,(n=138),卡铂,+,紫杉醇,(n=138),时间,(,月,),9.2,月,6.5,月,进展风险,60%,2.7,数据截止时间,2013,年,1,月,27,日,Zhou C, et al. J Clin Oncol 2015; 33:2197-2204.,1.0,0.8,0.6,0.4,0.2,0,6,12,18,24,30,36,总生存,时间,(,月,),贝伐珠单抗,+,卡铂紫杉醇,(n=138),卡铂,+,紫杉醇,(n=138),HR 0.68 (95% CI 0.500.93),p=0.0154,死亡风险,32%,24.3,月,17.7,月,6.6,三种治疗模式,EGFR,突变阳性人群,Bev+TKI,Bev+chemo,一线,二线,EGFR-TKI,Bev+chemo,EGFR-TKI,+BEV?,Chemo,+BEV?,JO25567,厄洛替尼,+,贝伐珠单抗,vs.,厄洛替尼单药 一线治疗晚期,EGFR,突变阳性的非鳞,NSCLC,的,随机,开放,研究,KATO T, et al. 2014 ASCO Abstract,8005.,Takashi Seto,et al.2014.Lancet Oncol.15(11): 1236-44.,“,厄洛替尼单药或联合贝伐珠单抗一线治疗EGFR突变,晚期非鳞NSCLC：一项多中心、随机、开放II期研究,”,“,比较厄洛替尼联合贝伐珠单抗与厄洛替尼单药一线治疗,晚期,EGR,突变非鳞,NSCLC,的一项开放随机研究,”,A+T,初探,：,BeTa (2,nd,/3,rd,line),研究,标准一线化疗或,放化疗治疗后进展,NSCLC,患者,（,N=636,）,厄洛替尼,150mg/d,贝伐珠单抗,15mg/kg d1 q3w,（,n=319,）,厄洛替尼,150mg/d,安慰剂（,n=317,）,治疗至,疾病进展,或毒性不耐受*,主要终点：,OS,次要终点：,PFS,客观缓解率,(,ORR,),客观缓解持续时间,安全性,EGFR,和,Kras,表达与疗效终点相关性评估,R,Herbst RS,et al.Lancet.2011;377(9780):1846-54.,研究终点,T + P(N=317),T + A(N=319),HR,(,P,Value),mOS*,9.2 mos,9.3 mos,0.97,(,P,=0.7583),mPFS (Inv),1.7 mos,3.4 mos,0.62(,P,0.0001),ORR (%),6.2,12.6,Erl+P Erl+Bev,Sample size,EGFR +,EGFR -,18,152,12,173,PFS,EGFR +,EGFR -,9.7 m,1.6 m,17.1 m,2.9 m,OS,EGFR +,EGFR -,20.2,9.1 m,NA,8.1 m,JO25567:,厄洛替尼,+,贝伐珠单抗,vs.,厄洛替尼单药 一线治疗晚期,EGFR,突变阳性的非鳞,NSCLC,的随机开放研究,设计,主要终点,: PFS(,独立审核基于标准,),计划目标样本量,150,例，基于以下假设,假设，,80%,的效力证明贝伐珠单抗联合厄洛替尼较厄洛替尼单药治疗的优效性，单侧,1,类错误概率为,次要终点,: OS,、肿瘤缓解，,QoL,、安全性,探索性终点,:,生物标志物评估,分层因素,:,性别，吸烟状态,临床分期,EGFR,突变类型,KATO T, et al. 2014 ASCO Abstract,8005.,Takashi Seto,et al.2014.Lancet Oncol.15(11): 1236-44.,EB,联合治疗组,厄洛替尼,150mg qd+,贝伐珠单抗,15mg/kg q3w,N=75,E,单药治疗组,厄洛替尼,150mg qd,N=75,R,1: 1,PD,PD,N=150,既往未接受化疗的,IIIB/IV,期,或术后复发的非鳞,NSCLC,*,活化,EGFR,突变*,19,号外显子缺失,21,号外显子,L858R,年龄,20,岁,ECOG PS 0-1,无脑转移,主要终点PFS: 独立评估,EB (n=75),中位,PFS=16.0,个月,E (n=77),中位,PFS=9.7,个月,HR=0.54 (95%CI: 0.36-0.79),P=0.0015,时间,(,月,),PFS,1.0,0,0,0.2,0.4,0.6,0.8,4,8,12,16,20,24,28,9.7,16.0,KATO T, et al. 2014 ASCO Abstract,8005.,Takashi Seto,et al.2014.Lancet Oncol.15(11): 1236-44.,EGFR突变状态与PFS,EB (n=40),中位,PFS=18.0,个月,E (n=40),中位,PFS=10.3,个月,时间,(,月,),PFS,EB (n=35),中位,PFS=13.9,个月,E (n=37),中位,PFS=7.1,个月,0,0,0.2,0.4,0.6,0.8,4,8,12,16,20,24,28,1.0,0,0,0.2,0.4,0.6,0.8,4,8,12,16,20,24,28,1.0,PFS,时间,(,月,),HR=0.41,(95%CI: 0.24-0.72),HR=0.67,(95%CI: 0.38-1.18),外显子,19,缺失,外显子,21 L858R,KATO T, et al. 2014 ASCO Abstract,8005.,Takashi Seto,et al.2014.Lancet Oncol.15(11): 1236-44.,OLCSG 1001:,吉非替尼,+,贝伐珠单抗一线治疗,NSCLC EGFR,突变患者的,2,期研究,“,2014 ESMO Abstract 12,85,P”,Nogami,et al. 2014 ESMO,“,吉非替尼联合贝伐珠单抗一线治疗活化,EGFR,基因突变,晚期,NSCLC,的,II,期研究：冈山肺癌研究协作组研究,1001,”,Eiki Ichihara et al,J Thorac Oncol.2015 Mar; 10(3): 486-91.,OLCSG 1001: 研究设计,主要终点,: 1,年,PFS,率,次要终点,: PFS/OS,肿瘤缓解,安全性,突变，,%,N=42,19,外显子,57,L858R(21,外显子,),38,18,外显子,(G719A),2.5,21,外显子,(G861A),2.5,Nogami,et al. 2014 ESMO Abstract 1285P,IIIB/IV,期,非鳞,NSCLC,EGFR,突变,ECOG PS 0-2,N=,42,贝伐珠单抗,(15mg/kg,，,q3w),+,吉非替尼,(250mg/d,),PD,无进展生存期: PFS,Eiki Ichihara et al,J Thorac Oncol.2015 Mar; 10(3): 486-91.,1.00,0.75,0.50,0.25,0.00,0,10,20,30,40,PFS,时间,所有,42,例患者,中位,PFS14.4,个月,生存时间,(,月,),PFS,1.00,0.75,0.50,0.25,0.00,0,10,20,30,40,EGFR,突变状态与,PFS,外显子,19,缺失突变患者中位,PFS18.0,个月,外显子,21 L858R,患者中位,PFS9.4,个月,生存时间,(,月,),PFS,结 论,对于,EGFR,突变,NSCLC,患者，,贝伐珠单抗联合吉非替尼疗效不错且耐受性良好,.,厄洛替尼联合贝伐珠单抗治疗有活性,EGFR,突变，伴和不伴有,T790M,突变的晚期,NSCLC,患者的一项,II,期研究：,SLCG,和,ETOP,BELIEF,研究,A phase II trial of erlotinib (E) and bevacizumab (B) in patients with advanced non-small-cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations with and without T790M mutation.The Spanish Lung Cancer Group (SLCG) and the European Thoracic Oncology Platform (ETOP) BELIEF trial,3BA,R.A. Stahel, et al. ECC 2015 3BA,EGFR,外显子,19,缺失或,L858R,突变,厄洛替尼,150mg/,天,贝伐珠单抗,15mg/kg q3w,直至进展或毒性不可耐受,推荐再活检,子研究,1,：,T790M+,（,n=35,）,子研究,2,：,T790M-,（,n=67,）,转化研究子项目,肿瘤活检、基因表达检测以及突变分析,肿瘤基因表达检测,血浆,EGFR,突变监测,筛查和注册阶段,治疗和评估阶段,进展后的流程,R.A. Stahel, et al. ECC 2015 3BA,主要终点：,联合厄洛替尼和贝伐珠单抗治疗的、伴或不伴,EGFR T790M,突变的,PFS,次要终点：,联合用药的疗效以及耐受性；,BRCA1 mRNA,、,AEG-1 mRNA,及,T790M,与,PFS,的关联,EGFR-TKI,和贝伐珠单抗治疗相关的分子标志物；包括,T790M,突变在内的,EGFR,突变的血浆纵向变化,研究设计,不同T790M突变状态PFS（n=109）,R.A. Stahel, et al. ECC 2015 3BA,事件,/N,中位,PFS (95% CI),12m PFS (95% CI),全部患者,57/109,13.8,月,(10.3-21.3),56.7% (46.0-66.0),T790M+,15/37,16.0,月,(13.1-NE),72.4% (53.4-84.7),T790M-,42/72,10.5,月,(9.2-16.2),49.4% (36.6-61.0),100,80,60,40,20,0,0,2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,全部患者,(n=109),T790M+(n=37),T790M-(n=72),时间,(,月,),PFS(%),所有亚组显示PFS在T790M+组有更好的倾向性,R.A. Stahel, et al. ECC 2015 3BA,15 VS 42,10 VS 20,5 VS 22,4 VS 14,11 VS 28,9 VS 26,6 VS 16,4 VS 8,7 VS 6,1 VS 7,3 VS 21,4 VS 7,1 VS 5,5 VS 4,5 VS 26,37 VS 72,25 VS 42,12 VS 30,10 VS 27,27 VS 45,23 VS 47,14 VS 25,8 VS 13,9 VS 11,6 VS 14,14 VS 34,7 VS 9,5 VS 10,8 VS 7,17 VS 46,共计,女性,男性,目前,/,既往,未曾,外显子,19,外显子,21,低,中,高,未知,低,中,高,未知,性别,吸烟情况,EGFR,突变,BRCA1,生物标志物,AFG1,生物标志物,0.0,0.5,1.0,1.5,2.0,2.5,3.0,3.5,4.0,0.61 (0.34, 1.11),0.90 (0.42, 1.94),0.37 (0.14, 0.97),0.67 (0.22, 2.03),0.59 (0.29, 1.19),0.73 (0.34, 1.58),0.43 (0.16, 1.11),1.11 (0.33, 3.69),0.94 (0.31, 2.82),0.24 (0.03, 2.02),0.31 (0.09, 1.04),0.19 (0.05, 0.66),0.31 (0.04, 2.64),0.68 (0.18, 2.56),0.57 (0.22, 1.48),事件数,患者数,亚组分析,HR (95% CI),T790M+,更佳,T790M-,更佳,肿瘤抗血管生成联合,TKI,应用病例,肿瘤抗血管生成联合,TKI,治疗晚期,NSCLC,研究进展,A+T,模式的未来研究发展,主要内容,正在开展的,A+T,临床研究,1. NCT01532089; 2. NCT01562028; 3. Nogami, et al. ESMO 2014,Erlotinib 150mg/day,Erlotinib 150mg/day + bevacizumab 15mg/kg i.v. q3w,Stage IV NSCLC,Non-squamous histology,ECOG PS 01,(n=150),R,ACCRU,USA,Primary endpoint: PFS,Erlotinib 150mg/day + bevacizumab 15mg/kg i.v. q3w,Stage IIIB/IV NSCLC,Non-squamous histology,ECOG PS 02,(n=102),Primary endpoint: PFS,Sub-study 1: T790M+ (n=35),Sub-study 2: T790M (n=67),RC1126,1,ETOP,EU,BELIEF,2,Gefitinib 250mg/day + bevacizumab 15mg/kg i.v. q3w,Stage IV NSCLC,Non-squamous histology,ECOG PS 02,(n=42),Primary endpoint: 1-yr PFS rate,OLCSG,JAPAN,OLCSG 1001,3,抗血管治疗的共识与争议,治疗时机及使用时间,共识：一线治疗且使用至疾病进展,争议：是否可以跨线使用？,维持治疗,共识：维持治疗可以延长患者总生存,争议：维持治疗的方案选择是什么？,适用人群选择,共识：所有一线非鳞,NSCLC,患者均可以使用,争议：脑转移,/,老年人,/,出血风险人群是否可以安全使用？,联合药物选择,共识：可以和所有化疗药物连用,争议：是否可以和其他靶向药物如,克唑替尼,连用？,与免疫治疗的联合,争议：是否可以和其他免疫治疗连用？,争议：,Bio-marker?,疗效评价标准？,小 结,TKI,单药是目前,EGFR,突变、,ALK,融合阳性,NSCLC,的一线治疗的标准,A+T,的模式值得更多的临床试验验证，需考虑经济因素及不良反应，临床应用需与患者充分沟通，代表着未来,