安维汀疗效和安全性研究回顾和进展.ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,.,*,Medical Division,Professional Communication Support,Click to edit Master title style,r,Click to edit Master text styles,Second level,Third level,.,*,Medical Division,Professional Communication Commitment,Click to edit Master title style,r,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Medical Division,Professional Communication Support,r,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Medical Division,Professional Communication Commitment,r,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,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,罗氏医学部 医学科学联络团队,抗血管生成治疗在,NSCLC,中,的研究回顾和进展,一线（尽早）应用,目 录,贝伐珠单抗疗效数据回顾和进展,贝伐珠单抗的安全性数据和适用人群,一线（尽早）应用,一线治疗,一线化疗到达“瓶颈”期，如何突破？,Schiller et al,NEJM,2002(346):92,E4599,研究：,贝伐珠单抗,+,卡铂,/,紫杉醇,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,（湿性）,/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,开放性,/,多中心,/,随机对照,/III,期临床研究,(,美国等，,2001-2005),贝伐珠单抗一线治疗晚期,NSCLC,E4599,研究,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:0.670.92),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,研究,：,OS,首,次超过,12,个月,贝伐珠单抗,贝伐珠单抗,PD,PD,PD,贝伐珠单抗,15mg/kg+CG,贝伐珠单抗,7.5mg/kg+CG,安慰剂,+CG,未经治疗,IIIB,IV,期或复发,非鳞型,NSCLC,N=1,043,随机,安慰剂,+CG,2,2,1,1,主要研究终点：,PFS,；次要研究终点：,OS,、,ORR,等,AVAiL,研究中入组亚洲患者,105,例,国际多中心,/,双盲,/,随机对照,/III,期临床研究,(20,个国家和地区，,2005-2007),AVAiL,研究：,贝伐珠单抗,+,顺铂,/,吉西他滨,贝伐珠单抗一线治疗晚期,NSCLC,AVAiL,研究,Reck,et al.JCO 2009,*CP:,顺铂,80mg/m,2,d1,吉西他滨,1250 mg/m,2,d1,8,q3w,共,6,周期,AVAiL,研究：总体和,亚洲人群,均有获益,亚洲人群,(n=105),总体人群,(n=1043,),*,Pl+c/g,N=33,Bv7.5+c/g,N=38,Bv15+c/g,N=34,Pl+c/g,N=347,Bv7.5+c/g,N=345,Bv15+c/g,N=351,中位,PFS,(,月,),6.,1,88,8.,7,6.,2,6.,8,6.,6,HR,(95%CI),0.,49,(0,.29;,0.83),0.6,1,(0.3,6,;1,.04),0.75,(,0.64-0.87),0.8,5,(,0.73-1.00),p value,0.0068,0.628,0.0003,0.0456,中位,OS(,月,),17.4,28.2,25.8,13.1,13.6,13.4,HR(95%CI),0.,46,(0,.22;,0.97),0.7,9,(0,.40;,1.57),0.,93,(0,.78;,1.1,1,),1.0,3,(0,.86;,1,.23),p value,0.0370,0.5028,0.42,0.76,总缓解率,1,5.2%,4,7.4%,41.2%,2,1.6%,3,7.8%,3,4.6%,p value,0.0038,0.0181,.0001,0.0002,CR,0,0,0,0,.3%,1.2%,0.9%,PR,1,5.2%,4,7.4%,41.2%,2,1.3%,3,6.5%,33.7%,SD,57.6%,42.1%,50.0%,4,6.0%,41.5%,35.2%,PD,21.2,%,0,0,1,6.4%,9,.6%,1,5.1%,*,各组计入总缓解率统计的患者数分别为,324,323,和,332,Reck,et al.JCO 2009,主要终点：安全性,次要终点：疾病进展时间,(TTP),、,OS,、六个月内发生,CNS,转移患者的安全性,单组、大样本量研究，更接近于临床应用的真实环境,一线化疗贝伐珠单抗,7.5,或,15 mg/kg,贝伐珠单抗维持至,PD,未经治疗的晚期,非鳞,NSCLC,ECOG=0-2,N=2,166,SAiL,研究,:,贝伐珠单抗,+,一线化疗,国际多中心,/,单组,/IV,期临床研究,(40,个国家和地区，,2006-2008),贝伐珠单抗一线治疗晚期,NSCLC,SAiL,研究,1.Dansin,et al.ECCO ESMO 2009;2.Laskin,et al.WCLC 2009,化疗最多不超过,6,周期,SAiL,研究,:,联合双铂,化疗方案,OS,超过,14,个月,1.Dansin,et al.ECCO ESMO 2009;2.Laskin,et al.WCLC 2009,Median OS(months),20,15,10,5,0,OverallSAiLpopulation,1,14.6,15.3,8.7,14.7,Avastin+single-agent CT,2,Avastin+non-platinum doublets,2,Avastin+carboplatin doublets,2,Avastin+cisplatin doublets,2,SAiL:efficacy by chemotherapy regimen,14.6,n=1,067,n=815,n=13,n=42,n=2,172,总体,缓解,率,（）,E4599,1,贝伐,珠,单抗,15mg/kg+CP(n=381),CP(n=392),p0.001,40,30,20,10,0,15,35,贝伐珠单抗,7.5mg/kg+CG(n=323),贝伐珠单抗,15mg/kg+CG(n=332),安慰剂,+CG(n=324),AVAiL,2,p=0.0023,p0.999),治疗过程中空洞,与严重肺出血,ARIES,SAiL,无空洞形成,0.8%,0.7%,有空洞形成,1.4%,0%,不良事件,(%),安慰剂组,(n=71),贝伐珠单抗组,(n=123),任何级别,出血,34,33,咯血,/,肺出血,2,3,Grade 34,出血,4,4,咯血,/,肺出血,0,0,不同肿瘤类型中的,3,个随机临床实验,Meta,分析,Leighl,et al.Br J Cancer 2011,PH=pulmonary haemorrhage,贝伐珠单抗,并未增加抗凝治疗患者的出血发生率,Meta,分析,Griesinger,et al.ASCO 2008,;,Wozniak,et al.ASCO 2010,10,5,0,无抗凝治疗,0.2%,0.7%,Grade 3 haemoptysis/PH(%),有抗凝治疗,SAiL,SAiL,ARIES,ARIES,*,Anticoagulation usedincluded heparin and warfarin,n=1,547,n=1,875,n=152,n=92,0.9%,0%,贝伐珠单抗,并未增加抗凝治疗患者的严重,肺,出血发生率,SAiL,和,ARIES,研究,NSCLC,患者本身肺出血的发生率有升高风险，主要原因是,疾病本身因素,。,贝伐和其他抗,VEGF,药物治疗,NSCLC,过程中，,肺出血的发生率是很少的,，但是,可能是比较严重的，,确切的发生机制还不明确。,以,鳞状细胞癌,为主的肺癌和,/,或,大于,2,度的肺出血史,（定义为,3,个月曾经出现过,=25ml,的鲜血）患者,不应接受,贝伐治疗,研究显示，,没有临床或影像学特征（包括空腔形成和中央肿瘤位置）为接受贝伐珠单抗治疗的患者发生重度肺出血的可靠预测因素。大血管浸润及支气管血管浸润、肿瘤包绕或临近血管可预测肺出血。,能否接受贝伐治疗,并不受到患者年龄、体力状况、服用抗凝或抗血小板药物的影响。,目前最佳的,NSCLC,患者肺出血处理方法尚未建立，在这个过程中，介入科和外科可能在挽救过程中有重要作用。,将来的主要研究方向是肺出血发生的病理生理机制以及与抗,VEGF,药物的相互关系，肺出血发生的危险因素等。,M.Reck et al.Annals of Oncology November 42011,预防和管理贝伐珠单抗治疗,NSCLC,患者可能引起的,肺出血,风险,专家共识,肺出血,中央型肿瘤,/,基线空洞,/,抗凝治疗,CNS,转移,老年患者,哪些患者适合贝伐珠单抗的治疗？,？,Besse B,et al.Clin Cancer Res,2010,16(1):269-78,13,项随机对照临床研究,8,443,例,贝伐珠单抗治疗组,对照组,CNS,转移是入组时排除标准,组织专家核查病例资料，发现基线隐匿性的或治疗过程中发生的,CNS,转移,分析,CNS,转移病人的脑出血情况,2,项贝伐珠单抗治疗的单组安全性研究,(SAiL,ATHENA),4,382,例,2,项入组经治,CNS,转移患者的前瞻性临床研究,(PASSPORT,ATLAS),845,例,A,B,C,CNS,出血率,(%),数据组,入组病人数,CNS,转移病人数,贝伐,珠,单抗组,对照组,A:13,个,随机对照研究,8,443,贝伐组,:n=91,非贝伐组,:n=96,3.29,1.04,B:2,个开放性研究,(ATHENA,和,SAiL),4,382,贝伐组,:n=321,0.93,C:2,个入组经治,CNS,转移患者的,前瞻性研究,845,贝伐组,:n=141,0.80,贝伐珠单抗治疗,并未增加,CNS,转移患者,2,级以上脑出血发生率,回顾性,Meta,分析,CNS,转移患者,接受贝伐治疗后脑出血非常罕见,基于在多种肿瘤中超过,13000,名患者应用下的数据,Besse,et al.Clin Cancer Res 2010,多种肿瘤中,超过,13000,患者,543,名患者,有,CNS,转移,543,名患者中,只有,7,人发生,CNS,出血,（,1.3,）,2009,年,3,月,25,日：,欧盟药事局撤销禁忌症，允许未经治疗的,CNS,转移患者,接受贝伐珠单抗治疗,肺出血,中央型肿瘤,/,基线空洞,/,抗凝治疗,CNS,转移,老年患者,哪些患者适合贝伐珠单抗的治疗？,？,=80y,（,n,128,）,PFS,（月）,6.0,6.4,6.9,6.7,5.9,OS,（月）,13.3,145,13.3,12.3,10.9,Wozniak et al.EMCC 2011,ARIES,老年患者亚组分析表明：,除了大于,80,岁以上的高龄老人外，其余年龄段获益相似。,老年患者,疗效分析,ARIES,研,究,80,岁,分析表明，,老年患者与,80,岁,近期大咯血史,肿瘤侵犯大血管,明显心功能不全,中央型,肿块,基线空洞,抗凝治疗,CNS,转移,老年患者,受,控的高血压,ECOG,PS,=,2,结论：,约,80,非鳞患者都可接受贝伐珠单抗治疗,大部分非鳞患者可以安全地接受,贝伐珠单抗,治疗,Avastin SmPC;,Besse,et al.Clin Cancer Res 2010,谢 谢！,既往未治疗的,IIIB-IV,期,非鳞癌,NSCLC,PS 0-1,(n=939),培美曲塞,N=359,安慰剂,N=180,培美曲塞,+,顺铂,CR/PR/SD,R,2,1,PARAMOUNT,研究设计,AVAPERL,一线诱导,4,周期,q3w,维持维持,治疗,q3w,直至,PD,既往未治疗的,IIIB-IV,期,非鳞癌,NSCLC,PS 0-1,(n=374),贝伐珠单抗,N=124,贝伐珠单抗,+,培美曲塞,N=128,贝伐珠单抗,+,培美曲塞,+,顺铂,CR/PR/SD,R,1,1,最佳总体疗效,PARAMOUNT&AVAPERL,入组的所有患者,Barlesi,et al.ECCO-ESMO 2011,Paz-Ares,et al.ASCO 2011,患者,(%),客观缓解率,绝对差异,10%,2/3,的患者疾病稳定,自诱导阶段的,PFS,54,培美曲塞,:6.9m,安慰剂,:5.6m,HR:0.59,P0.001,3 6 9 12 15,3 6 9 12 15,贝伐珠单抗,+,培美曲塞,:10.2m,贝伐珠单抗,:6.6m,HR:0.50,P0.001,时间,(,月,),100,75,50,25,0,时间,(,月,),AVAPERL,PARAMOUNT,100,75,50,25,0,3.6,个月,1.3,个月,AVAPERL:Barlesi,et al.ECCO-ESMO 2011,PARAMOUNT:Paz-Ares,et al.ASCO 2011,