,*,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,*,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,*,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,*,ToGA,研究报告,:,一项在,HER2,受体阳性的晚期胃癌中采用标准化疗联合赫赛汀作为一线治疗方案的,III,期临床研究,Eric Van Cutsem,et al;Abstract,LBA4509,ASCO 2009,1,HER2-,阳性胃癌患者中使用赫赛汀的原理,目前还没有全球统一的标准治疗方案,但是,基于,-,氟尿嘧啶,(,卡培他滨,/5-FU)/,铂类,(,顺铂,/,奥沙利铂,)-,的化疗方案被认为是较好的参考方案,有时也可以加入表柔比星或多西紫杉醇,生物学制剂仍然在研究当中,晚期胃癌仍然需要新的治疗方法,部分胃腺癌,为,HER2,阳性,无论在体内还是体外,研究中,，,均发现,赫赛汀能有效抑制,HER2,高表达的胃癌细胞株,Fujimoto-Ouchi et al 2007;Gravalos&Jimeno 2008,2,HER2,以及赫赛汀的作用机理,HER2,受体,赫赛汀,赫赛汀,抑制,HER2,阳性肿瘤中,HER2,介导的信号传导途径,通过阻断,HER2,受体细胞外区域分裂来抑制,HER2,活性,激活抗体依赖细胞介导的细胞毒性作用,3,ToGA,研究的设计,HER2-,阳性晚期胃癌患者,(n=584),5-FU,或 卡培他滨,a,+,顺铂,(n=290),R,a,由研究者的判别来选择,GEJ,胃食管连接部,5-FU,或 卡培他滨,a,+,顺铂,+,赫赛汀,(n=294),分层因素,局部晚期,vs,转移性,胃,癌,vs,胃食管,结合,部,癌,可测量,vs,不可测量,ECOG,评分,0-1 vs 2,卡培他滨,vs 5-FU,全球、多中心、随机、开放,III,期临床研究,1,Bang et al;Abstract 4556,ASCO 2009,3807,位患者接受筛选,1,810 HER2-,阳性,(22.1%),4,治疗方案,卡培他滨,1000 mg/m,2,bid d1-14 q3w x 6,5-FU,800 mg/m,2,/day,持续静脉滴注,d1-5 q3w x 6,顺铂,80 mg/m,2,q3w x 6,赫赛汀,起始剂量,8 mg/kg,，,之后,6 mg/kg q3w,直至进展,5,ToGA,研究目标,主要研究终点,:,总生存,（,OS,）,次要研究终点,无进展生存（,PFS,）,疾病进展时间（,TTP,）,总缓解率（,ORR,）,临床获益率（,DCR,）,缓解持续时间（,DR,）,生活质量（,QoL,）,安全性,疼痛强度,止痛剂,使用剂量,体重变化,药代动力学,样本量假设,中位,OS,从,10,个月提高至,13,个月,(HR 0.77),-,水平,=0.05,80%,把握度,所需样本量,:584,位患者 随机,1:1,分配,统计分析,第一次预先计划的中期分析在出现,230,个期望事件,(50%),发生后,第二次中期分析在独立数据检测委员会最终确认,345,个事件,(75%),发生后,6,主要的患者入排标准,排除标准,之前的,6,个月内使用过辅助化疗,针对晚期病灶使用过化疗,充血性心力衰竭或者左心室射血分数（,LVEF,）基线值,50%,肌酐清除率,60 mL/min,IHC,免疫组织化学,;FISH,荧光原位杂交,;LVEF,左心室射血分数,入选标准,胃或胃食管,结合部,腺癌,无法手术的局部晚期或转移性肿瘤,具有可测量病灶,(,根据,RECIST 1,.0,标准,),或,不可测量的,可评估,病灶,HER2-,阳性,(,通过中心实验室检测,),IHC 3+,和,/,或,FISH+,胜任,的,脏器功能,以及,ECOG,评分,2,签署知情同意书,7,患者的人口统计学以及基线特征,特征,F+C,n=290,F+C+,赫赛汀,n=294,性别,%,男性,/,女性,75/25,77/23,中位年龄,(,年龄范围,),岁,59.0(21-82),61.0(23-83),中位体重,(,体重范围,),公斤,60.3(28-105),61.5(35-110),地区,n(%),亚洲,美洲欧洲其他,166(56),26(9)95(32)9(3),158(53),27(9)99(33)14(5),胃癌的类型,(,中心实验室评估结果,),肠型,弥漫型混合型,74.2,a,8.7,a,17.1,a,76.8,b,8.9,b,14.3,b,曾行胃部切除术,21.4,24.1,入组最多的为韩国，日本，中国和俄罗斯,F,氟尿嘧啶,;C,顺铂,a,n=287;,b,n=293,8,分层因素,特征,%,F+C,n=290,F+C,+,赫赛汀,n=294,转移性,疾病,96.6,96.6,可测量病灶,88.6,91.5,原发病灶部位胃胃食管,结合,部,83.416.6,80.319.7,ECOG,评分,012,36.254.59.3,34.455.410.2,氟尿嘧啶卡培他滨,5-FU,87.912.1,87.112.9,9,主要研究终点,:OS,（总生存）,时间,(,月,),294,290,277,266,246,223,209,185,173,143,147,117,113,90,90,64,71,47,56,32,43,24,30,16,21,14,13,7,12,6,6,5,4,0,1,0,0,0,处于风险的患者数,11.1,13.8,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,事件,FC+,T,FC,事件,167182,HR,0.74,95%CI,0.60,0.91,p,值,0.0046,中位,OS,13.811.1,T,赫赛汀,10,次要研究终点,:PFS,（无进展生存）,0,2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,事件,294,290,258,238,201,182,141,99,95,62,60,33,41,17,28,7,21,5,13,3,9,3,8,2,6,2,6,1,6,1,4,0,2,0,0,0,5.5,6.7,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,时间,(,月,),FC+,T,FC,事件,226235,HR,0.71,95%CI,0.59,0.85,p,值,0.0002,中位,PFS,6.75.5,处于风险的患者数,11,次要研究终点,:,肿瘤缓解率,2.4%,5.4%,32.1%,41.8%,34.5%,47.3%,意向治疗人群（,ITT,）,总缓解率,(ORR)=,完全缓解率,(CR)+,部分缓解率,(PR),p=0.0599,p=0.0145,F+C,+,赫赛汀,F+C,p=0.0017,患者,(%),CR,PR,ORR,12,有效性分析,:OS,亚组分析,风险比,0.2,1,2,5,0.4,0.6,3,4,所有,所有,584,0.60,0.91,0.74,胃食管,结合,部,原发病灶部位,106,0.42,1.08,0.67,胃,478,0.60,0.96,0.76,地区,亚洲,319,0.61,1.11,0.82,美洲,52,0.21,0.90,0.44,欧洲,190,0.44,0.89,0.63,其他,23,0.48,3.08,1.22,0-1,ECOG,评分,527,0.56,0.89,0.71,2,57,0.51,1.79,0.96,279,0.84,60,305,0.49,0.88,0.66,氟尿嘧啶,5-FU,73,0.40,1.23,0.70,卡培他滨,511,0.60,0.95,0.75,分类,亚组,N,95%CI,HR,弥漫型,胃癌类型,51,0.56,2.05,1.07,肠型,438,0.54,0.88,0.69,混合型,91,0.51,1.46,0.86,1-2,转移灶数目,298,0.68,1.26,0.93,2,285,0.43,0.77,0.57,HER2,结果,IHC 0/FISH+,61,0.48,1.76,0.92,IHC 1+/FISH+,70,0.70,2.20,1.24,IHC 2+/FISH+,159,0.51,1.11,0.75,IHC 3+/FISH+,256,0.41,0.81,0.5