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,*,*,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,*,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,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,*,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,氟维司群和靶向治疗研究简介和总结,抗雌激素药物的化学结构,芙仕得,(,氟维司群,),OH,HO,(CH,2,),9,SO(CH,2,),3,CF,2,CF,3,7,雷洛昔芬,HO,S,OH,O,O,N,雌二醇,OH,HO,他莫昔芬,O,NMe,2,氟维司群是一种新型的雌激素受体拮抗剂,Howell A.Int Gynecol Cancer.2006;16(suppl2):521-523.,John F.Robertson et al.Cancer Research.2001;61:6739-6746.,Dowsett M,et al.Human Reproduction.1995;10(2):262-267.,Kuter I,et al.Breast Cancer Res Treat.2012;133:237-246.,氟维司群精准靶向、下调并降解雌激素受体,雌激素与雌激素受体结合并使之活化，导致乳腺肿瘤细胞的增殖和生长,氟维司群可降解雌激素受体，抑制肿瘤生长,氟维司群研究,CONFIRM,，,China CONFIRM,FIRST,FALCON,CONFIRM,（,III,期）,晚期、绝经后，既往内分泌,治疗后,疾病进展（辅助中或晚期一线后）,250mg VS 500mg,mPFS 5.5m VS 6.5m p0.05,mOS,22.3m VS 26.4m,p0.05,Nominal value,cannot,be claimed as statistically significant,CONFIRM,：主要终点,PFS,0,3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,PFS,时间,(,月,),500mg,250mg,HR=0.80,降低进展风险,20%,95%CI,：,0.68-0.94,P=0.006,Di Leo A,et al.J Clin Oncol 2010;28:4594-4600.,500mg,250mg,中位,PFS(,月,),6.5,5.5,0.1,0,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,4,8,12,16,20,24,28,32,36,40,44,48,52,56,60,64,68,72,76,80,氟维司群,500 mg,氟维司群,250 mg,362,333,288,254,227,202,178,163,141,123,114,98,81,64,47,30,26,15,8,1,0,500 mg,374,338,299,261,223,191,164,137,112,96,87,74,64,48,37,22,14,8,3,2,0,250 mg,Time(months),病人生存比例,处危险患者,HR(95%CI),0.81(0.69,0.96),p-value,0.016,a,至死亡中位时间（月）,氟维司群,500 mg26.4,氟维司群,250 mg 22.3,次要终点：,OS,Di leo et al;Cancer Research,volume 72(24 Suppl.)December 15,2012 Abs S1-4.,a,Nominal value,cannot be claimed as statistically significant,China CONFIRM,（,III,期）,内分泌治疗,复发或进展,的绝经后晚期乳腺癌,250mg VS 500mg,mPFS 2.9m VS 5.8m HR,为,0.65,AI,后亚组：氟维司群,500mg,中位,PFS5.8,个月降低疾病进展风险,35%,中位,PFS:,氟维司群,500 mg 5.8,个月,氟维司群,250 mg 2.9,个月,HR 0.65;95%CI 0.42,1.03,0,0.0,0.2,0.4,0.6,0.8,1.0,3,6,9,12,15,18,21,24,27,30,33,36,53,32,23,21,15,12,10,8,6,3,3,1,0,47,20,14,12,9,3,3,3,2,1,1,1,0,氟维司群,500mg,氟维司群,250mg,存在风险的患者数,无进展患者的比例,自随机分组开始的时间,(,月,),氟维司群,250 mg,氟维司群,500 mg,35%,FIRST,（,II,期）,绝经后激素受体阳性晚期乳腺癌,一线治疗,（未证实有明确的内分泌耐药）,氟维司群,500mg VS,阿那曲唑,1mg,mPFS 23.4m VS 13.1m p0.05,mOS 54.1m VS 48.4m p0.05,主要终点,阳性绝经后乳腺癌一线治疗,氟维司群,500mg n=102,阿那曲唑,1mg n=103,进展患者数,(,%,),63(61.8),79(76.7),中位时间,(,月,),23.4,13.1,11,FIRST,研究次要终点：,TTP,氟维司群组优于,AI,显著延长无疾病进展时间,10.3,个月,主要数据截止期后，进展由研究者确定,Robertson JFR,et al.Breast Cancer Res Treat 2012;136:503-511.,0,6,12,18,24,30,36,42,48,0.0,0.2,0.4,0.6,0.8,1.0,无进展存活患者比例,时间,(,月,),102,74,65,52,45,34,20,6,0,103,69,55,39,30,21,8,2,0,氟维司群,500mg,阿那曲唑,1mg,HR=0.66,95%CI(0.47,-,0.92),p=0.01,氟维司群,500 mg,阿那曲唑,1 mg,风险患者数：,0,12,18,42,48,月,36,30,24,6,氟维司群,500mgn=102,阿那曲唑,1mg n=103,死亡数,(,%,),63(61.8),74(71.8),中位总生存期,(,(,月,),54.1,48.4,FIRST,是唯一有总生存差异的内分泌治疗研究,氟维司群组总生存期获益长达,54.1,个月，优于,AI,组,12,死亡情况不详的患者在最后一次已知其存活的时间时进行右删失,Robertson JFR,et al.Breast Cancer Res Treat 2012;136:503-511.,0,6,12,18,24,30,36,42,108,0.0,0.2,0.4,0.6,0.8,1.0,存活患者比例,时间,(,月,),氟维司群,500mg,阿那曲唑,1mg,HR=0.70,95%CI(0.50,0.98),p=0.041,48,54,60,66,72,78,84,90,96,102,102,90,84,77,57,47,31,24,103,90,80,72,49,39,21,14,0,12,18,24,36,48,60,72,84,96,月,氟维司群,500mg,阿那曲唑,1mg,4,2,39,29,处于风险中的患者数,：,FIRST,研究主要终点：,CBR,CBR(%),74/102,69/103,OR=1.30;95%CI=0.72-2.38,P=0.386,Robertson JFR,et al.Presented at SABCS2010.,FALCON,（,III,期）,绝经后激素受体阳性晚期乳腺癌,未接受过内分泌治疗,氟维司群,500mg VS,阿那曲唑,1mg,mPFS 16.6m VS 13.8m p0.05,无内脏转移,22.3m VS 13.8m p0.05,mOS,31%,的成熟度,50%,FALCON,：主要终点,PFS,圆圈代表删失观察,CI=,置信区间；,HR=,风险比,HR 0.797(95%CI 0.637,0.999);p=0.0486,中位,PFS,氟维司群：,16.6,个月,阿那曲唑：,13.8,个月,处危险中的患者：,氟维司群,阿那曲唑,230,232,187,194,171,162,150,139,124,120,110,102,96,84,81,60,63,45,44,31,24,22,11,10,2,0,0,0,存活且无进展患者比例,时间,(,月,),0.9,1.0,0.7,0.8,0.5,0.6,0.3,0.4,0.1,0.0,0,3,6,9,12,15,18,21,24,27,30,36,33,39,0.2,氟维司群,(n=230),阿那曲唑,(n=232),FALCON,：,有无内脏疾病患者的,PFS,事后交互检验,p0.01,圆圈代表删失观察,CI=,置信区间；,HR=,风险比,无内脏转移,有内脏转移,HR 0.59(95%CI 0.42,0.84),中位,PFS,氟维司群：,22.3,个月,阿那曲唑：,13.8,个月,存活且无进展患者比例,时间,(,月,),0.9,1.0,0.7,0.8,0.5,0.6,0.3,0.4,0.1,0.0,0.2,存活且无进展患者比例,时间,(,月,),0.9,1.0,0.7,0.8,0.5,0.6,0.3,0.4,0.1,0.0,0,5,10,15,20,25,30,35,40,0.2,0,5,10,15,20,25,30,35,40,HR 0.99(95%CI 0.74,1.33),中位,PFS,氟维司群：,13.8,个月,阿那曲唑：,15.9,个月,氟维司群,(n=135),阿那曲唑,(n=119),氟维司群,(n=95),阿那曲唑,(n=113),FALCON,：,OS(31%,的成熟度,),中位随访,25.0,个月,圆圈代表删失观察,CI=,置信区间；,HR=,风险比,0,6,21,时间,(,月,),氟维司群,(N=230),阿那曲唑,(N=232),3,9,12,15,18,24,27,30,33,36,39,0.9,1.0,0.7,0.8,0.6,0.5,0.4,0.3,0.2,0.1,0.0,生存率,HR 0.88(95%CI 0.63,1.22);p=0.428,处危险患者：,氟维司群,阿那曲唑,230,232,221,223,208,213,200,197,188,186,180,175,168,164,153,155,129,122,92,94,57,61,31,37,17,18,0,0,无进展生存期分析在进展事件数为,306,例时进行,总生存期分析在死亡率为,50%,时进行,常见的热门联合用药,1,、CDK,4/6,抑制剂（,Palbociclib,、,Ribociclib,、,Abemaciclib,）,2,、,mTOR,抑制剂,（,依维莫司,、,西罗莫司,、,LNK128,、,AZD2014,）,3,、,PI3K,抑制剂,（,Buparlisib,、,Pilaralisib,、,Pictilisib,、,Alpelisib,、,Taselisib,）,4,、其他（,IGF-1R,抑制剂,Ganitumab,，,吉非替尼,，,FGFR,抑制剂,Dovitinib,、,Lucitanib,，,组蛋白去乙酰化酶抑制剂,Entinostat,）,CDK,4/6,抑制剂,Palbociclib,（PALOMA-,1,2,3,）,Ribociclib,（,MONALEESA-2,3,7,）,Abemaciclib,（,MONARCH-1,2,3,）,CDK4/6,是抗肿瘤的重要靶点,周期蛋白依赖性激酶,4/6(cycli