依维莫司为晚期乳腺癌治疗.ppt

mTOR抑制剂：依维莫司为HR+晚期乳腺癌患者治疗开启新时代,新药的不断面世为乳腺癌患者带来更多获益mBC的生存时间随着治疗进展而不断延长,FigureadaptedfromChiaS,etal.Cancer.2007;110(5):973-979.mBC=metastaticbreastcancer.,一项来自英国的统计显示，mBC患者自诊断起的生存时间不断延长1991-2001,N=2,150,1.0,1999-2001,1997-1998,1994-1995,1991-1992,0.8,OverallSurvival,0.6,0.4,0.2,0,1,2,3,Time,years,4,5,0,Cohorts332(3):190194;2SlamonDJ,etal.NEnglJMed2001;344:783792;3VogelCL,etal.JClinOncol2002;20:719726;4MillerK,etal.NEnglJMed2007;357:26662676;5GeyerCE,etal.NEnglJMed2006;356:27332743.,对于HR+mBC患者，LET较TAM疗效显著,MouridsenH,etal.JClinOncol.2003;21:2101-2109.,Abbreviation:MBC,metastaticbreastcancer.,期待新的药物能进一步提高内分泌疗效与AI相比，氟维司群单药并不能显著改善HR+mBC患者的疗效,Trial2098;2.ChiaS,etal,JClinOnco,2008;26(10);,未接受过TAM治疗的患者(n=414),治疗期间不允许接受其他类型的内分泌治疗和化疗入组时间2004.6-2009.6主要研究终点：PFS次要研究终点：OS及安全性,期待新的药物能进一步提高内分泌疗效氟维司群联合AI并不能显著改善既往未接受过TAM治疗的HR+mBC患者的疗效,内分泌作用通路与其他通路之间的CROSS-TALKPI3K/Akt/mTOR通路的激活与内分泌耐药相关,YueW,etal.JSteroidBiochemMolBiol.2007;106:102-110.,Abbreviations:E,estrogen;EGFR,epidermalgrowthfactorreceptor;ER,estrogenreceptor;IGF-1R,insulin-likegrowthfactor-1receptor;mTOR,mammaliantargetofrapamycin.,芳香化酶抑制剂：ER+乳腺癌,内分泌治疗耐药与肿瘤细胞信号传导通路的改变有关,在雌激素剥夺后的ER+乳腺癌细胞中观察到PI3K/AKTmTOR通路活化1,1.SantenRJ,etal.EndocrRelatCancer.2005;12suppl1:S61-S73;2.BoulayA,etal.ClinCancerRes.2005;11:5319-5328.,ER+的肿瘤细胞中观察到依维莫司和来曲唑具有协同作用2,*P2cm,RANDOMIZE,Letrozole2.5mg/dayEverolimus10mg/day,Letrozole2.5mg/dayPlacebo,SCREEN,Abbreviation:ER,estrogenreceptor.,依维莫司组的患者中57%Ki67表达降低(一种细胞增殖的标记物)，而对照组仅30%,BaselgaJ,etal.JClinOncol.2009;27:2630-2637.,Abbreviations:CR,completeresponse;PR,partialresponse.,新辅助LetrozoleEverolimus的II期临床研究,TAMRAD方案,随机，II期临床研究接受过AI治疗的HR+,HER2-的转移性乳腺癌患者分层因素:原发/继发内分泌耐药原发:AI治疗时发生复发转移，或AI治疗后6个月内继发:复发转移(6mo)或针对转移性病灶应用AI后出现进一步的疾病进展不允许交叉换药,BachelotT,etal.BreastCancerResTreat.2010;100suppl1;SABCS2010,abstractS1-6.,Abbreviation:TAM,tamoxifen.,14,患者人群特征,Bourgier，Abstract,ESMO,2011,临床获益率及至疾病进展时间(TTP),15,临床获益率P=0.045(exploratoryanalysis),0,10,20,30,40,50,60,70,TAM,TAM+EVE,CBR,%ofPatients(95%CI),42.1%(29.1-55.9),61.1%(46.9-74.1),至疾病进展时间TAM:4.5monthsTAM+EVE:8.6monthsHR(95%CI)=0.54(0.36-0.81)P=0.0021(exploratoryanalysis),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,随访时间，月,TTPProbability,TAM,Atrisk,57,54,45,39,34,28,26,25,20,19,17,14,10,3,3,2,1,44,30,24,22,16,13,11,7,6,4,2,2,1,0,0,TAM+EVE,Bourgier，Abstract,ESMO,2011,16,总生存,TAM,TAM+EVE,Bourgier，Abstract,ESMO,2011,根据内分泌耐药情况分析至疾病进展时间,17,原发性耐药TAM:3.8monthsTAM+EVE:5.4monthsHR=0.70(0.40-1.21)P=NS(exploratoryanalysis),继发性耐药TAM:5.5monthsTAM+EVE:14.8monthsHR=0.46(0.26-0.83)P=0.0087(exploratoryanalysis),Bourgier，Abstract,ESMO,2011,TAM,TAM+EVE,18,根据内分泌耐药情况分析总生存,原发性耐药N(%)ofeventsTAM:15(54%)TAM+EVE:12(46%)HR=0.73(0.34-1.55)P=0.41(exploratoryanalysis),继发性耐药N(%)ofeventsTAM:16(55%)TAM+EVE:4(15%)HR=0.21(0.07-0.63)P=0.002(exploratoryanalysis),Bourgier，Abstract,ESMO,2011,副反应分析,Bourgier，Abstract,ESMO,2011,20,TAMRAD小结,在这项mTOR抑制剂和抗雌激素药物联合应用的随机II期临床研究中：与他莫西芬单药治疗相比，他莫西芬联合依维莫司能有效提高患者CBR,TTP及总生存CBR:61vs42%TTP:HR=0.54;95%CI,0.36-0.81总生存:HR=0.45;95%CI,0.24-0.81对于继发性耐药患者，临床获益更大副反应可管理，与既往研究相一致,Bourgier，Abstract,ESMO,2011,正在进行的II期临床研究ER+且AI治疗失败的转移性乳腺癌患者应用Fulvestrant和Everolimus,11例AI治疗6个月内出现复发转移的ER+转移性乳腺癌Fulvestrant500mgonday1,then250mgondays14and28,andthenmonthlythereafterEverolimus5mg/dayinthefirstmoinfirst5patientsthen10mg/dayafterward;10mg/dayforsubsequentpatients疗效分析平均TTP:8.6mo临床获益率(CR+PR+SD24wk):55%,BadinF,etal.BreastCancerResTreat.2010;100suppl1;SABCS2010,abstractP4-02-05.,Abbreviations:AE,adverseevent;AI,aromataseinhibitor;CR,completeresponse;ER,estrogenreceptor;MBC,metastaticbreastcancer;PR,partialresponse;SD,stabledisease.,依西美坦依维莫司治疗晚期乳腺癌患者(III期),依维莫司10mgPOqd+依西美坦25mgPOqd(n=485),安慰剂POqd+EXE25mgPOqd(n=239),R,研究终点：主要:PFS（当地及中央评估）次要:OS,ORR,至ECOG体能状态评分下降时间,安全性,生活质量变化,.,2:1,直到疾病进展或出现严重毒性反应,N=705绝经后ER+不可切除的局部晚期或转移性乳腺癌来曲唑或阿那曲唑治疗后疾病进展,22,BOLERO-2:患者基线特征,aAllotherpatientshad1bonelesion.,PresentedbyJ.Baselgaatthe2011EuropeanMultidisciplinaryCancerCongress(ECCO/ESMO),September26,2011.Abstract:9LBA.,23,BOLERO-2:前期治疗,LET:letrozole,ANA:anastrozole,PresentedbyJ.Baselgaatthe2011EuropeanMultidisciplinaryCancerCongress(ECCO/ESMO),September26,2011.Abstract:9LBA.,24,BOLERO-2(随访12个月):PFS当地评估,0,20,40,60,80,100,0,6,12,18,24,30,36,42,48,54,60,66,72,78,84,90,96,Time(weeks),Probability(%)ofEvent,HR=0.44(95%CI:0.36-0.53)LogrankPvalue:1x10-16EVE+EXE:7.4monthsPBO+EXE:3.2months,EVE+EXE(E/N=267/485),PBO+EXE(E/N=190/239),Everolimus,Placebo,Numberofpatientsstillatrisk,485,436,365,303,246,188,136,96,64,45,34,21,13,9,2,2,0,239,190,131,95,63,45,29,19,12,8,6,6,4,2,0,0,0,HortobagyiG.etal,SABCS2011(Abstract#S3-7),BOLERO-2(随访12个月):PFS中央评估,HortobagyiG.etal,SABCS2011(Abstract#S3-7),Everolimus,Placebo,Numberofpatientsstillatrisk,485,422,351,284,224,176,119,86,57,38,32,22,12,7,2,2,0,239,179,112,74,56,36,23,18,8,5,4,4,3,1,0,0,0,0,20,40,60,80,100,0,6,12,18,24,30,36,42,48,54,60,66,72,78,84,90,96,Probability(%)ofEvent,HR=0.36(95%CI:0.28-0.45)LogrankPvalue:1x10-16EVE+EXE:11.0monthsPBO+EXE:4.1months,EVE+EXE(E/N=155/485),PBO+EXE(E/N=127/239),Time(weeks),HortobagyiG.etal,SABCS2011(Abstract#S3-7),BOLERO-2(随访12个月):PFS亚组分析,HortobagyiG.etal,SABCS2011(Abstract#S3-7),BOLERO-2(随访12个月):反应率PFS=progression-freesurvival.HortobagyiGetal.SABCS2011(Abstract#S3-7),BOLERO-2(长期随访数据):QOLQoL分级评分:至评分恶化5%的时间,HortobagyiG.etal,SABCS2011(Abstract#S3-7),0,20,40,60,80,100,0,6,12,18,24,30,36,42,48,54,60,66,72,78,84,90,96,Time(weeks),Probability(%)ofEvent,HR=0.81(97.5%CI:0.62-1.06)Logrankpvalue:0.0396EVE+EXE:7.0monthsPBO+EXE:5.6months,EVE+EXE(E/N=246/485),PBO+EXE(E/N=106/239),Everolimus,Placebo,Numberofpatientsstillatrisk,485,425,299,239,187,149,109,75,56,33,25,14,11,8,2,1,0,239,200,115,82,60,44,27,17,9,7,4,4,1,0,0,0,0,QOLevaluatedusingtheEORTC-QLQ-30scale,BOLERO-2(随访12个月):骨标记物,EVE=everolimus;EXE=exemestane;PBO=placebo.HortobagyiGetal.SABCS2011(Abstract#S3-7),%ChangeFromBaseline,-5.6,-20.3,-6.3,-3.6,-26.7,-0.4,20.9,35.5,29.5,18.1,40.7,40.3,-40,-30,-20,-10,0,10,20,30,40,50,BSAP,P1NP,CTX,BSAP,P1NP,CTX,6周,12周,EVE+EXE,PBO+EXE,27%,56%,36%,22%,6