尼洛替尼与达沙替尼差异

1|Forinternaluseonly.Nottobeshown,distributedordiscussedwithanyoneoutsideNovartis.1|Forinternaluseonly.Nottobeshown,distributedordiscussedwithanyoneoutsideNovartis.DifferentiationTAS1411242042|Forinternaluseonly.Nottobeshown,distributedordiscussedwithanyoneoutsideNovartis.目录•作用机理•ENESTnd&DASISION•安全性和合并症区隔TAS1411242043|Forinternaluseonly.Nottobeshown,distributedordiscussedwithanyoneoutsideNovartis.作用机理区隔TAS1411242044|Forinternaluseonly.Nottobeshown,distributedordiscussedwithanyoneoutsideNovartis.达希纳优先精准抑制Bcr-Abl•目前公认Ph+CML是一种“单一靶点疾病”•Bcr-Abl是Ph+CML的确切病因和关键驱动因素•在伊马替尼治疗耐药的CP或APCML患者中，90%是由于Bcr-Abl重新激活所致•与多靶点抑制相比，优先靶向作用于Bcr-Abl，能减少不需要的非靶向不良事件DeiningerMWN,DrukerBJ.PharmacolRev.2003;55:401-423.TKI靶向作用于酪氨酸激酶的先后顺序尼洛替尼（达希纳®）Bcr-AblPDGFRc-KIT伊马替尼PDGFRc-KITBcr-Abl达沙替尼SrcBcr-AblPDGFRc-KITTAS1411242045|Forinternaluseonly.Nottobeshown,distributedordiscussedwithanyoneoutsideNovartis.多靶点抑制与相关不良事件的发生GilesFJ,O'DwyerM,SwordsR.Leukemia.2009;23(10):1698-1707AlfonsoQuinta´s-Cardama,etal,JClinOncol25:3908-3914.EurJClinInvest2009;39(12):1098–1109.激酶抑制不良事件类型临床表现野生型ABL抑制心脏不良事件充血性心力衰竭，左心室功能不全以及QT间期延长Src激酶抑制骨髓抑制贫血，中性粒细胞减少以及血小板减少胸膜渗出胸腔积液免疫系统抑制易继发感染PDGFR抑制骨代谢异常低磷血症，低钙血症，尿中甲状旁腺激素水平升高体液潴留周围性水肿C-KIT抑制皮肤毒性皮疹，皮肤色素改变骨髓抑制贫血，中性粒细胞减少以及血小板减少TAS1411242046|Forinternaluseonly.Nottobeshown,distributedordiscussedwithanyoneoutsideNovartis.ENESTnd&DASISION各5年的数据解读TAS1411242047|Forinternaluseonly.Nottobeshown,distributedordiscussedwithanyoneoutsideNovartis.ENESTnd研究终点MMR符合CML发展方向试验名称入组基本情况主要研究终点随访时间目前中断治疗比例ENESTnd达希纳300mgBid282达希纳400mgBid281格列卫400mgQD28312个月MMR目前5年结果，延展随访到10年达希纳300mgBid29.1%达希纳400mgBid33.8%格列卫400mgQD33.6%DASISIONDasatinib100mgqd(259)Imatinib400mgqd(260)12个月CCyR已结束5年随访，实验关闭Dasatinib39%Imatinib37%TAS1411242048|Forinternaluseonly.Nottobeshown,distributedordiscussedwithanyoneoutsideNovartis.HabuckyK,MegyeriA.Tasigna(nilotinib)150mgand200mghardcapsulescoredatasheetversion1.3.WestSussex,UnitedKingdom:NovartisEuropharmLimited;2014:1-61.RatesofMMRby5yearsremainedhigherinbothTasignaarmsthanintheimatinibarm达希纳12个月获得MMR患者更多，且5年结果两组仍然维持显著差异100908070605040302010060544842353024181260By5Years77%P.000160%By4Years76%P.000156%By3Years73%P.000153%By2Years71%P.000144%By1Year55%P.000151%P.000127%TimeSinceRandomization,monthsPatientsWithMMR,%Δ28%Δ17%nTasigna300mgBID282Tasigna400mgBID281Imatinib400mgQD283Δ27%Δ20%Δ20%TAS1411242049|Forinternaluseonly.Nottobeshown,distributedordiscussedwithanyoneoutsideNovartis.DASISION:达沙组累积MMR高于伊马替尼组466467737628465560640102030405060708090100By1YearBy2YearsBy3YearsBy4YearsBy5YearsPatientswithMMR,%Dasatinib100mgQD(n=259)Imatinib400mgQD(n=260)∆18∆12∆13∆12MMR=majormolecularresponse,BCR-ABL(IS)≤0.1%;IS=InternationalScale.P=.0022∆18TAS14112420410|Forinternaluseonly.Nottobeshown,distributedordiscussedwithanyoneoutsideNovartis.MR4.5,molecularresponseofBCR-ABLIS≤0.0032%.1.HabuckyK,MegyeriA.Tasigna(nilotinib)150mgand200mghardcapsulescoredatasheetversion1.3.WestSussex,UnitedKingdom:NovartisEuropharmLimited;2014:1-61.2.LarsonRA,etal.JCO.2013;31(18s):[abstract7052].达希纳MR4.5结果组间差异随时间延长逐年增高，有统计学差异•达希纳和伊马替尼MR4.5差异随时间延长逐年增高•获得MR4.5无一例患者发生疾病进展AP/BC100908070605040605448423530By5Years54%P.000131%By4Years40%P.000123%By3Years32%P.000115%By2Years25%P.0001TimeSinceRandomization,monthsPatientsWithMR4.5,%30By1Year0241812609%20101%11%P.0001Δ10%Δ23%nTasigna300mgBID282Imatinib400mgQD283Δ17%Δ17%Δ16%TAS14112420411|Forinternaluseonly.Nottobeshown,distributedordiscussedwithanyoneoutsideNovartis.DASISION:累积MR4.5两组差异有缩小趋势5192434423813233305101520253035404550By1YearBy2YearsBy3YearsBy4YearsBy5YearsPatientswithMR4.5,%Dasatinib100mgQD(n=259)Imatinib400mgQD(n=260)MR4.5=BCR-ABL(IS)≤0.0032%;IS=InternationalScale.P=.0251∆11∆11∆11∆9TAS14112420412|Forinternaluseonly.Nottobeshown,distributedordiscussedwithanyoneoutsideNovartis.aProgressiontoAP/BCeventsincludedprogressionstoAP/BC(excludingclonalevolution)orCML-relateddeathsoccurringoncoretreatmentoronstudy(oncoreorextensiontreatmentorduringfollow-upaftertreatmentdiscontinuation).HabuckyK,MegyeriA.Tasigna(nilotinib)150mgand200mghardcapsulescoredatasheetversion1.3.WestSussex,UnitedKingdom:NovartisEuropharmLimited;2014:1-61CML治疗的基本目标是防止疾病进展达希纳是唯一被证明可以降低疾病进展风险的2ndTKI•2组达希纳降低疾病进展的发生均低于伊马替尼，且300mg组99%患者维持在慢性期•核心治疗组自从2年分析后无一例发生新的疾病进展病例051015202(0.7%)12(4.2%)P=.0059Tasigna300mgBIDImatinib400mgQDENESTnd核心治疗中进展到AP/BC5年结果AP,acceleratedphase;BC,blastcrisis;BID,twicedaily;QD,oncedaily.DASISION5yearsDasatinib100mgQD(n=259)Imatinib400mgQD(n=260)进展AP/BP,n12(4.6%)19(7.3%)差异无统计学意义TAS141124204进展AP/BP,n13|Forinternaluseonly.Nottobeshown,distributedordiscussedwithanyoneoutsideNovartis.安全性和合并症区隔TAS14112420414|Forinternaluseonly.Nottobeshown,distributedordiscussedwithanyoneoutsideNovartis.Dasatinib胸膜腔积液仍为最主要安全性问题(发生率30%)DASISION5-YearFinalStudyResultsDiarrheaHeadacheMusculoskeletalpainSkinrashFatigueAbdominalpainNauseaFaceedemaPeripheraledemaMyalgiaMusclespasmsVomitingPleuralEffusion05101520253035Grade1-2Grade3-4Grade1-2Grade3-4}Dasatinib100mgQDImatinib400mgQD}Patients,%TAS14112420415|Forinternaluseonly.Nottobeshown,distributed