mTOR抑制剂在癌症治疗中的应用.ppt

mTORInhibitors(mTOR抑制剂)inCancerTherapy,RuiRongYuan,MD,PhDOncology,NovartisresponsewereobservedinpreviouslytreatedmRCC(uncontrolledphaseIIstudy),BetterInhibitionofp70S6KinaseWithDailySchedule,0,1,2,3,4,5,6,7,Tumor,0,50,100,Time,days,Inhibitionofp70S6KinaseActivity,%,Continuoustargetinhibitionispredictedtobeachievablethroughtheuseofdailydosingschedules,Tanakaetal.,manuscriptinpreparation2007.,PhaseIITrialofRAD001inmRCC(Amato),Jacetal.ASCO,2007.Abstract5107,N=37,N=39,Median=11.17+(2.0031.53+)Months,Median=24.17+Months,Progression-FreeSurvival,OverallSurvival,Time(months),Time(months),Objectives(endPoint)Primary:PFSSecondary:Safety;Response;Patientsreportedoutcome;OS,RECORD-1(REnalCellcancertreatmentwithOralRAD001givenDaily)随机III期试验:比较RAD001与安慰剂(phaseIII,double-blind,randomizedtrialofRAD001+BSCvsPlacebo+BSC),RECORD-1PhaseIIIstudydesign(随机III期试验:比较RAD001与安慰剂),410patientsrandomizedbetweenSeptember2006andOctober2007Secondinterimanalysiscut-off:October15,2007,basedon191PFSeventsIndependentDataMonitoringCommitteerecommendedterminationofstudy,RANDOMIZATION2:1,Placebo+BSC(n=138),UponDiseaseProgression,Interimanalysis,Interimanalysis,N=410StratificationPriorVEGFRTKI:1or2舒尼替尼或索拉非尼治疗后进展的患者MSKCCriskgroup:favorable,intermediate,orpoor,=,Finalanalysis,Everolimus+BSC(n=272),Placebo+BSC(n=138),Everolimus+BSC(n=272),Placebo+BSC(n=138),RAD001+BSC(n=272),透明细胞癌,Treatmentgivenin28-daycycles,Progression-FreeSurvivalbyTreatmentCentralRadiologyReview,延长无进展生存期,MotzerRJ,etal.ASCO2008andLancet2008;372:44956,Progression-FreeSurvivalbyTreatmentInvestigatorAssessment,MotzerRJ,etal.ASCO2008andLancet2008;372:44956,SubgroupAnalysisofProgression-FreeSurvivalCentralRadiologyReview,1.Motzeretal.JClinOncol.2004;22:454-463.,1,MotzerRJ,etal.ASCO2008andLancet2008;372:44956,Treatment-RelatedAdverseEvents*,*10%ofeverolimuspatientsandadditionalselectedAEs.Significantdifferencebetweensumofgrade3/4eventsforeverolimusandplacebogroups(P.05).,Conclusions,Everolimusprolongsprogression-freesurvivalinRCCpatientsafterprogressiononVEGFr-TKItherapiesEverolimusisthefirstandonlyagentwithestablishedclinicalbenefitforthetreatmentofpatientswithRCCafterVEGFr-TKItherapyEverolimusshouldbestandard-of-careinthissetting,StandardsforRCCTherapybyPhaseIIITrialafterASCO2008,*MSKCCriskstatus,MotzerRJ,etal.ASCO2008,Everolimus:DevelopmentOverview,ActiveinmultipletumortypesRCCandNET-firstindicationsLymphomaandTSC-pivotaltrialscominggenerallywell-tolerat