肉瘤化疗SUCCEED ASCO 2011ppt课件.ppt

ResultsofthePhase3 placebo controlledtrial SUCCEED evaluatingthemTORinhibitorridaforolimusasmaintenancetherapyinadvancedsarcomapatientsfollowingclinicalbenefitfrompriorstandardcytotoxicchemotherapy S P Chawla J Y Blay I Ray Coquard A LeCesne A P Staddon M M Milhem N Penel R F Riedel B BuiNguyen L D Cranmer P Reichardt E Bompas Y Song R M Lee J E Eid J Loewy F G Haluska P F Dodion G D Demetri onbehalfofallSUCCEEDinvestigators mTORsignalingdysregulatedinmultiplesarcomasRidaforolimus arapamycinanalogandpotentmTORinhibitorClinicalactivityinsarcomasinPhase1and2studies ThePI3K AKT mTORpathwayregulatescellgrowth proliferationandmetabolisminsarcoma Ridaforolimus antitumoractivityinsarcoma Ridaforolimus previousactivitydemonstratedinsarcomas Clinicalbenefitrate CR PR SD 4months PD Metastaticsarcomaafter1 3linesCT perSOC Ineligible RidaforolimusPlacebo 40mgQDx5perweek SOCwatchfulwaiting IRC CR PR SD randomization SarcomastandardcareandtheSUCCEEDpivotalPhaseIIItrialdesign SUCCEEDstudyendpoints PrimaryendpointImprovementinPFSbyindependentradiologyreviewSecondaryendpointsOverallsurvivalBesttargetlesionresponseCancer relatedsymptomsSafetyandtolerability PivotalPhaseIIItrialdesignstatisticsandkeyfeatures Statisticaldesign 650patientswith90 powertodetect33 improvementinPFS 516PFSevents 0 025 one sided Stratifiedforlineoftherapy histology andgeographyTwointerimanalyses711patientsenrolledbetweenOct 07andJan 10 702patientsreceivedeitherridaforolimusorplaceboLargestrandomizedstudyeverinthesofttissueandbonesarcomapopulation Patientcharacteristicswerebalancedatstudyentry PFSperindependentradiologyreview IndependentRadiologyReview HR 0 72 p 0 0001 Weeks Datacut offdate10 25 2010 PFSrateMedianPFS3mon6monRidaforolimus17 7weeks70 34 Placebo14 6weeks54 23 PFSperinvestigatorassessment Weeks InvestigatorAssessment HR 0 69 p 0 0001 Datacut offdate10 25 2010 PFSrateMedianPFS3mon6monRidaforolimus22 4weeks72 37 Placebo14 7weeks55 23 Consistentprogressionfreesurvivalimprovementacrossmultiplesubgroupanalyses favorrida favorplacebo SUCCEED trendinOverallSurvival OS 386deatheventsbasedondatacut offdate4 30 2011 6monthsafterPFSdatacut offdate HR0 88 p 0 2256MedianOSridaforolimus 21 4monthsPlacebo 19 2months Tumorresponse ClinicalBenefitRate CBR 4months Exploratoryanalysisofcancer relatedsymptoms Questionnairescompletedbythepatientsperiodicallyin3categories pain coughandshortnessofbreathVastmajority 90 ofpatientswhostayedontherapywerefreeofseveresymptomsinbothtreatmentgroupsSmallnumericalimbalancesfavoringplaceboatsometimepointsLargeamountofmissinginformationmainlyduetotreatmentdiscontinuationGreaterinplacebopatientsovertimeAnalysisisinconclusiveduetolargeamountofmissinginformationFollowingdiseaseprogression noinformationaboutcancer relatedprogressionwascollected SUCCEED ridaforolimusinhibitedtumorgrowth Waterfallplots Besttargetlesionresponse mean Ridaforolimus 1 3 Placebo 10 3 p 0 0001 Survivalfollowingdiseaseprogressionwassimilarfortheridaforolimusandplacebogroups Post progressionsurvival durationfromdiseaseprogressiontodeath HR 0 94 95 CI 0 76 1 18 p 0 6152 RidaforolimusPlacebo Weeks AdverseeventsnotedduringSUCCEEDtrial AdverseeventsreportedwiththeclassofmTORinhibitors 6deathsdueto pulmonarydisorders withridaforolimusvs noneinplacebo 1drug relatedpneumonitis 2pleuraleffusion 1pulmonaryembolism 2respiratorydistress Summary Ridaforolimusimprovesdiseasecontroltomaintainbenefitofpriortherapy StudymettheprimaryendpointinPFSimprovement HR0 72 p 0 0001 TrendtowardOSbenefit HR0 88 p 0 2256 BettertumorgrowthcontrolNoadverseimpactonsurvivalfollowingdiseaseprogressionNomajorunexpectedAEs andtoxicitiessimilartoothermTORinhibitors Acknowledgements AllofthesarcomapatientsandtheirfamilieswhomadethistrialSUCCEEDAlloftheworldwideinvestigatorsandstudyteammembersThestudysponsors MerckandAriadPharmaceuticals Backupslides ComparisonofIndependentradiologyreviewandinvestigatorassessment concordancerate80 Weeks InvestigatorAssessment HR 0 69 p 0 0001 RidaforolimusPlacebo IndependentRadiologyReview HR 0 72 p 0 0001 RidaforolimusPlacebo Efficacyresultofpediatricpopulations Ridaforolimusgroup7patient