kadcyla申报材料综述

CENTERFORDRUGEVALUATIONANDRESEARCHAPPLICATIONNUMBER:125427Orig1s000SUMMARYREVIEWDivisionDirectorReviewPage2of27MaterialReviewed/ConsultedONDActionPackage,including:NamesofdisciplinereviewersMedicalOfficerReviewLalehAmiri-Kordestani,GideonBlumenthalStatisticalReviewsQiangXu,ShenghuiTang,MeiyuShenPharmacologyToxicologyReviewsWilliamMcGuinn,ToddPalmby,JohnLeightonOBPReviewsLinanHa,WendyWeinberg,KimberlyRainsONDQAAnneMarieRussell,Xiao-HongChen,AliAlHakimProductQualityMicrobiologyBoChi,PatriciaHughes,ReyesCandau-ChaconOMPQ/NDMABLindaNgClinicalPharmacologyReviewSarahSchrieber,JianWang,PengfeiSongOPDPMarybethToscanoOSILaurenIacono-ConnorsCDTLReviewPatriciaCortazarOSE/DMEPAJibrilAbdus-SamadOSE/OMEPRMSuzanneRobottomIRT-QTConsultationSatjitBrar,KevinKudys,MohNg,QianyuDang,NormanStockbridgeCDRH/OIVDKevinLorickOND=OfficeofNewDrugsDPDP=DivisionofProfessionalDrugPromotionOSE=OfficeofSurveillanceandEpidemiologyDMEPA=DivisionofMedicationErrorPreventionandAnalysisOSI=OfficeofScientificInvestigationsDDRE=DivisionofDrugRiskEvaluationDRISK=DivisionofRiskManagementCDTL=Cross-DisciplineTeamLeaderIRT-QT=InterdisciplinaryReviewTeamforQTStudiesN/A=notapplicableReferenceID:3265340DivisionDirectorReviewPage3of27DivisionDirectorSummaryReview1.IntroductionThisBiologicsLicenseApplication(BLA)forKADCYLA(ado-trastuzumabemtansine)isdatedAugust24,2012,andwasreceivedonAugust27,2012.Thefinalindicationis“KADCYLA™,asasingleagent,isindicatedforthetreatmentofpatientswithHER2-positive,metastaticbreastcancerwhopreviouslyreceivedtrastuzumabandataxane,separatelyorincombination.Patientsshouldhaveeither:•Receivedpriortherapyformetastaticdisease,or•Developeddiseaserecurrenceduringorwithinsixmonthsofcompletingadjuvanttherapy.”Thisreviewwillsummarizetheefficacyandsafetydatasupportingapproval,theissuesidentifiedbyandrecommendationsofeachreviewdiscipline,andtheriskbenefitassessment.Thisapplicationwasgrantedapriorityreview.Anexpeditedreviewoflessthanfourmonthswasplannedbutwasnotpossiblebecauseofmanufacturingissuesdescribedbelowwhichwerediscoveredduringthereviewandmanufacturingsiteinspections.2.BackgroundTheproductanditsmechanismofactionaresummarizedinthefollowingexcerptfromtheagreed-uponpackageinsert.Ado-trastuzumabemtansineisaHER2-targetedantibody-drugconjugate.Theantibodyisthehumanizedanti-HER2IgG1,trastuzumab.Thesmallmoleculecytotoxin,DM1,isamicrotubuleinhibitor.Uponbindingtosub-domainIVoftheHER2receptor,ado-trastuzumabemtansineundergoesreceptor-mediatedinternalizationandsubsequentlysosomaldegradation,resultinginintracellularreleaseofDM1-containingcytotoxiccatabolites.BindingofDM1totubulindisruptsmicrotubulenetworksinthecell,whichresultsincellcyclearrestandapoptoticcelldeath.Inaddition,invitrostudieshaveshownthatsimilartotrastuzumab,ado-trastuzumabemtansineinhibitsHER2receptorsignaling,mediatesantibody-dependentcell-mediatedcytotoxicityandinhibitssheddingoftheHER2extracellulardomaininhumanbreastcancercellsthatoverexpressHER2.TheregulatoryhistoryissummarizedintheCDTLReview.ReferenceID:3265340DivisionDirectorReviewPage11of275.ClinicalPharmacology/BiopharmaceuticsTheClinicalPharmacologyReviewstatedthatthisBLAisconsideredacceptablefromaclinicalpharmacologyperspectiveandprovidedthefollowingsummaryoftheclinicalpharmacology.Trastuzumabemtansine(T-DM1,xxx-trastuzumabemtansine)isaHER-2-directedantibody-drugconjugate(ADC)consistingoftrastuzumab,ahumanizedanti-HER2IgG1isotypemonoclonalantibody,emtansine(DM1),ananti-microtubuleagentderivedfrommaytansine,andSMCC,alinkermoleculeusedtoconjugateDM1totrastuzumab.MechanismofAction:ThemechanismofactionofT-DM1consistsofamulti-stepprocess.T-DM1bindstoHER2thenundergoesreceptor-mediatedinternalization,whichresultsintheintracellularreleaseofDM1andsubsequentlycelldeath.Efficacy:TheproposedindicationisforthetreatmentofpatientswithHER2-positive,metastaticbreastcancerwhohavereceivedpriortreatmentwithtrastuzumabandataxane.Onephase3randomized(1:1),open-label,active-controltrialwasconductedtosupporttheproposedindicationatadoseof3.6mg/kgT-DM1givenasanintravenousinfusionover30minutesonceeverythreeweeks.Overallsurvival(OS)andprogressionfreesurvival(PFS)weresignificantlylongerintheT-DM1armcomparedtotheactivecontrolarm(lapatinibpluscapecitabine).Exposure-Response(EfficacyandSafety):Afteraccountingforbaselineriskfactors,theexposure-responseanalysisdemonstratedthatincreasesinT-DM1exposuresarerelatedwithbetterefficacy(OS,PFS,andobjectiveresponserate(ORR)).Exposure-responserelationshipsforsafetyidentifiedaninversetrendforGrade3orworsehepatotoxicity,butnosignificantexposure-responserelationshipswereidentifiedforthrombocytopenia.Pharmacokinetics(PK):DataonthePKofT-DM1,totalantibody,andDMisavailablefromonephase1trial,fourphase2trials,andonephase3trial.ApopulationPKanalysisestimatedtheT-DM1clearanceandterminaleliminationhalf-lifeas0.68L/dayand~4days,respectively;inter-individualvariabilityofCLis19.1%.T-DM1accumulationwasnotobservedfollowingmultipledosing.Nodoseadjustmentsarerequiredforsignificantcovariates(sumoflongestdiameteroftargetlesionsbyRECIS