Neoadjuvant Therapy as a Platform for Drug Developmentand Approval in Breast Cancer新辅助治疗作为药物开发的平台 乳腺癌的批准

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1、CCRFOCUSNeoadjuvantTherapyasaPlatformforDrugDevelopmentandApprovalinBreastCancer12AdityaBardiaandJoseBaselgaAbstractThetraditionaldrugdevelopmentprocessinbreastcancerbasedonlargephaseIIIstudieshasseriouslimitationsandneedsamajoroverhaul.Searchingfornewapproaches,thetestingofnovelagen

2、tsinthepreoperative(neoadjuvant)settingapproachoffersapotentiallyrapidandefficientstrategyfordrugdev-elopmentutilizingpathologiccompleteresponse(pathCR),asurrogatemarkerforsurvival,astheprimaryendpoint.Inaddition,neoadjuvantstudiesallowtheassessmentofdrugeffectsonthetarget(pharmaco-dyn

3、amicresponse)andthedevelopmentofpredictivebiomarkersofresponse.Molecularprofilingoftheresidualtumorinthesurgicalspecimenmayalsoprovideinsightsintoactionablemechanismsofresistance.Recognizingthepotentialofneoadjuvanttrialsfordrugdevelopment,theU.S.FoodandDrugAdminis-tration(FDA)recently

4、announcedconsiderationofneoadjuvanttrialsforaccelerateddrugapprovalinearlybreastcancer,particularlyfortumorswithhighriskofrecurrenceandunfavorableprognosis,andprovidedacceleratedapprovaltoneoadjuvantpertuzumabinSeptember2013.TheFDAhasemphasizedthatwhileimprovementinpathCRcouldbeutiliz

5、edfor"accelerated"approval,improvementinsurvivalwillstillneedtobedemonstratedfor"regular"approval.Keyconsiderationsinconductofsuchneoadjuvantdrugdevelopmenttrialsinclude(i)studydesignsuchasutilizationofbiomarkerstratifieddesigntoevaluateabiomarkerthatcouldenrichresponse,(ii)definitionof

6、pathCR,(iii)distributionoffactorsthatinfluencepathCRbetweenthetreatmentarms,(iv)prespecifiedplanforfollow-uptoobtaindataonsurvival,and(v)safetyasitinvolvesapatientpopulationwithcurabledisease.Intheyearstocome,weanticipateanincreaseinthenumberofneoadjuvanttrialstestingnoveltherapiesthath

7、opefullywillopenanewpathinbringingefficaciousnewtherapiestopatientswithbreastcancer.ClinCancerRes;19(23);636070.Ó2013AACR.IntroductionInthisreview,weprovideanoverviewoftheongoinginitiativesintheneoadjuvantspaceandanalyzethekeyNeoadjuvanttherapy,alsoknownaspreoperativether-consideration

8、sandc