Zykadia是一种口服、选择性间变性淋巴瘤激酶抑制剂

　　2015年3月2日讯/生物谷BIOON/--瑞士制药巨头诺华（Novartis）肺癌新药Zykadia（ceritinib）近日在欧盟监管方面传来好消息。欧洲药品管理局（EMA）人用医药产品委员会（CHMP）已建议批准Zykadia，用于经ALK抑制剂Xalkori（crizotinib，克唑替尼）治疗后病情恶化的间变性淋巴瘤激酶阳性（ALK+）转移性非小细胞肺癌（NSCLC）成人患者的治疗。如果获批，Zykadia将成为欧洲Xalkori经治ALK+NSCLC患者的首个治疗方案，将解决这一群体中远未满足的医疗需求。欧盟委员会（EC）在做出最终审查决定时，通常都会采纳CHMP的建议。这意味着，Zykadia将在未来3个月内获批上市，这也标志着Zykadia继美国FDA批准之后的又一个监管里程碑。
　　在全球范围内，肺癌是癌症死亡的主要病因之一，据估计每年有160万人确诊肺癌。非小细胞肺癌（NSCLC）是最常见类型，约占所有病例的85-90%，其中2-7%病例由ALK基因重排驱动，导致癌细胞加速生长。Xalkori是由辉瑞研发的全球首个间变性淋巴瘤激酶（ALK）靶向治疗药物，该药的上市极大地改变了晚期ALK+NSCLC患者的临床治疗，但病情恶化往往不可避免，当肿瘤对Xalkori无响应后，患者鲜有治疗方案，Zykadia将成为这一群体的重要治疗选择。
　　CHMP的积极建议，是基于2项全球性多中心开放标签单组研究（StudyA和StudyB）的数据。StudyA是一项I期研究，包括一个剂量递增阶段和一个扩展阶段（推荐剂量750mg）。该研究在246例ALK+NSCLC患者中开展，其中163例既往接受过一种ALK抑制剂（Xalkori）治疗，另外83例为ALK抑制剂初治。数据显示，Xalkori经治组（n=163），总缓解率（ORR）为56.4%（95%CI，48.5-64.2%），中位缓解持续时间（DOR）为8.3个月（95%CI,6.8-9.7个月），中位无进展生存期（PFS）为6.9个月（95%CI,5.6-8.7个月）。StudyB研究是一项II期研究，评估了750mg剂量Zykadia治疗局部晚期或转移性ALK+NSCLC的疗效和安全性，涉及140例既往经1-3线化疗后接受crizotinib治疗病情恶化的患者。
　　Zykadia是一种口服、选择性间变性淋巴瘤激酶（ALK）抑制剂。在肺癌的临床治疗中，ALK是一个重要的治疗靶标。ALK基因能够与其他基因融合，表达一种异常的融合蛋白，促进癌细胞的形成和生长。目前，Zykadia已获美国、墨西哥、智利、韩国、危地马拉及厄瓜多尔批准。此外，中北美、南美、中美洲及亚洲的监管审查正在进行中。
英文原文：NovartislungcancerdrugZykadia®recommendedforEUapprovalinpatientswithALK+NSCLCpreviouslytreatedwithcrizotinib
-Ifapproved,Zykadia(ceritinib)wouldbethefirsttreatmentoptionforpatientsinEuropewithALK+NSCLCpreviouslytreatedwithcrizotinib
-ALK+NSCLCisdrivenbyarearrangementoftheALKgene,whichisresponsibleforcancercellgrowthin2-7%ofpatientswithNSCLC[1]
-PositiveCHMPopinionrepresentsacriticalmilestoneforZykadia;nowapprovedinseveralcountriesworldwide,withadditionalregulatoryfilingsunderway
Basel,February27,2015-NovartisannouncedtodaythattheCommitteeforMedicinalProductsforHumanUse(CHMP)oftheEuropeanMedicinesAgencyadoptedapositiveopinionforZykadia®(ceritinib)totreatadultpatientswithanaplasticlymphomakinase(ALK)-positiveadvancednon-smallcelllungcancer(NSCLC)previouslytreatedwithcrizotinib[2].IfapprovedintheEuropeanUnion(EU),ZykadiawillbethefirsttreatmentoptiontoaddressanunmetmedicalneedforpatientswithALK+NSCLCpreviouslytreatedwithcrizotinib.
"PatientswithadvancedALK+NSCLChavefewoptionswhentheircancerdoesnotrespondtocurrentlyapprovedtherapy,"saidAlessandroRiva,MD,GlobalHead,NovartisOncologyDevelopmentandMedicalAffairs."Asaleaderinthedevelopmentofprecisiononcologymedicines,NovartisiscommittedtodevelopingandbringingtomarketnewtreatmentsforpatientswithALK+NSCLC.ThispositiveCHMPopinionforZykadiabringsusonestepclosertoprovidingthelungcancercommunitywithnewhopeinthefightagainstthisterribledisease."
Eachyear,thereare1.6millionpeoplediagnosedwithlungcancer,theleadingcauseofcancerdeathworldwide[3].ThemostcommontypeoflungcancerisNSCLC,accountingfor85-90%ofallcases[4].Ofthose,2-7%aredrivenbyarearrangementoftheALKgene,whichincreasesthegrowthofcancercellsandcanbeidentifiedbyamoleculartestofthecancertumor[1].DespitesignificanttreatmentadvancesforpatientswithALK+NSCLC,diseaseprogressionisofteninevitableandmoretreatmentoptionsareneeded[5].
IntheEU,theEuropeanCommissiongenerallyfollowstherecommendationsoftheCHMPanddeliversitsfinaldecisionwithinthreemonthsoftheCHMPrecommendation.Thedecisionwillbeapplicabletoall28EUmemberstatesplusIceland,NorwayandLiechtenstein.ZykadiaiscurrentlyapprovedintheUnitedStates,Mexico,Chile,SouthKorea,GuatemalaandEcuador.AdditionalregulatoryreviewsareunderwayinNorthAmerica,SouthAmerica,CentralAmericaandAsia.
TheCHMPrecommendationforZykadiawasbasedonresultsfromtwoglobal,multicenter,open-label,single-armstudies(StudyAandStudyB).Comparativeefficacydatafromrandomizedclinicalstudiesarenotyetavailable.Theprimaryefficacyendpointforthesestudieswasoverallresponserate(ORR),includingcompleteresponseandpartialresponse,forpatientswhoweretreatedwitha750mgdoseofZykadia,confirmedbyrepeatassessmentsperformednotlessthanfourweeksafterthecriteriaforresponsewasfirstmet.Additionalevaluationsincludeddurationofresponse(DOR)andprogression-freesurvival(PFS)byinvestigatorandblindedindependentreviewcommittee(BIRC)assessment,andoverallsurvival(OS).TumorevaluationswereperformedaccordingtoResponseEvaluationCriteriainSolidTumors(RECIST)1.0inStudyAandRECIST1.1inStudyB[2].
AbouttheZykadiaClinicalTrialsStudyAwasaPhaseIstudythatincludedadose-escalationphaseandanexpansionphase,attherecommendeddoseof750mg.Thestudyevaluatedatotalof246ALK+NSCLCpatientswhoweretreatedwith750mgofZykadia:163hadreceivedpriortreatmentwithanALKinhibitorand83wereALKinhibitor-naïve.InpatientswhohadpreviouslyreceivedtreatmentwithanALKinhibitor,theORRwas56.4%[95%CI,48.5-64.2%],themedianDORwas8.3months[95%CI,6.8-9.7months]andthemedianPFSwas6.9months[95%CI,5.6-8.7months]basedoninvestigatorassessment[2].
StudyBwasaPhaseIIstudydesignedtoevaluatetheefficacyandsafetyof750mgZykadiainpatientswithlocallyadvancedormetastaticALK+NSCLC.StudyBinvolved140patientswhohadbeenpreviouslytreatedwithonetothreelinesofchemotherapyfollowedbytreatmentwithcrizotinib,andwhohadthenprogressedoncrizotinib[2].
InStudiesAandB,brainmetastasesatbaselinewereseenin60.1%and71.4%ofpatientswhohadreceivedpriortreatmentwithanALKinhibitor,respectively.TheORR,DORandPFS(byBIRCassessment)forpatientswithbrainmetastasesatbaselineweresimilarwiththosereportedfortheoverallpopulationofthesestudies[2].
Themostcommonadversereactionswithanincidenceof>=10%werediarrhea,nausea,vomiting,tiredness(fatigue),liverfunctiontestabnormalities(requirebloodtestmonitoring),abdominalpain,decreasedappetite,constipation,rash,kidneyfunctiontestabnormalities(requirebloodtestmonitoring),heartburnandanaemia.Grade3-4adversereactionswithanincidenceof>=5%wereliverfunctiontestabnormalities,tiredness(fatigue),diarrhea,nauseaandhyperglycemia[2].
AboutZykadiaZykadiaisanoral,selectiveinhibitorofanaplasticlymphomakinase(ALK),agenethatcanfusewithotherstoformanabnormal"fusionprotein"thatpromotesthedevelopmentandgrowthofcertaintumorsincancersincludingnon-smallcelllungcancer(NSCLC).ZykadiaiscurrentlyapprovedintheUnitedStates,Mexico,Chile,SouthKorea,GuatemalaandEcuadortotreatadultpatientswithALK+NSCLC.AdditionalregulatoryreviewsareunderwayinNorthAmerica,SouthAmerica,CentralAmericaandAsia.
IntheEuropeanUnion,Zykadia(ceritinib)isaninvestigationalagentandhasnotbeenapprovedbyregulatoryauthorities.
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