默沙东牵手卫材深度挖掘PD-1免疫疗法Keytruda临床潜力

2015年3月5日讯/生物谷BIOON/--目前，PD-1/PD-L1免疫竞赛激烈程度无法想象，其市场峰值高达350亿美元，默沙东（Merck）、百时美施贵宝（BMS）、阿斯利康（AZN）、罗氏（Roche）均在火速推进各自的临床项目，同时广泛合作深度挖掘各自免疫疗法的临床潜力。就在近日，百时美与BavarianNordic签署高达10亿美元协议，合作开发癌症免疫鸡尾酒（相关链接：癌症疫苗迎来春天？百时美签署$10亿协议开发癌症免疫鸡尾酒）；而今儿一大早，更是爆出其PD-1免疫疗法Opdivo获FDA批准肺癌适应症，从开始受理到批准仅4个工作日！（相关链接：四个工作日！施贵宝公司肿瘤新药Opdivo获批速度创纪录）相对黑色素瘤，肺癌是更加有利可图的广阔市场，元宵节当天拿到肺癌批文，百时美无疑是这个春节最大的赢家。
而其他各方也没闲着。默沙东近日就与日本药企卫材（Eisai）宣布了一项战略合作开展多个临床试验，评估其PD-1免疫疗法Keytruda（pembrolizumab）与卫材肿瘤学药物Lenvima（lenvatinib）和Halaven（eribulin）组合疗法的疗效和安全性。双方已计划开展的研究包括：一项Ib/II研究将调查Keytruda+Lenvima组合疗法用于特定实体瘤；一项Ib/II研究评估Keytruda+Halaven用于三阴乳腺癌（TNBC）。这些研究预计将从2015年第二季度开展，相关财务细节尚未披露。
Lenvima是卫材自主研发的新型抗癌药，于今年2月获FDA批准用于放射性碘难治性分化型甲状腺癌（RR-DTC），该药是一种口服多受体酪氨酸激酶（RTK）抑制剂，具有新颖的结合模式，除抑制参与肿瘤增殖的其他促血管生成和致癌信号通路相关RTK外，还能够选择性抑制血管内皮生长因子（VEGF）受体的激酶活性。目前，卫材也正在评估lenvatinib用于其他类型肿瘤的治疗，包括肝细胞癌癌、肾细胞癌、非小细胞肺癌等。Halaven则是卫材自主研发的一种新型海洋抗癌药物，该药是一种微管动力学抑制剂，具有一种全新的作用机制，能够抑制生长期微管导致细胞周期阻断最终导致细胞凋亡。目前，Halaven已获全球60个国家批准作用于转移性乳腺癌。
Keytruda则属于当前备受瞩目的PD-1/PD-L1免疫疗法，该类药物旨在利用人体自身的免疫系统抵御癌症，通过阻断PD-1/PD-L1信号通路使癌细胞死亡，在临床试验中针对多种类型肿瘤均表现出强大的疗效。根据此前公布的数据，罗氏MPDL3280A和默沙东Keytruda针对三阴乳腺癌（TNBC）均表现出积极的疗效。
英文原文：EisaiandMerckEnterCollaborationtoExploreNovelCombinationRegimensofAnti-PD-1TherapywithMulti-targetingRTKInhibitorandMicrotubuleDynamicsInhibitorinMultipleTypesofCancer
Combinationclinicalstudiesoflenvatinib,eribulinandpembrolizumabtobeexplored
TOKYO&KENILWORTH,N.J.--(BUSINESSWIRE)--EisaiCo.,Ltd.andMerck(NYSE:MRK),knownasMSDoutsidetheU.S.andCanada,throughasubsidiary,announcedtodayaclinicaltrialcollaborationtoevaluatethesafety,tolerabilityandefficacyofMerck’santi-PD-1therapy,pembrolizumab(marketedintheU.S.underthebrandnameKEYTRUDA®),incombinationwithEisaioncologycompoundslenvatinibmesylate(amulti-targetingRTKinhibitormarketedintheU.S.underthebrandnameLENVIMA™,“lenvatinib”)anderibulinmesylate(amicrotubuledynamicsinhibitormarketedinnearly60countriesincludingJapan,theU.S.,andEuropeunderthebrandnameHALAVEN®,“eribulin”)inmultipleclinicaltrials.
Theplannedstudiesincludeamulticenter,open-labelPhase1b/2studyoflenvatinibpluspembrolizumabinselectsolidtumorsandanopen-label,single-arm,multicenterPhase1b/2studytoevaluatetheefficacyandsafetyoferibulinincombinationwithpembrolizumabinmetastatictriple-negativebreastcancer.EisaiandMerckwillestablishaJointDevelopmentCommitteetooverseeclinicaldevelopmentactivities.Thestudiesareexpectedtobegininthesecondhalfof2015.Financialtermsoftheagreementwerenotdisclosed.
“Thiscollaborationcouldbeamajorstepinthedirectionofdevelopingcombinationregimensindifferenttypesofcancer,potentiallymaximizingthevalueoferibulinandlenvatinib,”saidKenichiNomoto,PhD,president,oncologyproductcreationunit,EisaiProductCreationSystems.“Together,EisaiandMerckseektoexplorecombinationregimensthathavethepotentialtocreatesynergisticeffectsbetweenlenvatinibandpembrolizumabaswellasbetweeneribulinandpembrolizumab.Ourhopeisthatwewillbringtreatmentstomarketthatmakeadifferenceinthelivesofpeoplebattlingcancer.”
“Cancerisacomplexdiseasethatoftenrequiresdifferentapproachestohelppatientsachievethebestpossibleoutcome,”saidDr.EricRubin,therapeuticareahead,oncologyearly-stagedevelopment,MerckResearchLaboratories.“ThecollaborationwithEisaiexemplifiesMerck’sfocusonadvancingbreakthroughscienceinimmuno-oncology.Welookforwardtoevaluatingpembrolizumabincombinationwitheribulinandalsowithlenvatinibindifferenttumortypes.”
Thecombinationsoflenvatinibandpembrolizumab,anderibulinandpembrolizumab,areinvestigational.Theefficacyandsafetyofthesecombinationshavenotbeenestablished.
AboutLENVIMA™(lenvatinibmesylate)
LENVIMA,discoveredanddevelopedbyEisai,isanoralmoleculartargetedagentthatselectivelyinhibitsthekinaseactivitiesofvascularendothelialgrowthfactor(VEGF)receptors(VEGFR1(FLT1),VEGFR2(KDR)andVEGFR3(FLT4)),andfibroblastgrowthfactor(FGF)receptorsFGFR1,2,3and4inadditiontootherproangiogenicandoncogenicpathway-relatedRTKs(includingtheplatelet-derivedgrowthfactor(PDGF)receptorPDGFRα;KIT;andRET)involvedintumorproliferation.Inparticular,LENVIMApossessesanewbindingmode(TypeV)toVEGFR2,asconfirmedthroughX-raycrystalstructuralanalysis,andexhibitsrapidandpotentinhibitionofkinaseactivity,accordingtokineticanalysis.
LENVIMAwasapprovedonFebruary13,2015andlaunchedonFebruary26,2015forthetreatmentofpatientswithlocallyrecurrentormetastatic,progressive,radioactiveiodine-refractorydifferentiatedthyroidcancerintheUnitedStates,andiscurrentlyundergoingregulatoryreviewforthisindicationinJapan,theEU,Switzerland,SouthKorea,Canada,Singapore,Russia,AustraliaandBrazil.Meanwhile,EisaiiscurrentlyconductingstudiesclinicalstudiesofLENVIMAinseveraltypesofcancerincludinghepatocellularcarcinoma(PhaseIII),renalcellcarcinoma(PhaseII),non-smallcelllungcancer(PhaseII)andendometrialcancer(PhaseII).Furthermore,lenvatinibhasbeengrantedOrphanDrugDesignationinJapan(forthyroidcancer),theUnitedStates(forthetreatmentoffollicular,medullary,anaplastic,andmetastaticorlocallyadvancedpapillarythyroidcancer),andEurope(forfollicularandpapillarythyroidcancer).
AboutHALAVEN®(eribulinmesylate)
HALAVEN,ahalichondrinclassmicrotubuledynamicsinhibitorwithanovelmechanismofaction,belongstoaclassofantineoplasticagents,thehalichondrins,whicharenaturalproductsisolatedfromthemarinespongeHalichondriaokadai.Itisbelievedtoworkbyinhibitingthegrowthphaseofmicrotubuledynamicswithoutaffectingtheshorteningphaseandsequesteringtubulinintononproductiveaggregates.
HALAVENwasfirstapprovedasatreatmentformetastaticbreastcancerintheUnitedStatesinNovember2010,andisnowapprovedinnearly60countriesworldwide,includingJapanandcountriesintheAmericas,EuropeandAsia.IntheUnitedStates,HALAVENInjectionisindicatedforpatientswithmetastaticbreastcancerwhohavereceivedatleasttwochemotherapeuticregimensforthetreatmentofmetastaticbreastcancer.Priortherapyshouldhaveincludedananthracyclineandataxaneineithertheadjuvantormetastaticsetting.InJapan,HALAVENhasbeenapprovedtotreatinoperableorrecurrentbreastcancerandwaslaunchedinthecountryinJuly2011.SinceJune2014,EisaihasbeenobtainingapprovalincountriesinEuropeandAsiafortheindicationexpansionofHALAVENtocontributetoearliertreatmentofpatientswithlocallyadvancedormetastaticbreastcancerwhohaveprogressedafteratleastonechemotherapeuticregimenforadvanceddisease.Priortherapyshouldhaveincludedananthracyclineandataxaneineithertheadjuvantormetastaticsetting,unlesspatientswerenotsuitableforthesetreatments.Inaddition,HALAVENhasbeendesignatedasanorphandrugforsoft-tissuesarcomaintheUnitedStatesandJapan.
AboutKEYTRUDA®(pembrolizumab)
KEYTRUDA(pembrolizumab)isahumanizedmonoclonalantibodythatblockstheinteractionbetweenPD-1(programmeddeathreceptor-1)anditsligands,PD-L1andPD-L2.KEYTRUDAisindicatedintheUnitedStatesatadoseof2mg/kgadministeredasanintravenousinfusionover30minuteseverythreeweeksforthetreatmentofpatientswithunresectableormetastaticmelanomaanddiseaseprogressionfollowingipilimumaband,ifBRAFV600mutationpositive,aBRAFinhibitor.Thisindicationisapprovedunderacceleratedapprovalbasedontumorresponserateanddurabilityofresponse.Animprovementinsurvivalordisease-relatedsymptomshasnotyetbeenestablished.Continuedapprovalforthisindicationmaybecontingentuponverificationanddescriptionofclinicalbenefitintheconfirmatorytrials.
Merckisadvancingabroadandfast-growingclinicaldevelopmentprogramforKEYTRUDAwithmorethan70clinicaltrials–acrossmorethan30tumortypesandover8,000patients–bothasamonotherapyandincombinationwithothertherapies.
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