重磅！百时美免疫组合Opdivo+Yervoy一线治疗黑色素瘤获巨大成功

2015年4月21日讯/生物谷BIOON/--百时美施贵宝（BMS）近日公布了备受业界关注的免疫组合疗法Opdivo+Yervoy用于黑色素瘤一线治疗的积极顶线数据。与Yervoy单药疗法相比，Opdivo+Yervoy组合疗法取得了非常高的客观缓解率（61%vs11%），完全缓解率22%，疾病恶化或死亡风险降低60%，疗效之强劲在黑色素瘤治疗领域前所未有。业界认为，该方案将为晚期黑色素瘤提供一个极其重要的一线治疗选择，再次证明了不同免疫疗法的组合方案在肿瘤临床治疗中的巨大潜力。
此次公布的名为CheckMate-069的II期研究，在初治晚期黑色素瘤患者中开展，包括BRAF野生型和BRAF突变型黑色素瘤，评估了PD-1免疫疗法Opdivo（nivolumab）与Yervoy（ipilimumab）的组合疗法相对于Yervoy单药疗法用于初治晚期不可切除性（3-4阶段）黑色素瘤一线治疗的疗效和安全性。数据显示，针对BRAF野生型黑色素瘤，Opdivo+Yervoy方案取得了更高的客观缓解率（ORR=61%，n=44/72），与Yervoy单药（ORR=11%，n=4/37）相比具有统计学显著差异（p＜0.001），达到了研究的主要终点；同时，Opdivo+Yervoy治疗组有22%（n=16）患者实现完全缓解，Yervoy单药组为0%；中位无进展生存期（PFS）数据尚未获得。
针对BRAF突变型黑色素瘤，Opdivo+Yervoy方案也取得了相似的结果，中位无进展生存期（PFS：8.5个月vs2.7个月），疾病恶化或死亡风险降低60%。此外，客观缓解率（ORR）独立于PD-L1状态：PD-L1阳性肿瘤中ORR为58%，PD-L1阴性肿瘤中ORR为55%。该研究中，安全性与既往评估Opdivo+Yervoy方案的相关研究一致，主要包括3-4级结肠炎（17%）、腹泻（11%）、丙氨酸转氨酶升高（11%）。
这些数据已提交至4月18-22日举行的2015年美国癌症研究协会（AACR）年会上。同时，相关结果也将发表于《新英格兰医学杂志》（NEJM）。
哈佛医学院达纳-法伯癌症研究所(Dana-FarberCancerInstitute)医学副教授F.StephenHodi医师对该项研究给予了非常高的评价，他表示，这些疗效数据在晚期黑色素瘤临床治疗中前所未有，Opdivo+Yervoy方案所取得的高缓解率在其他免疫肿瘤学制剂临床研究中也未见报道，CheckMate-069研究证实了该方案在转移性黑色素瘤的治疗潜力，有望为该群体提供一个非常重要的一线治疗选择。
Opdivo和Yervoy均属于肿瘤免疫疗法，通过靶向免疫系统中特定的调控元件，利用人体自身的免疫系统对抗肿瘤。Opdivo能够结合至活化T细胞上表达的免疫检查点受体PD-L1，阻断该通路使免疫系统攻击肿瘤。Opdivo于2014年12月获FDA加速批准，用于治疗无法手术切除或已经出现转移且对其它药物无应答的晚期黑色素瘤患者。
Yervoy能够有效阻断细胞毒性T淋巴细胞相关抗原4（CTLA-4）。CTLA-4是一种T细胞活化的负调控因子，Yervoy与CTLA-4结合后，能阻断CTLA-4与其配体CD80/CD86的相互作用。而阻断CTLA-4已被证明能够增强T细胞的活化和增殖。Yervoy在黑色素瘤患者中的疗效作用机制，是间接通过T细胞介导的抗肿瘤免疫反应。Yervoy于2011年3月获FDA批准用于不能手术切除或转移性黑色素瘤，目前该药已获全球40多个国家批准。
关于黑色素瘤：
黑色素瘤（melanoma）是一种高度恶性肿瘤，复发率和死亡率非常高。根据其原位特性（厚度、溃烂）、是否已扩散至淋巴结、远处转移程度，黑色素瘤可分为5级（0-4阶段）。3阶段黑色素瘤已到达区域性淋巴结，但尚未扩散到远端淋巴结或机体其他部位（转移），需要外科手术切除原发肿瘤及所涉及的淋巴结。3阶段黑色素瘤复发风险很高，总存活率一直很低；许多患者会在治疗后5年内复发，其中近90%复发病例发生于高复发风险人群。一旦病情复发，存活率将非常低，历史数据为11%-20%。
英文原文：FirstRandomizedStudyEvaluatingOpdivo(nivolumab)+Yervoy(ipilimumab)RegimenDemonstratesSuperiorEfficacyVersusYervoyAloneinPatientswithPreviouslyUntreatedAdvancedMelanoma
Opdivo+Yervoyregimenachievesobjectiveresponserateof61%,includinga22%completeresponserate,inpreviouslyuntreated,advancedmelanomapatientswithBRAFwild-typemutationstatus
Opdivo+YervoyregimendecreasedriskofmelanomaprogressionordeathcomparedtoYervoyaloneby60%,baseduponhazardratioof0.4;medianprogression-freesurvivalfortheregimennotreachedwithaminimumfollow-upof11months
SafetyprofileoftheOpdivo+Yervoyregimenfromthistrial(CheckMate-069)wasconsistentwithpreviously-reportedstudies
PRINCETON,N.J.--(BUSINESSWIRE)--Bristol-MyersSquibbCompany(NYSE:BMY)todayannouncedpositiveresultsfromaPhaseIItrial(CheckMate-069),evaluatingtheOpdivo(nivolumab)+Yervoy(ipilimumab)regimenversusYervoyaloneinpatientswithpreviouslyuntreatedadvancedmelanoma.PatientswithBRAFwild-typemutationstatustreatedwiththeOpdivo+Yervoyregimenexperiencedahigherobjectiveresponserate(ORR)of61%(n=44/72)–theprimarystudyendpoint–comparedto11%(n=4/37)forpatientsadministeredYervoymonotherapy(P<0.001).Completeresponseswerealsoreportedin22%(n=16)ofpatientswithBRAFwild-typemutationstatusadministeredtheOpdivo+YervoyregimenandinnopatientswhoreceivedYervoymonotherapy.SimilarresultswerealsoobservedinBRAFmutation-positivepatients.Thesafetyprofilewasconsistentwithpreviously-reportedstudiesevaluatingtheOpdivo+Yervoyregimenandincludedgrade3-4colitis(17%),diarrhea(11%),andincreasedalanineaminotransferase(11%).
ThesedatawillbepresentedtodayattheAmericanAssociationforCancerResearch(AACR)AnnualMeetingandfeaturedduringapressbriefingat8:30AMEDT[Abstract#2860].TheresultswillalsobepublishedinTheNewEnglandJournalofMedicine(NEJM).
“Thesedataareunprecedentedinadvancedmelanoma,showingefficacyresultsthathavenotpreviouslybeenobservedwithImmuno-Oncologyagents,”saidF.StephenHodi,M.D.,AssociateProfessorofMedicine,Dana-FarberCancerInstituteandanauthoroftheNEJMmanuscript.“WiththeOpdivo+Yervoyregimen,weobservedmuchhigherresponserateswhichweresustained,aswellassignificantreductionintumorburdenthanwithYervoy.TheseresponsesseeninCheckMate-069demonstratethepotentialofthisregimeninpatientswithmetastaticmelanoma.”
Melanomaisthemostseriousformofskincancerandstrikesadultsofallages.Whilemelanomarepresentslessthan5%ofskincancers,itresultsinmostdeaths.TheCheckMate-069trialisthefirstrandomizedstudyreportingoutcomesinthefirst-linesettingforadvancedmelanomapatientstreatedwitharegimenofimmunecheckpointinhibitorscomparedtoYervoy.TheefficacyandsafetyresultsofCheckMate-069areconsistentwiththePhaseIbdose-rangingtrial(CheckMate-004),whichevaluatedthesafetyandactivityoftheregimeninpatientswithadvancedmelanoma.
“TheCheckMate-069resultsreinforceourbeliefthatthefutureliesinthecombinationofImmuno-Oncologyagents,includingOpdivoandYervoy,thatcanleveragetheimmunesysteminordertooffercancerpatientsoptionswithgreaterefficacybeyondcurrenttreatmentapproaches,”saidMichaelGiordano,seniorvicepresident,HeadofDevelopment,Oncology.“OurstrategyhasalwaysbeentobuilduponthesuccessachievedwithYervoy.In2011,long-termsurvivalformetastaticmelanomapatientswasunheardof,buttheintroductionofYervoyhashelpedtomakethisarealityforsomepatients.NowwearebuildingonthissuccesswithOpdivo,whichwasthefirstPD-1inhibitortodemonstrateanimprovedsurvivalbenefit.”
AboutCheckMate-069
CheckMate-069isaPhaseIIdouble-blind,randomizedstudythatevaluatedtheOpdivo+YervoyregimeninpatientswithpreviouslyuntreatedunresectableStage3and4melanoma.ThestudyincludedpatientswithbothBRAFwild-typeandBRAFmutation-positivemelanoma.
Thetrialenrolled142patientswhowererandomizedtoreceiveeithertheOpdivo+Yervoy(n=95)regimenorYervoy(n=47)monotherapy.RandomizationwasstratifiedbyBRAFmutationstatus(V600wild-typetumorsversusBRAFmutation-positivetumorsasassessedbyanFDA-approvedtest).PatientsintheOpdivo+Yervoyregimengroupreceived1mg/kgofOpdivoplus3mg/kgofYervoyevery3weeksfor4dosesfollowedby3mg/kgofOpdivoperevery2weeksuntilprogressionorunacceptabletoxiceffects.IntheYervoymonotherapygroup,patientsweretreatedwiththesamedosingscheduleplusmatchingplacebo.
TheprimaryendpointwasORRinpatientswithBRAFwild-typetumors.Secondaryendpointsincludedprogression-freesurvival(PFS)inBRAFwildtypepatientsandORRandPFSinBRAFV600mutation-positivepatients,alongwithsafety.
AlongwithhigherORRandmorecompleteresponses,theregimendecreasedriskofprogressionforBRAFmutantandwild-typepatients(hazardratios=0.4[95%CI:0.23,0.68;P<0.001]and0.38[95%CI:0.15,1.00],respectively),representinga60-62%reductionofriskofprogressionordeath.InBRAFwild-typepatients,medianPFSwasnotreached.InBRAFmutation-positivepatients,medianPFSwas8.5monthsfortheregimenand2.7monthsforYervoyalone.Inaddition,ORRwasindependentofPD-L1status:58%amongpatientswithPD-L1positivetumorsand55%amongthosewithandPD-L1negativetumors.Theminimumfollow-upperiodafterrandomizationwas11months.
CheckMate-069isthefirstrandomizedstudytocharacterizethesafetyprofileoftheOpdivo+YervoyregimenversusYervoymonotherapy.ThesafetyprofilewasconsistentwiththatpreviouslyreportedfortheOpdivo+Yervoyregimen.Thetreatment-relatedadverseeventratewassimilar(91%fortheOpdivo+Yervoyregimenversus93%forYervoymonotherapy).Theincidenceofgrade3/4adverseevents(drug-relatedAEs)washigherwiththeOpdivo+Yervoyregimen(54%)comparedto24%ofpatientswhoreceivedYervoymonotherapyandmanagedusingestablishedsafetyguidelinesandthemajority(approximately80%)improvedorresolvedwithappropriatemonitoringanduseofcorticosteroids.Themostcommongrade3/4AEswiththeOpdivo+Yervoyregimenwerecolitis(17%),diarrhea(11%),andincreasedalanineaminotransferase(11%).TheOpdivo+Yervoyregimenwasdiscontinuedduetoadverseeventsin47%ofpatientsversus17%forYervoymonotherapy.Ofthosepatientswhodiscontinuedduetoadverseevents,68%continuedtoexperienceacompleteorpartialresponse.Therewerethreedrug-relateddeathsassociatedwiththeOpdivo+Yervoyregimen.
AboutOpdivoandYervoy
Cancercellsmayexploit“regulatory”pathways,suchascheckpointpathways,tohidefromtheimmunesystemandshieldthetumorfromimmuneattack.OpdivoandYervoyarebothmonoclonalantibodiesandimmunecheckpointinhibitorsthattargetseparate,distinctcheckpointpathways.InhibitionoftheseimmunecheckpointpathwaysresultsinenhancedTcellfunctiongreaterthantheeffectsofeitherantibodyalone.
OpdivobecamethefirstPD-1immunecheckpointinhibitortoreceiveregulatoryapprovalanywhereintheworldonJuly4,2014whenOnoPharmaceuticalCo.announcedthatitreceivedmanufacturingandmarketingapprovalinJapanforthetreatmentofpatientswithunresectablemelanoma.IntheU.S.,theU.S.FoodandDrugAdministration(FDA)granteditsfirstapprovalforOpdivoforthetreatmentofpatientswithunresectableormetastaticmelanomaanddiseaseprogressionfollowingYervoy(ipilimumab)and,ifBRAFV600mutationpositive,aBRAFinhibitor.Recently,onMarch5,2015,OpdivoreceiveditssecondFDAapprovalforthetreatmentofpatientswithmetastaticsquamousnon-smallcelllungcancer(NSCLC)withprogressiononorafterplatinum-basedchemotherapy.
IntheEuropeanUnion,theEuropeanMedicinesAgency(EMA)hasvalidatedforreviewtheMarketingAuthorizationApplicationforOpdivoinadvancedmelanoma.TheapplicationhasalsobeengrantedacceleratedassessmentbytheEMA’sCommitteeforMedicinalProductsforHumanUse(CHMP).TheEMAalsovalidatedforreviewtheMAAforOpdivoinNSCLC.
OnMarch25,2011,theFDAapprovedYervoy3mg/kgmonotherapyforpatientswithunresectableormetastaticmelanoma.Yervoyisnowapprovedinmorethan40countries.
Bristol-MyersSquibbhasabroad,globaldevelopmentprogramtostudyOpdivoinmultipletumortypesconsistingofmorethan50trials–asmonotherapyorincombinationwithothertherapies–inwhichmorethan7,000patientshavebeenenrolledworldwide.
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