基于循证医学依据的肿瘤生物治疗

基于循证学依据的肿瘤生物治疗昆明医科大学第三附属医院云南省肿瘤医院宋鑫肿瘤生物治疗概念肿瘤生物治疗（tumorbiotherapy）是应用现代生物学技术、生物制剂和小分子化合物等，通过免疫、基因和靶向治疗的方法，激发机体免疫保护机制，干预肿瘤关键基因和信号传导通路中的重要分子，达到治疗肿瘤和预防其复发的目的。肿瘤生物治疗分类生物免疫治疗过继性免疫细胞治疗肿瘤疫苗免疫调节剂基因治疗靶向治疗小分子药物单克隆抗体抗血管生成抑制剂肿瘤免疫治疗发展简史及里程碑式成果基于免疫细胞的肿瘤生物治疗标志性进展全球开展细胞治疗临床试验概况肿瘤生物免疫细胞治疗临床试验肿瘤生物免疫细胞治疗面临现状及挑战我中心免疫治疗概况主讲内容肿瘤免疫治疗发展简史KirkwoodJMetal,CACancerJClin20122014年7月7日，PMDA批准BMS公司的PD-1单抗Nivolumab在日本上市，用于治疗晚期黑色素瘤；2014年9月4日，FDA批准Merk公司的PD-1单抗MK-3475应用于晚期黑色素瘤肿瘤免疫治疗发展简史及里程碑式成果基于免疫细胞的肿瘤生物治疗标志性进展全球开展细胞治疗临床试验概况肿瘤生物免疫细胞治疗临床试验肿瘤生物免疫细胞治疗面临现状及挑战我中心免疫治疗概况主讲内容基于免疫细胞的肿瘤生物治疗标志性进展过继性免疫细胞TILCAR-T肿瘤疫苗DC疫苗—Provenge(Sipuleucel-T)BLP25脂质体疫苗免疫检查点抑制剂抗CTLA-4单抗抗PD-1单抗抗PDL-1单抗抗CTLA-4单抗联合抗PD-1/PDL-1单抗TILAdoptiveCellTherapyforPatientsWithMetastaticMelanoma:EvaluationofIntensiveMyeloablativeChemoradiationPreparativeRegimensRosenbergSA,etal.JClinOncol2008MarkE.Dudley,JamesC.Yang,RichardSherry,MarybethS.Hughes,RichardRoyal,UdaiKammula,PaulF.Robbins,JianPingHuang,DeborahE.Citrin,SusanF.Leitman,JohnWunderlich,NicholasP.Restifo,ArmenThomasian,StephanieG.Downey,FranzO.Smith,JacobKlapper,KathleenMorton,CarolynLaurencot,DonaldE.White,andStevenA.Rosenberg试验Cy,cyclophosphamideFlu,fludarabineTBI,total-bodyirradiationNMV,non-myeloablative(N=43)(N=25)(N=25)入组患者情况生存曲线TBI,total-bodyirradiationNMV,nonmyeloablative2年OS:30%vs42%NMAvsTBI1,200DurableCompleteResponsesinHeavilyPretreatedPatientswithMetastaticMelanomaUsingTCellTransferImmunotherapyStevenA.Rosenberg,JamesC.Yang,RichardM.Sherry,UdaiS.Kammula,MarybethS.Hughes,GiaoQ.Phan,DeborahE.Citrin*,NicholasP.Restifo,PaulF.Robbins,JohnR.Wunderlich,KathleenE.Morton,CarolynM.Laurencot,SethM.Steinberg**,DonaldE.White,andMarkE.DudleyRosenbergSA,etal.ClinCancerRes.2011ABTBI1200组3年、5年生存率分别为36%、29%既往接受CTLA-4治疗组5年生存率为44%(DTIC：2YrOSrate15%)TIL治疗疗效Treatmentwithtumor-infiltratinglymphocytes(TIL)inmetastaticmelanomaandclinicalbenefitregardlessofsiteoforigin,mutationstatus,orpriorcheckpointblockadeIsabellaClaudiaGlitza,ChantaleBernatchez,RolandL.Bassett,etal. 2014ASCO:JClinOncol32:5s,2014(suppl;abstr9079)Background: Inthisreportwedescribetheassociationofspecificpatientattributes,suchasmutationstatus,priortreatmentwithcheckpointblockade,andlocationofprimarytumorwithtreatmentresponsetotherapyTILtherapy. Methods: StageIIIc-IVpatients(pts)wereenrolledandtreatedinanongoingnon-randomizedphaseIITILtrialatMDAndersonCancerCenter.Coxproportionalhazardsregression(overallsurvival(OS),progression-freesurvival(PFS))andlogisticregression(response)wereusedtoassesstheassociationbetweenoutcomesandcovariatesofinterest. Results: 56(19female,37male)ptswereenrolled.Mostcommonsiteoforiginwascutaneous(N=45),whileasubgroupofptshadmelanomaderivedofacral(N=7)ormucosalorigin(N=3).Staging(69%MIc),mutationalstatus(BRAFV600,NRASmutations)orthepresenceofbrainmetastasisdidnotsignificantlyimpacttheoddsofresponseorsurvival(OS,PFS).Overallresponseratewas44%(2ptsCR,22ptsPR)in54ptsavailableforanalysis,whilestablediseasewasobservedin20pts.22ptsreceivedpriorcheckpointblockadewithipilimumaband/oranti-PD1.Amongsubgroupsofpts,30%oftheacral/mucosalmelanomapts,30%oftheptswithpreviouscheckpointblockadeand53%ofpatientswithBRAFV600mutationsresponded.HighernumbersofCD8+T-cellsinfusedwassignificantlyassociatedwithgreaterlikelihoodofresponse(p=0.03)andlongerPFS(p=0.01).PFSwassignificantlyworse(p=0.01)afterpriorcheckpointblockade(1-yearPFS:14%versus27%)andwithhigherpre-treatmentLDHlevel(p=<0.001)andECOGPSscore(p=0.002).OSwasnotaffectedbysiteoforigin(1-yearOS:68%acral/mucosal),BRAFV600status(62%),orpriorcheckpointblockade(61%).HigherECOGPSscore(p=<0.001)andLDHlevel(p=<0.001)wereassociatedwithgreaterriskofdeath. Conclusions: PatientswithBRAFV600mutationsandwithmucosaloracralorigindobenefitfromTILtherapy.DespiteshorterPFS, patientsthathadpreviouslyfailedcheckpointblockadetherapystillexperiencebenefitfromTILtherapy,arguingitsuseinthishighlyrefractorypopulation.小结：TIL联合高剂量IL-2治疗转移性黑色素瘤患者，能使患者获益；TIL联合高剂量IL-2输注前进行清髓处理，其疗效明显优于未清髓组CAR-TCAR-TSchematicrepresentationofchimericantigenreceptor(CAR)structure.CheadleEJ,etal.ImmunolRev2014CAR-TCARsusuallyincludeaT‑cellactivationdomain,oneormoreco-stimulatorydomains,ahingeregion,acellmembrane-spanningtransmembranedomain,andanantigen-recognitionmoietythatisusuallyderivedfromanantibody.Aschematicofananti-CD19CAR-expressingT cellrecognizingaCD19+malignantcell.KochenderferJN,etal.NatRevClinOncol2013临床疗效ABAThebaselinespecimenshowshypercellularbonemarrow(60%)withtrilineagehematopoiesis,maturelymphocytesthataccountfor40%oftotalcellularity.Residuallymphoidaggregates(10%)thatwerenegativeonday23,withoutlymphoidaggregatesandcontinuedabsenceat6monthsafterinfusion.BRegressionofaxillarylymphadenopathyoccurredwithin1monthafterinfusionandwassustained.B-celldepletionandremissionsofmalignancyalongwithcytokine-associatedtoxicityinaclinicaltrialofanti-CD19chimeric-antigen-receptor–transducedTcellsJamesN,etal.Blood2012JamesN.Kochenderfer,MarkE.Dudley,StevenA.Feldman,etal.患者特征及临床疗效ThepatientsreceiveddosesofCAR-expressingTcellsthatrangedfrom0.3×107to3.0×107CAR-Tcells/kg.Adenopathyregressedbyday32afterCAR-transducedT-cellinfusion.Theenlargedlymphnodescontinuedtosubstantiallyregressbetween32and132daysafterCAR-transducedT-cellinfusion.临床疗效小结：CAR-T对治疗白血病显示良好的疗效；输注前进行清髓处理其效果更佳；CAR-T治疗实体瘤的疗效有待于进一步的临床试验验证。过继性免疫细胞TILCAR-T肿瘤疫苗DC疫苗—Provenge(Sipuleucel-T)BLP25脂质体疫苗免疫检查点抑制剂抗CTLA-4单抗抗PD-1单抗抗PDL-1单抗抗CTLA-4单抗联合抗PD-1/PDL-1单抗基于免疫细胞的肿瘤生物治疗标志性进展Provenge(Sipuleucel-T)（FDA批准的首个疫苗）PhilipWetal,NENGLJMED2010试验设计2:1Modified-DCDC临床疗效亚组分析主要不良事件Table2.(Continued)Sipuleucel-T作为治疗性疫苗，用于晚期激素抵抗性前列腺癌患者总生存期无明显获益，但中位生存期延长了4.1个月主要毒副作用是发烧、发冷、疲劳和疼痛，不良反应可控，3/4级不良反应少小结BLP25脂质体疫苗ThatcherNetal,Oncologist2010Day−3i.v.cyclophosphamide/saline6-weeklytreatmentRandomize2:1L-BLP25+BSCPlacebo+BSCDiseaseprogressionSurvivalfollow-upWeeklytreatmentScreening试验设计s.c.administrationsL-BLP25/placeboPrimaryendpoint:Overallsurvival*Chemo/RT≥2cyclesofplatinum-basedchemotherapyandradiation≥50GyRandomizationstrata:StageIIIAvs.IIIBatfirstdiagnosisCR/PRvs.SDtoinitialchemo/RTConcurrentvs.sequentialchemo/RTGeographicalregionUnresectableNSCLCstageIIIA/BNoprogressionfollowingchemo/RT*患者入组情况(1)Table1.(Continued)患者入组情况(1)同步放化疗患者Tecemotide治疗后OS同步放化疗患者Tecemotide治疗后亚组OS分析超过10%患者的主要不良事件所有患者不良事件小结：脂质体疫苗治疗III期非小细胞肺癌患者，OS无明显提高；同步放化疗联合脂质体疫苗治疗III期非小细胞肺癌患者，其中位生存时间为个30.8个月，较对照组延长10.2个月；不良反应可控、可耐受性好；过继性免疫细胞TILCAR-T肿瘤疫苗DC疫苗—Provenge(Sipuleucel-T)BLP25脂质体疫苗免疫检查点抑制剂抗CTLA-4单抗抗PD-1单抗抗PDL-1单抗抗CTLA-4单抗联合抗PD-1/PDL-1单抗基于免疫细胞的肿瘤生物治疗标志性进展抗CTLA-4单抗(Ipi首个延长生存的药物)TcellTCRCTLA4APCMHCCD287B7CTLA-4blocksco-stimulation:NoT-cellactivationCTLA4-单抗阻断CTLA4介导的免疫抑制AdaptedfromLebbéetal.ESMO2008IpilimumabblocksCTLA-4:T-cellactivationipilimumabTcellTCRAPCMHCCD28B7Co-stimulationviaCD28:T-cellactivationTcellTCRCD28CTLA4APCMHCB7临床试验RANDOMIZE复治的晚期黑色素瘤患者(N=676)(N=137)(N=136)(N=403)gp100+placebo1mgq3weeksX4dosesIpilimumab+placeboIpilimumab+gp1003mg/kgq3weeksX4dosesO’DaySatalJCO2010;28:18s(Abstract4)StudyDesignRANDOMIZE复治的晚期黑色素瘤患者(N=676)(N=137)(N=136)(N=403)gp100+placebo1mgq3weeksX4dosesIpilimumab+placeboIpilimumab+gp1003mg/kgq3weeksX4dosesStudyDesign总生存期SurvivalRateIpi+gp100N=403Ipi+placeboN=137gp100+placeboN=136Difference(Avs.C;Bvs.C)1year44%46%25%19%;21%2year22%24%14%8%;10%组间生存比较*p<0.05comparedtogp100arm#p<0.05comparedtoipilimumab+gp100armDiseasecontrolrate:Total%ofpatientswithCR+PR+SDIpiIpi+gp100gp100KornPFS(median)2.9mos*#2.8mos*2.8mos1.7mosPFS(6months)24%*16%10%15%OS(median)10.1mos*10.0mos*6.4mos6.2mosOS(12months)46%*44%*25%26%Overallresponserate10.9%*#5.7%*1.5%-Diseasecontrolrate28.5%*#20.1%*11.1%-亚组OS分析主要不良事件IpilimumabversusplaceboaftercompleteresectionofstageIIImelanoma:InitialefficacyandsafetyresultsfromtheEORTC18071phaseIIItrial2014ASCO:(suppl;abstrLBA9008)AlexanderM.Eggermont,VannaChiarion-Sileni,JeanJacquesGrob,ReinhardDummer,JeddD.Wolchok,HenrikSchmidt,OmidHamid,CarolineRobert,PaoloAntonioAscierto,JonM.Richards,CelesteLebbe,VirginiaFerraresi,MichaelSmylie,JeffreyS.Weber,MicheleMaio,CyrilKonto,RavichandraKarraGurunath,VeerledePril,StefanSuciu,AlessandroTestoriCancerInstituteGustaveRoussy,Villejuif,France;IOV-IRCCS,MelanomaOncologyUnit,Padova,Italy;HôpitaldelaTimone,Marseille,France;UniversityofZürichHospital,Zürich,Switzerland;MemorialSloanKetteringCancerCenter,NewYork,NY;AarhusUniversityHospital,Aarhus,Denmark;TheAngelesClinicandResearchInstitute,LosAngeles,CA;InstitutGustaveRoussy,Villejuif,France;IstitutoNazionaleTumoriFondazione“G.Pascale”,Naples,Italy;OncologySpecialistsS.C.,ParkRidge,IL;HôpitalSaint-Louis,Paris,France;IstitutiFisioterapiciOspitalieri,Rome,Italy;CrossCancerInstitute,Edmonton,AB,Canada;H.LeeMoffittCancerCenter&ResearchInstitute,Tampa,FL;UniversityHospitalofSiena,IstitutoToscanoTumori,Siena,Italy;Bristol-MyersSquibb,Wallingford,CT;EORTCHeadquarters,Brussels,Belgium;Bristol-MyersSquibb,Braine-l'Alleud,Belgium;EuropeanInstituteofOncology,Milan,Italy研究设计：Ipilimumab辅助治疗Ⅲ期临床试验Treatmentuptoamaximum3years,oruntildiseaseprogression,intolerabletoxicity,orwithdrawalStratificationfactors:Stage(ⅢAvsⅢBvsⅢC1-3positivelymphnodesvsⅢC≥4positivelymphnodes)Regions(NorthAmerica,EuropeancountriesandAustralia)N=475N=476Week1Week12Week24N=951无复发生存期（RFS）PatientsAliveWithoutRepapse(%)Median:26.1mo*Stratifiedbystage.**Dataarenotyetmature.Median:17.1moMonthsHDI^：2-YearRFSrate:48%3-YearRFSrate:42%^E1684.JClinOncol.1996;14:7-17.9moPatientsatRiskONIpilimumab2344752762056750Placebo2944762601936240　　　IpilimumabPlaceboEvents/patients234/475294/476HR(95%CI)0.75(0.64-0.90)Log-rankPvalue*0.00132-YearRFSrate(%)51.543.83-YearRFSrate(%)**46.534.8治疗相关不良反应HDI^：严重不良反应约67%　Ipilimumab(n=471)Placebo(n=474)Discontinuation,%91.7%83.1%Reasonsfordiscontinuation,%Normalcompletion7.016.2Diseaseprogression28.057.6AErelatedtostudydrug48.81.7Otherreasons7.97.6Mediandoses,perpatient4.08.0Meandoses,perpatient5.78.8%Receiving≥1maintenancedose42.070.0%Receiving≥7doses(1yroftherapy)28.956.8小结Ipilimumab辅助治疗的中位无复发生存期（RFS）约26.1个月不良反应不容忽视：药物相关致死事件发生率达1.1%该研究使用的Ipilimumab剂量10mg/kg明显高于FDA批准的使用剂量（3mg/kg）抗PD-1单抗抑制PD-1与PD-L1的结合肿瘤细胞可通过PD-1/PD-L1信号逃避免疫监视抑制PD-1/PD-L1间相互作用可恢复T细胞的抗肿瘤活性，引起持久的免疫应答XXPD-1单抗研究进展概要既往不同Ipilimumab治疗患者疗效对比总体疗效对比　ORRmPFS1YrOSrate　PriorIPINonIPIPriorIPINonIPIPriorIPINonIPIPembrolizumab（MK3475）28%40%5.4mo5.6mo65%74%Pidilizumab(CT011)5%7%2.8mo1.9mo65.7%63.1%Pembrolizumab(MK3475)Nivolumab(BMS-936558)Pidilizumab(CT011)ORR37%28%6%1YrOSrate69%62%64.5%DTIC13.4%27%Ipilimumab11%46%1.Anti-PD-1,IgG4(Lambrolizumab/Pembrolizumab,MK-3475)Efficacyandsafetyoftheanti-PD-1monoclonalantibodyMK-3475in411patients(pts)withmelanoma(MEL)AntoniRibas,F.StephenHodi,RichardKefford,OmidHamid,AdilDaud,JeddD.Wolchok,Wen-JenHwu,TaraC.Gangadhar,AmitaPatnaik,AnthonyM.Joshua,PeterHersey,JeffreyS.Weber,RoxanaStefaniaDronca,HassaneM.Zarour,KevinGergich,Xiaoyun(Nicole)Li,RobertIannone,SoonmoPeterKang,ScotEbbinghaus,CarolineRobertUniversityofCalifornia,LosAngeles,LosAngeles,CA;Dana-FarberCancerInstitute,Boston,MA;WestmeadHospitalandMelanomaInstituteAustralia,UniversityofSydney,Westmead,Australia;TheAngelesClinicandResearchInstitute,LosAngeles,CA;UniversityofCalifornia,SanFrancisco,SanFrancisco,CA;MemorialSloanKetteringCancerCenter,NewYork,NY;TheUniversityofTexasMDAndersonCancerCenter,Houston,TX;AbramsonCancerCenteroftheUniversityofPennsylvania,Philadelphia,PA;MoffittCancerCenter,ComprehensiveMelanomaResearchCenter,Tampa,FL;MayoClinic,DepartmentofMedicalOncology,Rochester,MN;UniversityofPittsburghCancerInstitute,Pittsburgh,PA;Merck&Co,Inc,NorthWales,PA;Merck,NorthWales,PA;Merck&Co,Inc,Rahway,NJ;InstitutGustaveRoussy,Paris,France2014ASCO:(suppl;abstrLBA9000^).PresentedbyAntoniRibasIPINaive,ipilimumab治疗≤2次;IPITreated,曾接受ipilimumab治疗;研究设计:MK3475Ⅰ期剂量试验Nonrandomizedcohorts(N=135)Cutoffforcurrentanalysis(18October2013)IPIRefractory10vs2mg/kgQ3W(n=173)IPINaïve10vs2mg/kgQ3W(n=103)Nonrandomizedcohorts(N=276)1120122013DJFMAMJJASONDJFMAMASO剂量安全性评估：MK34752013ASCO:(suppl;abstr9009)2014ASCO:(suppl;abstrLBA9000)20132014　IPI-Nn=190IPI-Tn=221合计N=4113-5级治疗相关不良反应14%11%12%中位治疗时间（范围），周342830(0.1–97)(0.1–90)(0.1–97）中位剂量（范围），剂11910(1–47+)(1–46)(1–47)　10mg/kgQ2Wn=5710mg/kgQ3Wn=562mg/kgQ3Wn=22合计N=135所有等级的治疗相关不良反应91%73%64%79%3-4级治疗相关不良反应23%4%9%13%中位治疗时间（范围），周40.120.618.123.1(1.0–53.3+)(1.0–48.1+)(1.0–39.1+)(1.0–53.3+)中位剂量（范围）126.578(1–26+)(1–18+)(1–14+)(1–26+)*包括不能确定的进展,所有剂量的总客观缓解率（ORR）为44%；10mg/kgQ2W为56%；10mg/kgQ3W为36%；2mg/kgQ3W为35%.“+”indicatescensoredobservation.2013ASCO:(suppl;abstr9009)既往不同ipilimumab治疗患者的ORR:MK347520132014MK3475剂量既往IPI治疗情况RECIST1.1,irRC,独立中心评估研究者评估NORR,NORR,%(95%CI)%(95%CI)合计11738(25–44)*13537(29–45)10mg/kgQ2WNaive3949(32–65)4156(40–72)Treated1362(32–86)1656(30–80)Total5252(38–66)5756(42–69)10mg/kgQ3WNaive1926(9–51)2433(16–55)Treated2627(12–48)3222(9–40)Total4527(15–42)5627(16–40)既往IPI治疗情况NCR,%ORR,%(95%CI)RECIST1.1,独立中心评估IPINaive168840(32–48)IPITreated197228(22–35)Total365534(29–39)irRC,研究者评估IPINaive190843(36-51)IPITreated221331(25-37)Total411537(32-41)肿瘤体积变化(独立中心评估，RECIST1.1标准)20132014无进展生存期（PFS）:MK34752014ASCO:(suppl;abstrLBA9000)PFS(%)Time(Months)Ptsatrisk4113622801531449446423613100DTIC：mPFS＜2moPopulationMedian,mo95%,CIRate,6moTotal5.53.8-6.245%IPI-N5.63.7-11.049%IPI-T5.43.2-5.641%总生存期（OS）2628OverallSurvival(%)Time(Months)Ptsatrisk4113883473243072812502081569578622760MedianOSnotreached69%OSrateat12months(74%forIPI-N,65%forIPI-T)62%OSrateat18monthsDTIC：1YrOSrate27%小结对于既往未接受Ipilimumab的晚期黑色素瘤患者，MK3475治疗：-ORR40%,中位PFS5.6mo,1年总生存率74%曾使用Ipilimumab治疗的晚期黑色素瘤患者，MK3475治疗：-ORR28%，中位PFS5.4mo,1年总生存率65%ORR远高于常见化疗药物DTIC(9.8%~13.4%)和TMZ(14.5%)总中位PFS约5.5个月,优于DTIC(<2个月)不良反应可控、可耐受性好2.Anti-PD-1,IgG4(Nivolumab,BMS-936558,MDX-1106)Long-termsurvivalofipilimumab-naivepatients(pts)withadvancedmelanoma(MEL)treatedwithnivolumab(anti-PD-1,BMS-936558,ONO-4538)inaphaseItrialF.StephenHodi,MarioSznol,HarrietM.Kluger,DavidF.McDermott,RichardD.Carvajal,DonaldP.Lawrence,SuzanneLouiseTopalian,MichaelB.Atkins,JohnD.Powderly,WilliamHowardSharfman,IgorPuzanov,DavidC.Smith,PhilipD.Leming,EvanJ.Lipson,JanisM.Taube,RobertAnders,ChristineE.Horak,GeorgiaKollia,AshokKumarGupta,JeffreyAlanSosmanDana-FarberCancerInstitute,Boston,MA;YaleCancerCenter,YaleSchoolofMedicine,NewHaven,CT;BethIsraelDeaconessMedicalCenter,Boston,MA;MemorialSloanKetteringCancerCenter,NewYork,NY;MassachusettsGeneralHospitalCancerCenter,Boston,MA;TheSidneyKimmelComprehensiveCancerCenteratJohnsHopkins,Baltimore,MD;GeorgetownLombardiComprehensiveCancerCenter,Washington,DC;CarolinaBioOncologyInstitute,Huntersville,NC;Vanderbilt-IngramCancerCenter,VanderbiltUniversity,SchoolofMedicine,Nashville,TN;UniversityofMichigan,AnnArbor,MI;TheChristHospitalCancerCenter,Cincinnati,OH;Bristol-MyersSquibb,Princeton,NJ;VanderbiltUniversityMedicalCenter,Nashville,TNJClinOncol32:5s,2014(suppl;abstr9002)研究设计：NivolumabⅠ期剂量试验Primaryobjective:safety&tolerabilityofmultiokedosesifnivolumabmonotherapySecondaryobjectives:preliminaryefficacyanddose-responserelationshipsStudyamendedtocollectoverallsurvivalSubgroupanalysisofresponsetokeypatientprognosticfeaturesExploratoryPD-L1analysis*—Positivityisdefinedastumormembranestainingatanyintensity,analyzedwithacutoffvalueof1%of5%expression*PD-L1expressionwasmeasuredusingtheBMS/Dakoimmunohistochemistry(IHC)assay.Eligiblepatientswithadvancedmelanomawereassignedto5nivolumabdoselevels(N=107)Treatmentforamaximumof96weeksECOGPS≤21to5linesofpriorsystemictherapiesNivolumab0.1mg/kgIVQ2W(n=17)Nivolumab0.3mg/kgIVQ2W(n=18)Nivolumab1mg/kgIVQ2W(n=35)Nivolumab3mg/kgIVQ2W(n=17)Nivolumab10mg/kgIVQ2W(n=20)发生率≥1%的药物相关不良反应指标所有分级%（n）3-4级不良反应（n）所有不良反应54（58）5（5）皮肤36（38）0胃肠道18（19）2（2）内分泌13（14）2（2）肝7（7）1（1）输液反应6（6）0肺4（4）0肾2（2）1（1）剂量相关ORR：Nivolumab*：选择该剂量继续下一期临床试验剂量,mg/kgORR%,（n/N）中位疗效持续时间，周（范围）所有剂量32(34/107)99.4(17.0+~117.0+)0.135(6/17)NR(24.1~80.1+)0.328(5/18)NR(18.4~93.3)134(12/35)104(17.0+~108.1+)3*41(7/17)75(40.1+~115.4+)1020(4/20)112(173.9+~117.0+)剂量相关PFS与OS剂量,mg/kg中位PFS,月（95%CI）中位OS，月（95%CI）所有剂量3.7（1.9,9.3）17.3(12.5,36.7)0.13.6（1.7,11.4）16.2(4.6,NE)0.31.9（1.7,9.3）12.5(5.4,26.9)19.1（1.8,29.6）43.1(14.9,NE)39.7（1.8,16.4）20.3(7.2,NE)103.7（1.7,20.5）11.7(4.5,37.8)总生存率Died/TreatedMedian,OS,Mo(95%CI)64/10717.3(12.5,36.7)1yearOS63%2yearOS48%3yearOS41%MonthsSinceTreatmentInitiationOverallsurvival(%)PatientsatRiskTotal107978671635450474431252222191893210DataasofSept2013(DTIC：2YrOSrate15%)(DTIC：3YrOSrate12%)OSPtsatrisk,nRate,%(95%CI)6Mo8682(74,88)1Yr6363(53,71)2Yr4448(38,57)3Yr2241(31,51)PD-L1达程度与Nivolumab治疗ORRTumortissuecollectionwasretrospective:41samplesavailableMaximum%ResponseinBaselineTargetlesions1%cutoff5%cutoffPatientPatientPD-L1statuspositivenegativePD-L1statuspositivenegativePD-L1表达程度与Nivolumab治疗PFSPFSOSPD-L1表达阳性患者，Nivolumab治疗无进展生存期（PFS）明显获益1%cutoff5%cutoffProportionProgression-FreeProportionProgression-FreeMonthsMonthsGroupEvens/DosedMedianPFS,mo(95%,CI)Positive15/269(2,NE)Negative11/152(2,4)GroupEvens/DosedMedianPFS,mo(95%,CI)Positive9/189(2,NE)Negative17/232(2,4)CensoredPD-L1statuspositivenegativeCensoredPD-L1statuspositivenegative1.00.90.80.70.60.50.40.30.20.10.0036912151821242730331.00.90.80.70.60.50.40.30.20.10.003691215182124273033PtsatriskPositive2614111186633210Negative1543322211000PtsatriskPositive18119966633210Negative2375542211000PFSOS1%cutoff5%cutoffProportionProgression-FreeProportionProgression-Free1.00.90.80.70.60.50.40.30.20.10.0MonthsMonthsPtsatriskPositive2624211817151515149744442000Negative1513119244442000000000PD-L1表达程度与Nivolumab治疗OSPD-L1表达阳性患者，Nivolumab治疗总生存期（OS）明显获益PtsatriskPos2616131312111111106544442000Neg152119141288885200000000GroupEvens/DosedMedianOS,mo(95%,CI)Positive14/2625(9,NE)Negative11/1512(5,27)GroupEvens/DosedMedianOS,mo(95%,CI)Positive9/18NR(6,NE)Negative16/2313(8,32)CensoredPD-L1statuspositivenegativeCensoredPD-L1statuspositivenegative1.00.90.80.70.60.50.40.30.20.10.003691215182124273033363942454851540369121518212427303336394245485154小结Nivolumab治疗最高ORR可达41%中位PFS9.7个月，中位OS17.3个月1年、2年及3年总生存率分别为63%、48%和41%DTIC治疗1年、2年及3年总生存率分别为27%、15%和12%Nivolumab疗效与肿瘤组织PD-L1表达程度具有明显相关性:-ORR44%v13%;中位PFS9mov2mo;中位OSNRv13mo3.Anti-PD-1,IgG1ĸ(Pidilizumab,CT-011)Pidilizumabinmetastaticmelanoma:ResultsfromamulticenterphaseII,openlabel,randomizedtrialMichaelB.Atkins,RaginiReineyKudchadkar,MarioSznol,DavidF.McDermott,MichalLotem,JacobSchachter,JeddD.Wolchok,WalterJohnUrba,TimothyKuzel,LynnMaraSchuchter,CraigL.Slingluff,MarcS.Ernstoff,JosephW.Fay,PhilipAdamFriedlander,ThomasGajewski,HassaneM.Zarour,RinatRotem-Yehudar,JeffreyAlanSosmanJClinOncol32:5s,2014(suppl;abstr9001)研究设计：PidilizumabⅡ期临床研究1:11:1剂量安全性评估：Pidilizumab(2%)项目1.5mg/kg(N=50)（%）6.0mg/kg(N=52)（%）PriorIpi(N=45)(%)NoPriorIpi(N=50)(%)合计N=93不良反应9492909693药物相关不良反应6473677068严重不良反应2819291824药物相关严重不良反应44222不良反应导致停药22222不良反应导致死亡102666药物相关死亡病例00000既往不同ipilimumab治疗患者的疗效应答（irRC）指标1.5mg/kgn=456.0mg/kgn=48PriorIpilimumabn=45NoPriorIpilimumabn=48合计N=93入组人数4144414485ORR(irCR+irPR)7%5%5%7%6%irSD39%34%54%21%37%irPD54%61%42%73%58%ConfirmedirPD24%41%24%41%33%失访44448无进展生存期（PFS）:PidilizumabProgression-FreeSurvivalestimatesProgression-FreeSurvivalestimatesTime(Months)Time(Months)BydoseBypriorIpiornot1212CT0111.5mg/kgCT0116.0mg/kgIpilimumabNonipilimumabRiskCT0111.5mg/kg5114440CT0116.0mg/kg5214643RiskPrioripi5321861Nonprioripi509222Category1.5mg/kg(n=51)6.0mg/kg(n=52)PriorIpilimumab(n=45)NoPriorIpilimumab(n=48)All(N=103;ITT)PFS(median,months;90%CI)2.0[1.9,2.8]2.0[1.9,2.1]2.8[1.9,3.6]1.9[1.9,2.0]1.9[1.9,2.1]LogrankPvalue0.91480.0165SurvivalestimatesSurvivalestimatesTime(Months)Time(Months)AllBydose总生存期（OS）:Pidilizumab1yearOS64.5%12CT0111.5mg/kgCT0116.0mg/kgRisk10390758351RiskCT0111.5mg/kg5143373128CT0116.0mg/kg524738322512Category1.5mg/kg(n=51)6.0mg/kg(n=52)PriorIpilimumab(n=45)NoPriorIpilimumab(n=48)All(N=103;ITT)12monthsSurvival64.2[51.4,74.4]64.6[51.5,75.0]65.7[53.2,75.5]63.1[49.7,73.8]64.5[55.6,72.0]LogrankPvalue0.90340.561小结Pidilizumab(CT-011)治疗的总反应率约6%1年总生存率64.5%既往曾接受ipilim