肺癌免疫治疗进展ppt课件

肺癌免疫治疗进展,FutureOutlook,UpdateofcheckpointInhibitorsinlungcancertherapy,CancerImmunotherapy,1,2,3,Outline,.,2,FutureOutlook,UpdateofcheckpointInhibitorsinlungcancertherapy,CancerImmunotherapy,1,2,3,Outline,.,3,肿瘤免疫治疗攻克肿瘤的新希望,人类抗击肿瘤的历史肿瘤免疫治疗具有特异性和靶向性，一直为临床医师高度关注，近年进步显著，使得免疫治疗成为更具期待的领域,进入21世纪，分子靶向治疗如火如荼,.,4,e,Keyeventsinthehistoryofcancerimmunotherapy,1890s1stCAvaccinedeveloped(coley),1973discoveryofthedendriticcell(steinman),19761ststudywithBCGinbladderCA,1978DiscoveryoftumorspecificmABs,19851ststudywithadoptiveT-celltransferinCA,1986IFN(cytokine)approvedforCA,1990sDiscoveryofroleofcheckpointsinCA,1992Il-2(Cytokine)approvedforCA,19971stmABapprovedforCA,20101stcellularimmunotherapyapprovedforCA,20111stcheckpointinhibitorapprovedforCA,20142ndcheckpointinhibitorapprovedforCA,Enthusiasmphase1976-1985,Skepticismphase1986-1992,Renaissancephase1997-,.,5,美国Science杂志:2013年六大值得关注的科学领域单细胞测序“普朗克”探测微波背景辐射人类连接组计划探索南极冰下世界癌症免疫疗法基础植物研究,.,6,Breakthroughofyear2013,Science.2013Dec20;342(6165):1432-3,.,7,Immunity.39(1)25July2013,Pages110,StimulatoryandInhibitoryFactorsintheCancer-ImmunityCycle,.,8,CTLA-4andPD-1/PD-L1checkpointblockadeforcancertreatment,9,CTLA-4andPD-1/PD-L1CheckpointBlockadeforCancerTreatment,ImmunecheckpointblockadeincludesagentstargetingthenegativeregulatorsCTLA-4andPD-1CTLA-4attenuatestheearlyactivationofnaiveandmemoryTcellsinthelymphnodesAgentstargetingCTLA-4includeipilimumabandtremelimumabIncontrast,PD-1modulatestheeffectorphaseofTcellactivityinperipheraltissuesviainteractionwithPD-L1andPD-L2AgentstargetingPD-1includenivolumabandMK-3475AgentstargetingPD-L1includeMPDL3280AandMEDI4736,KyiC,etal.FEBSLett.2014;588:368-376,.,10,ComparingCTLA-4andPD-1,CritRevOncolHematol.2014;89:140-165.,CTLA-4andPD-1haveseparatebutcomplimentaryrolesinimmuneresponses,.,11,FutureOutlook,UpdateofcheckpointInhibitorsinlungcancertherapy,CancerImmunotherapy,1,2,3,Outline,.,12,CTLA-4CheckpointInhibitor,.,13,Anti-CTLA-4antibodiescaninduceclinicalresponseinabroadvarietyofcancer,AdaptedformLebbeetal.ESMO2008,PresentedByLawrenceFongat2014ASCOAnnualMeeting,BladderRenalEsophagealCNSColorectalGlioblastomaLeukemiaSoftTissueSarcoma,.,14,JClinOncol.2012Jun10;30(17):2046-54,AnnOncol.2013Jan;24(1):75-83,.,15,JClinOncol.2012Jun10;30(17):2046-54,IpilimumabincombinationwithPCasfirst-linetherapyinstageIIIB/IVNSCLC,.,16,KaplanMeierplotsforOS,JClinOncol.2012Jun10;30(17):2046-54,Deaths/patients51/6651/68Median(95%CI),months8.28(6.80to12.39)12.22(9.26to14.39)HR(95%CI)0.87(0.59to1.28)Log-rankP0.23,Control,PhasedIpi,Deaths/patients51/6651/70Median(95%CI),months8.28(6.80to12.39)9.69(7.59to12.48)HR(95%CI)0.99(0.67to1.46)Log-rankP0.48,Concurrentlpi,Control,.,17,Events/patients61/6658/70Median(95%CI),mo4.21(2.76to5.32)4.11(2.76to5.32)HR(95%CI)0.88(0.61to1.27)Log-rankP.25,JClinOncol.2012Jun10;30(17):2046-54,KaplanMeierplotsforPFSperimmune-related(ir)responsecriteria(irPFS)andmodifiedWHOcriteria(mWHO-PFS).,Events/patients56/6654/68Median(95%CI),4.63m(4.14to5.52)5.68(4.76to7.79)HR(95%CI)0.72(0.50to1.06)Log-rankP.05,Control,PhasedIpi,Events/patients56/6655/70Median(95%CI),4.63m(4.14to5.52)5.52(4.17to6.74)HR(95%CI)0.81(0.55to1.17)Log-rankP.13,Control,Concurrentlpi,Events/patients61/6656/68Median(95%CI),mo4.21(2.76to5.32)5.13(4.17to5.72)HR(95%CI)0.69(0.48to1.00)Log-rankP.02,Control,PhasedIpi,Control,Concurrentlpi,.,18,AdverseEvents,JClinOncol.2012Jun10;30(17):2046-54,.,19,Follow-UPEvery12wksForsurvival,SCREENING,INDUCTION,MAINTENANCE,FOLLOW-UP,CA184-104:phaseIIItrialcomparingthetheefficacyofipilimumab(Ipi)withPCversusplacebowithPCinpatients(pts)withstageIV/recurrentNSCLCofsquamoushistology,TumorassessmentEvery12wks,JClinOncol31,2013(suppl;abstrTPS8117),primaryendpointOSsecondaryendpointsOSamongptswhoreceiveblindedtherapyPFSbestoverallresponserate,TumorassessmentWks7,13,19,25,ExclusionCriteria:BrainMetastasesAutoimmunediseases,PCPaclitaxel(175mg/m2,IV)+Carboplatin(AUC=6,IV),.,20,CA184-156:PhaseIIITrialComparingtheEfficacyofIpiPlusEtoposide/PlatinumVersusEtoposide/PlatinuminSubjectsWithNewlyDiagnosedED-SCLC,JClinOncol30,2012(suppl;abstrTPS7113),primaryendpointOSsecondaryendpointsOSamongptswhoreceiveblindedtherapyimmune-relatedandmWHOPFSbestoverallresponseratedurationofresponse,ExclusionCriteria:PriorsystemictherapyforlungcancerSymptomaticCNSmetastasesHistoryofautoimmunedisease,IpiQ3W2cycle,EP：etoposide(100mg/m2,IVonDays1-3Q3W)+cisplatin(75mg/m2,IV)or+carboplatin(AUC=5,IV)onceQ3WIpi:(10mg/kg,IV,Q3W),PlaceboQ3W2cycle,.,21,APhaseIIIStudyofNivolumabinCombinationwithYervoyinPatientswithAdvancedNon-SmallCellLungCancer,.,22,PD-1/PD-L1CheckpointInhibitors,.,23,PD-1andPD-L1antibodiesinphaseIIIdevelopment,24,Phase1Nivolumab(anti-PD-1;BMS-936558,ONO-4538)multidoseregimen,Eligibility:advcancedmelanoma,NSCLC,RCC,CRC,orCRPCwithPDafter1-5systemictherapies,25,SelectAes(1%)occuringinPtswithNSCLCtreatedwithNivolumab(N=129),Drug-relatedpneumonitis(anygrade)occurredin8NSCLCPts(6%)VS12Pts(4%)intheoverallstudypopulation-3Pts(2%)withNSCLChadgradepneumonitis,26,EfficacyofNivolumabmonotherapyinPtstreatedwithNSCLC,27,NivolumabincombinationwithPT-DCinadvancedNSCLC,AntoniaSJ,etal.2014ASCOAbstract8113.,ResultsandConclusions,治疗的前6周没有发生剂量限制毒性3-4级治疗相关不良事件发生率为45%ORR：33-50%1年OS：59-87%,AntoniaSJ,etal.2014ASCOAbstract8113.,AntoniaSJ,etal.2014ASCOAbstract8113.,OngoingNivolumabClinicalTrialsinPatientsWithNSCLC,ClinicalT.NCT02041533.2.ClinicalT.NCT01642004.3.ClinicalT.NCT01673867.4.ClinicalT.NCT01721759.5.ClinicalT.NCT01968109.6.ClinicalT.NCT01714739.7.ClinicalT.NCT01454102.,30,PartsCtoF:AdditionalMELandNSCLCcohorts,MK3475(Pembrolizumab,Anti-PD-1):PhaseITrialDesign,IPI-N10q2w(n=41),IPI-N10q3w(n=24),PartA:DoseEscalation,IPI-N2q3w(n=22),IPI-T10q2w(n=16),IPI-T10q3w(n=32),PartB:Metastaticorlocallyadvanced,unresectableMEL,RibasAetal.ASCO2013.Abstract9009.,.,31,KEYNOTE-001：NSCLC扩大队列研究设计(N=307),*前11例患者随机分入2mg/kgq3w和10mg/kgq3w组，剩余34例患者随机接受10mg/kgq2w和10mg/kgq3w组*非随机队列的45例接受2mg/kgq3w的患者分析截止日期为2014年9月11日数据截止日期：2014年3月3日GaronEB,etal.2014ESMOAbstractLBA43.,主要终点：ORR(RECISTv1.1独立中心评估)次要终点：免疫相关疗效标准(irRC)研究者评估Pembrolizumab(MK3475)治疗持续直至PD，不可接受的毒性或死亡,KEYNOTE-001：基线特征,GaronEB,etal.2014ESMOAbstractLBA43.,KEYNOTE-001：治疗暴露与治疗相关不良事件汇总,4例患者(1.5%)发生输注相关反应发生率=50%的肿瘤细胞PD-L1弱阳性：1-49%的肿瘤细胞染色阴性为PD-L1无表达GaronEB,etal.2014ESMOAbstractLBA43.,PD-L1强阳性患者较弱阳性/阴性患者的PFS更长(HR=0.52;95%CI:0.33-0.80)PD-L1强阳性患者较弱阳性/阴性患者的OS更长(HR=0.59;95%CI:0.35-0.99),KEYNOTE-001：总结与结论,在初治(ORR26%)和复治(ORR20%)晚期NSCLC患者中，所有剂量和方案都观察到很好的抗肿瘤活性2mg/kgq3w剂量下，ORR为20%(irRC)缓解持久安全性及毒性可管理PD-L1强表达与缓解率(37%)、PFS(HR=0.52)、OS(HR=0.59)的改善相关在KEYNOTE-001研究额外入组的300例患者中将前瞻性验证PD-L1的截点,GaronEB,etal.2014ESMOAbstractLBA43.,4/49,PD-L1IdentifiesPtsWithNSCLCMostLikelytoBenefitFromMK-3475(Pembrolizumab,Anti-PD-1),StrongPD-L1positivestainingwasconsidered50%oftumorcells,andweakwasdefinedasstainingbetween1%to49%ofpositivelystainingtumorcells.NegativehadnotumorstainingforPD-L1.,ResponseRate(%),3/42,7/46,15/41,25/129,GandhiL,etal.AACR2014.AbstractCT105.Reprintedwithpermission.,RR-RECIST1.1,50,40,30,20,10,0,19,37,15,7,Total1%-49%PD-L1staining,50%PD-L1stainingPD-L1negative,ResponseRate(%),4/53,20/44,28/146,RR-irRC,50,40,30,20,10,0,19,46,8,8,n/N:,n/N:,.,44,OngoingMK-3475(Pembrolizumab,Anti-PD-1)ClinicalTrialsinPatientsWithNSCLC,1.ClinicalT.NCT02085070.2.ClinicalT.NCT02129556.3.ClinicalT.NCT01905657.4.ClinicalT.NCT02142738.5.ClinicalT.NCT02039674.,.,45,ExamplesofPD-L1NSCLCSampleIHCStaining*,PD-L1Negative,PD-L1Positive,*Clinicaltrialassay.,GandhiL,etal.AACR2014.AbstractCT105.Reprintedwithpermission.,.,46,PhaseIStudyofMPDL3280A(Anti-PDL-1)inNSCLC,MPDL3280A:antiPD-L1antibodyengineeredforenhancedsafetyandefficacyPatientswithmetastaticsolidtumorsEGFRandKRASstatusassessedatbaselineStudydesign:MPDL3280AIVevery3wksx16cycles(1yr)Primaryendpoint:safetySecondaryendpoint:ORRbyRECISTv1.1Baselinedemographics,*Safetyevaluablepatients(n=85)withNSCLC.DatacutoffApril30,2013.Systemicregimensadministeredinthemetastatic,adjuvantorneoadjuvantsetting.3%ofpatientshadnoprevioussystemicregimens.,HornL,etal.WCLC2013.AbstractMO18.Reprintedwithpermission.,.,47,DurationofTreatmentandResponse,Wk,HistologyIHC,NSIHC0,SIHC3,NSIHC0,NSIHC1,NSIHC0,SIHC2,NSIHC3,SIHC3,NSIHC3,NSIHC0,NSIHC3,NSIHC1,*PD-LIstatusdeterminedusingproprietaryGenentechRocheIHC.ORRincludesinvestigator-assessedunconfirmedandconfirmed(u/c)PRperRECIST1.1.Patientsfirstdosedat1-20mg/kgbyOctober1,2012.DatacutoffApril30,2013.,MPDL3280A(Anti-PDL-1)inNSCLC:BestResponsebyPD-L1StatusandDOT/DOR,HornL,etal.WCLC2013.AbstractMO18.Reprintedwithpermission.,0,6,12,18,24,30,36,42,48,54,60,66,72,78,84,Onstudy,ontreatmentOnstudy,posttreatmentTreatmentdiscontinuedOngoingresponseFirstresponseFirstPD,.,48,*ORRincludesinvestigator-assessedu/cPRbyRECIST1.1.Patientsfirstdosedat1-20mg/kgbyOctober1,2012.DatacutoffApril30,2013.,Former/CurrentSmokers,NeverSmokers,ResponsebySmokingStatus(ORR*),SmokingStatus(NSCLC;n=53),PtsWithPR(%),EGFRMutant,EGFRStatus(NSCLC;n=53),Unknown,ResponsebyEGFRStatus(ORR*),PtsWithPR(%),KRASStatus(NSCLC;n=53),ResponsebyKRASStatus(ORR*),PtsWithPR(%),KRASMutant,Unknown,EGFRWT,EGFRMutant,KRASWT,KRASMutant,11/43,1/10,9/40,1/6,8/27,1/10,MPDL3280A(Anti-PDL-1)PhaseIa:ResponsebySmokingandMutationalStatus,HornL,etal.WCLC2013.AbstractMO18.Reprintedwithpermission.,50,40,30,20,10,0,50,40,30,20,10,0,50,40,30,20,10,0,Former/CurrentSmokers,NeverSmokers,26%,10%,23%,17%,30%,10%,51%,30%,19%,76%,13%,11%,81%,19%,KRASWT,EGFRWT,.,49,MajorityofAEsweregrade1/2anddidnotrequireinterventionNoMTDordose-limitingtoxicitiesNograde3-5pneumonitisobservedTreatment-relateddeath(cardio-respiratoryarrest)in1patientwithsinusthrombosisandlargetumormassinvadingtheheartatbaselineImmune-relatedgrade3.4AEs:1patientwithlarge-cellneuroendocrineNSCLC(diabetesmellitus,1%),MPDL3280A(Anti-PDL-1):Treatment-RelatedAdverseEventsinPatientsWithNSCLC,*AEsoccurringin5%ofpatients.Grade3/4treatment-relatedAEslistedincludetreatment-relatedAEsforwhichtheanygradeoccurrencewas5%ofpatients.DatacutoffApril30,2013.,HornL,etal.WCLC2013.AbstractMO18.Reprintedwithpermission.,.,50,OngoingMPDL3280A(Anti-PDL-1)ClinicalTrialsinPatientsWithNSCLC,1.ClinicalT.NCT02108652.2.ClinicalT.NCT01846416.3.ClinicalT.NCT01903993.4.ClinicalT.NCT01984242.5.ClinicalT.NCT02013219.6.ClinicalT.NCT01988896.7.ClinicalT.NCT01633970.,.,51,MED14736(Anti-PD-L1):Emergingpr