肺癌免疫治疗进展.ppt

肺癌免疫治疗进展 FutureOutlook UpdateofcheckpointInhibitorsinlungcancertherapy CancerImmunotherapy 1 2 3 Outline FutureOutlook UpdateofcheckpointInhibitorsinlungcancertherapy CancerImmunotherapy 1 2 3 Outline 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 靶向治疗 进入21世纪 分子靶向治疗如火如荼 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 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 Breakthroughofyear2013 Science 2013Dec20 342 6165 1432 3 Immunity 39 1 25July2013 Pages1 10 StimulatoryandInhibitoryFactorsintheCancer ImmunityCycle CTLA 4andPD 1 PD L1checkpointblockadeforcancertreatment CTLA 4andPD 1 PD L1CheckpointBlockadeforCancerTreatment ImmunecheckpointblockadeincludesagentstargetingthenegativeregulatorsCTLA 4andPD 1CTLA 4attenuatestheearlyactivationofnaiveandmemoryTcellsinthelymphnodesAgentstargetingCTLA 4includeipilimumabandtremelimumabIncontrast PD 1modulatestheeffectorphaseofTcellactivityinperipheraltissuesviainteractionwithPD L1andPD L2AgentstargetingPD 1includenivolumabandMK 3475AgentstargetingPD L1includeMPDL3280AandMEDI4736 KyiC etal FEBSLett 2014 588 368 376 ComparingCTLA 4andPD 1 CritRevOncolHematol 2014 89 140 165 CTLA 4andPD 1haveseparatebutcomplimentaryrolesinimmuneresponses FutureOutlook UpdateofcheckpointInhibitorsinlungcancertherapy CancerImmunotherapy 1 2 3 Outline CTLA 4CheckpointInhibitor Anti CTLA 4antibodiescaninduceclinicalresponseinabroadvarietyofcancer AdaptedformLebbeetal ESMO2008 PresentedByLawrenceFongat2014ASCOAnnualMeeting BladderRenalEsophagealCNSColorectalGlioblastomaLeukemiaSoftTissueSarcoma JClinOncol 2012Jun10 30 17 2046 54 AnnOncol 2013Jan 24 1 75 83 JClinOncol 2012Jun10 30 17 2046 54 IpilimumabincombinationwithPCasfirst linetherapyinstageIIIB IVNSCLC Kaplan MeierplotsforOS 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 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 Kaplan MeierplotsforPFSperimmune 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 AdverseEvents JClinOncol 2012Jun10 30 17 2046 54 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 CA184 156 PhaseIIITrialComparingtheEfficacyofIpiPlusEtoposide PlatinumVersusEtoposide PlatinuminSubjectsWithNewlyDiagnosedED SCLC JClinOncol30 2012 suppl abstrTPS7113 primaryendpointOSsecondaryendpointsOSamongptswhoreceiveblindedtherapyimmune relatedandmWHOPFSbestoverallresponseratedurationofresponse ExclusionCriteria PriorsystemictherapyforlungcancerSymptomaticCNSmetastasesHistoryofautoimmunedisease IpiQ3W2cycle EP etoposide 100mg m 2 IVonDays1 3Q3W cisplatin 75mg m 2 IV or carboplatin AUC 5 IV onceQ3WIpi 10mg kg IV Q3W PlaceboQ3W2cycle APhaseIIIStudyofNivolumabinCombinationwithYervoyinPatientswithAdvancedNon SmallCellLungCancer PD 1 PD L1CheckpointInhibitors PD 1andPD L1antibodiesinphaseIIIdevelopment Phase1Nivolumab anti PD 1 BMS 936558 ONO 4538 multidoseregimen Eligibility advcancedmelanoma NSCLC RCC CRC orCRPCwithPDafter1 5systemictherapies SelectAes 1 occuringinPtswithNSCLCtreatedwithNivolumab N 129 Drug relatedpneumonitis anygrade occurredin8NSCLCPts 6 VS12Pts 4 intheoverallstudypopulation 3Pts 2 withNSCLChadgrade pneumonitis EfficacyofNivolumabmonotherapyinPtstreatedwithNSCLC 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 ClinicalTrials gov NCT02041533 2 ClinicalTrials gov NCT01642004 3 ClinicalTrials gov NCT01673867 4 ClinicalTrials gov NCT01721759 5 ClinicalTrials gov NCT01968109 6 ClinicalTrials gov NCT01714739 7 ClinicalTrials gov NCT01454102 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 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 1 的其他潜在免疫调节不良事件为结肠炎和低钠血症 GaronEB etal 2014ESMOAbstractLBA43 KEYNOTE 001 肿瘤大小自基线最大变化 RECISTv1 1 中心评估 可评估患者为根据中心评估基线有可测量病灶且至少接受一次基线后肿瘤评估GaronEB etal 2014ESMOAbstractLBA43 KEYNOTE 001 抗肿瘤活性 RECISTv1 1 中心评估 a包括确认和未确认缓解 b数据截止日期为2014年3月3日GaronEB etal 2014ESMOAbstractLBA43 KEYNOTE 001 抗肿瘤活性 irRC 研究者评估 a包括确认和未确认缓解 b数据截止日期为2014年9月11日GaronEB etal 2014ESMOAbstractLBA43 额外45例接受2mg kgq3w治疗的患者中 ORRa为20 95 CI 10 35 b KEYNOTE 001 至缓解时间 缓解持续时间 a包括确认和未确认缓解GaronEB etal 2014ESMOAbstractLBA43 KEYNOTE 001 生存期评估 初治vs 复治 GaronEB etal 2014ESMOAbstractLBA43 KEYNOTE 001 生存期评估 不同剂量 GaronEB etal 2014ESMOAbstractLBA43 KEYNOTE 001 PD L1表达水平与缓解率 GaronEB etal 2014ESMOAbstractLBA43 KEYNOTE 001 生存期评估 PD L1表达 PD L1强阳性 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 L1positivestainingwasconsidered 50 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 OngoingMK 3475 Pembrolizumab Anti PD 1 ClinicalTrialsinPatientsWithNSCLC 1 ClinicalTrials gov NCT02085070 2 ClinicalTrials gov NCT02129556 3 ClinicalTrials gov NCT01905657 4 ClinicalTrials gov NCT02142738 5 ClinicalTrials gov NCT02039674 ExamplesofPD L1NSCLCSampleIHCStaining PD L1Negative PD L1Positive Clinicaltrialassay GandhiL etal AACR2014 AbstractCT105 Reprintedwithpermission PhaseIStudyofMPDL3280A Anti PDL 1 inNSCLC MPDL3280A anti PD L1antibodyengineeredforenhancedsafetyandefficacyPatientswithmetastaticsolidtumorsEGFRandKRASstatusassessedatbaselineStudydesign MPDL3280AIVevery3wksx16cycles 1yr Primaryendpoint safetySecondaryendpoint ORRbyRECISTv1 1Baselinedemographics Safetyevaluablepatients n 85 withNSCLC DatacutoffApril30 2013 Systemicregimensadministeredinthemetastatic adjuvantorneoadjuvantsetting 3 ofpatientshadnoprevioussystemicregimens HornL etal WCLC2013 AbstractMO18 Reprintedwithpermission 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 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 MajorityofAEsweregrade1 2anddidnotrequireinterventionNoMTDordose limitingtoxicitiesNograde3 5pneumonitisobservedTreatment relateddeath cardio respiratoryarrest in1patientwithsinusthrombosisandlargetumormassinvadingtheheartatbaselineImmune relatedgrade3 4AEs 1patientwithlarge cellneuroendocrineNSCLC diabetesmellitus 1 MPDL3280A Anti PDL 1 Treatment RelatedAdverseEventsinPatientsWithNSCLC AEsoccurringin 5 ofpatients Grade3 4treatment relatedAEslistedincludetreatment relatedAEsforwhichtheanygradeoccurrencewas 5 ofpatients DatacutoffApril30 2013 HornL etal WCLC2013 AbstractMO18 Reprintedwithpermission OngoingMPDL3280A Anti PDL 1 ClinicalTrialsinPatientsWithNSCLC 1 ClinicalTrials gov NCT02108652 2 ClinicalTrials gov NCT01846416 3 ClinicalTrials gov NCT01903993 4 ClinicalTrials gov NCT01984242 5 ClinicalTrials gov NCT02013219 6 ClinicalTrials gov NCT01988896 7 ClinicalTrials gov NCT01633970 MED14736 Anti PD L1 Emergingpromisingclinicalactivityinselecttumors MED14736 Anti PDL1 safety Nocolitis nohighgradepneumonitis nodrug relateddeaths OngoingMEDI4736 Anti PDL 1 ClinicalTrialsinPatientsWithNSCLC 1 ClinicalTrials gov NCT02087423 2 ClinicalTrials gov NCT02125461 3 ClinicalTrials gov NCT01975831 4 ClinicalTrials gov NCT02000947 5 ClinicalTrials gov NCT02088112 6 ClinicalTrials gov NCT02118337 NSCLC otherkeyPD 1 PD L1datapresentedat2014ASCO FutureOutlook UpdateofcheckpointInhibitorsinlungcancertherapy CancerImmunotherapy 1 2 3 Outline TumorChemo Targeted HormoneTherapyRapidActivity TumorShrinkage Targetingtumorandtumormicroenvironment Targetinghostimmunesystem highlyspecificanti tumorimmunity memory Durableresponse cure UnderstandingofTumorBiology ImmunologyEnablesRationalImmuno Combination Effectsofimmunotherapyandtargetedtherapyonmelanomasurvivalcurves ClinCancerRes 2012 18 336 341 CombiningImmunotherapyandConventionalTherapies Yrs Immunotherapy TargetedTherapy Survival Combination Controls ConventionalTherapy ClinCancerRes 2012 18 336 341 Targetingtumorandtumormicroenvironment Targetinghostimmunesystem highlyspecificanti tumorimmunity memory Durableresponse cure TumorChemo Targeted HormoneTherapyRapidActivity TumorShrinkage HOW THANKYOU 谢谢