肺癌免疫治療進(jìn)展培訓(xùn)課件

肺癌免疫治療進(jìn)展FutureOutlookUpdateofcheckpointInhibitorsinlungcancertherapyCancerImmunotherapy123Outline2肺癌免疫治療進(jìn)展FutureOutlookUpdateofcheckpointInhibitorsinlungcancertherapyCancerImmunotherapy123Outline3肺癌免疫治療進(jìn)展

腫瘤免疫治療—攻克腫瘤的新希望

人類抗擊腫瘤的歷史腫瘤免疫治療具有特異性和靶向性，一直為臨床醫(yī)師高度關(guān)注，近年進(jìn)步顯著，使得免疫治療成為更具期待的領(lǐng)域靶向治療進(jìn)入21世紀(jì)，分子靶向治療如火如荼4肺癌免疫治療進(jìn)展eKeyeventsinthehistoryofcancerimmunotherapy1890s1stCAvaccinedeveloped(coley)1973discoveryofthedendriticcell(steinman)19761ststudywithBCGinbladderCA1978DiscoveryoftumorspecificmABs19851ststudywithadoptiveT-celltransferinCA1986IFNα(cytokine)approvedforCA1990sDiscoveryofroleofcheckpointsinCA1992Il-2(Cytokine)approvedforCA19971stmABapprovedforCA20101stcellularimmunotherapyapprovedforCA20111stcheckpointinhibitorapprovedforCA20142ndcheckpointinhibitorapprovedforCAEnthusiasmphase1976-1985Skepticismphase1986-1992Renaissancephase1997-5肺癌免疫治療進(jìn)展美國《Science》雜志:2013年六大值得關(guān)注的科學(xué)領(lǐng)域單細(xì)胞測序“普朗克”探測微波背景輻射人類連接組計劃探索南極冰下世界癌癥免疫療法基礎(chǔ)植物研究6肺癌免疫治療進(jìn)展Breakthroughofyear2013

Science.2013Dec20;342(6165):1432-37肺癌免疫治療進(jìn)展Immunity.39(1)25July2013,Pages1–10StimulatoryandInhibitoryFactorsintheCancer-ImmunityCycle8肺癌免疫治療進(jìn)展CTLA-4andPD-1/PD-L1checkpoint

blockadeforcancertreatment9肺癌免疫治療進(jìn)展CTLA-4andPD-1/PD-L1

CheckpointBlockadeforCancerTreatmentImmunecheckpointblockadeincludesagentstargetingthenegativeregulatorsCTLA-4andPD-1CTLA-4attenuatestheearlyactivationofnaiveandmemoryTcellsinthelymphnodes

AgentstargetingCTLA-4includeipilimumabandtremelimumabIncontrast,PD-1modulatestheeffectorphaseofTcellactivityinperipheraltissuesviainteractionwithPD-L1andPD-L2AgentstargetingPD-1includenivolumabandMK-3475

AgentstargetingPD-L1includeMPDL3280AandMEDI4736KyiC,etal.FEBSLett.2014;588:368-37610肺癌免疫治療進(jìn)展ComparingCTLA-4andPD-1CTLA-4PD-1BiologicalfunctionInhibitoryreceptorInhibitoryreceptorExpressiononTcellsatthetimeofinitialresponsetoantigen(activatedCD8+Tcells)ActivatedTcells,Bcells,NKcellsTILsindifferenttumortypesMajorroleRegulatestheearlystageofT-cellactivationLimitsT-cellactivityinperipheraltissueafterinflammatoryresponseLimitsautoimmunityLigandsB7.1(CD80)B7.2(CD86)PD-L1(B7-H1/CD274)PD-L2(B7-CD/CD273)MechanismofactionAfterligandbinding:BindingwithPI3K,phosphatasesSHP-2andPP2ABlockadeoflipid-raftexpressionBlockadeofmicroclusterformationAfterligandbinding:Recruitsinhibitoryphosphatase,SHP-2DecreasesexpressionofcellsurvivalproteinBcl-xLInhibitskinases(PI3K/AKT)involvedinT-cellactivationCritRevOncolHematol.2014;89:140-165.CTLA-4andPD-1haveseparatebutcomplimentaryrolesinimmuneresponses11肺癌免疫治療進(jìn)展FutureOutlookUpdateofcheckpointInhibitorsinlungcancertherapyCancerImmunotherapy123Outline12肺癌免疫治療進(jìn)展CTLA-4CheckpointInhibitor13肺癌免疫治療進(jìn)展Anti-CTLA-4antibodiescaninduce

clinicalresponseinabroadvarietyofcancerAdaptedformLebbeetal.ESMO2008PresentedByLawrenceFongat2014ASCOAnnualMeetingBladderRenalEsophagealCNSColorectalGlioblastomaLeukemiaSoftTissueSarcoma14肺癌免疫治療進(jìn)展JClinOncol.2012Jun10;30(17):2046-54AnnOncol.2013Jan;24(1):75-8315肺癌免疫治療進(jìn)展JClinOncol.2012Jun10;30(17):2046-54IpilimumabincombinationwithPCasfirst-linetherapyinstageIIIB/IVNSCLC16肺癌免疫治療進(jìn)展Kaplan–MeierplotsforOSJClinOncol.2012Jun10;30(17):2046-54Deaths/patients51/6651/68Median(95%CI),months8.28(6.80to12.39)12.22(9.26to14.39)HR(95%CI)

0.87

(0.59

to

1.28)Log-rankP0.23ControlPhasedIpiDeaths/patients51/6651/70Median(95%CI),months8.28(6.80to12.39)9.69(7.59to12.48)HR(95%CI)

0.99(0.67to1.46)Log-rankP0.48ConcurrentlpiControl17肺癌免疫治療進(jìn)展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.25JClinOncol.2012Jun10;30(17):2046-54Kaplan–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.05ControlPhasedIpiEvents/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.13ControlConcurrentlpiEvents/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.02ControlPhasedIpiControlConcurrentlpi18肺癌免疫治療進(jìn)展AdverseEventsJClinOncol.2012Jun10;30(17):2046-5419肺癌免疫治療進(jìn)展Follow-UPEvery12wksForsurvivalSCREENINGINDUCTIONMAINTENANCEFOLLOW-UPCA184-104:phaseIIItrialcomparingthetheefficacyofipilimumab(Ipi)withPCversusplacebowithPCinpatients(pts)withstageIV/recurrentNSCLCofsquamoushistologyTumorassessmentEvery12wksIpi10mg/kg+PCWks7,10,13,16stageIV/recurrentsquamousNSCLCECOG≤1Placebo+PCWks7,10,13,162cyclePC

Wks1,

4Ipi10mg/kgEvery12wksPlaceboEvery12wksRJClinOncol31,2013(suppl;abstrTPS8117)primaryendpointOSsecondaryendpointsOSamongptswhoreceiveblindedtherapyPFSbestoverallresponserateTumorassessmentWks7,13,19,25ExclusionCriteria:BrainMetastasesAutoimmunediseasesPCPaclitaxel(175mg/m2,

IV)+Carboplatin(AUC=6,

IV)20肺癌免疫治療進(jìn)展CA184-156:PhaseIIITrialComparingtheEfficacyofIpiPlusEtoposide/PlatinumVersusEtoposide/PlatinuminSubjectsWithNewlyDiagnosedED-SCLCJClinOncol30,2012(suppl;abstrTPS7113)Ipi+EPQ3W2cycleED-SCLCECOG0-1Placebo+EPQ3W2cycleSCREENINGINDUCTIONMAINTENANCE2cycleEP

Ipi10mg/kgQ12WPlaceboQ12WRprimaryendpointOSsecondaryendpointsOSamongptswhoreceiveblindedtherapyimmune-relatedandmWHOPFSbestoverallresponseratedurationofresponseExclusionCriteria:PriorsystemictherapyforlungcancerSymptomaticCNSmetastasesHistoryofautoimmunediseaseIpiQ3W2cycleEP：etoposide(100mg/m^2,IVonDays1-3Q3W)+cisplatin(75mg/m^2,IV)or+carboplatin(AUC=5,IV)onceQ3WIpi:(10mg/kg,IV,Q3W)PlaceboQ3W2cycle21肺癌免疫治療進(jìn)展APhaseIIIStudyofNivolumabinCombinationwithYervoyinPatientswithAdvancedNon-SmallCellLungCancer22肺癌免疫治療進(jìn)展PD-1/PD-L1CheckpointInhibitors23肺癌免疫治療進(jìn)展PD-1andPD-L1antibodiesinphaseIIIdevelopment24肺癌免疫治療進(jìn)展Phase1Nivolumab(anti-PD-1;BMS-936558,ONO-4538)multidoseregimenEligibility:advcancedmelanoma,NSCLC,RCC,CRC,orCRPCwithPDafter1-5systemictherapies25肺癌免疫治療進(jìn)展SelectAes(>1%)occuringinPtswithNSCLCtreatedwithNivolumab(N=129)Drug-relatedpneumonitis(anygrade)occurredin8NSCLCPts(6%)VS12Pts(4%)intheoverallstudypopulation-3Pts(2%)withNSCLChadgrade?pneumonitis26肺癌免疫治療進(jìn)展EfficacyofNivolumabmonotherapy

inPtstreatedwithNSCLC27肺癌免疫治療進(jìn)展NivolumabincombinationwithPT-DCinadvancedNSCLCAntoniaSJ,etal.2014ASCOAbstract8113.28肺癌免疫治療進(jìn)展ResultsandConclusions治療的前6周沒有發(fā)生劑量限制毒性3-4級治療相關(guān)不良事件發(fā)生率為45%ORR：33-50%1年OS：59-87%Nivo10+gem/cis鱗癌Nivo10+pem/cis非鱗癌Nivo10+pac/carb鱗+非鱗癌Nivo5+pac/carb鱗+非鱗癌N12151514ORR,n(%)4(33)7(47)7(47)7(50)mDOR(范圍)，周20.9(12.1-41.7)32.0(13,1-42.1)25.6(11.4-39.0)NA(11.4-37.3)PD為BOR,n(%)003(20)1(7)24周時PFS,%367138571年OS,%598759NAAntoniaSJ,etal.2014ASCOAbstract8113.AntoniaSJ,etal.2014ASCOAbstract8113.29肺癌免疫治療進(jìn)展OngoingNivolumabClinical

TrialsinPatientsWithNSCLCLineoftherapyPhasePD-L1SelectionComparatorSingleagentNivolumab1stline[1]IIIYesChemotherapy2ndline,squamous[2]IIINoDocetaxel2ndline,adeno[3]IIIYesDocetaxel≥2ndline,squamous[4]IINoNACombinationNivolumab≥2ndline[5]INo+LAG3≥2ndline[6]INo+lirilumab(KIR)1stline[7]INoSingleagent;+chemotherapy;+bevacizumab;+erlotinib;+ipilimumabClinicalT.NCT02041533.2.ClinicalT.NCT01642004.3.ClinicalT.NCT01673867.4.ClinicalT.NCT01721759.5.ClinicalT.NCT01968109.6.ClinicalT.NCT01714739.7.ClinicalT.NCT01454102.30肺癌免疫治療進(jìn)展PartsCtoF:AdditionalMELandNSCLCcohortsMK3475(Pembrolizumab,Anti-PD-1):

PhaseITrialDesign20112012AprNovDecJanFebMarAprMayJunJulAugSepOctNovDecIPI-N10q2w

(n=41)IPI-N10q3w

(n=24)PartA:DoseEscalationIPI-N2q3w

(n=22)IPI-T10q2w

(n=16)IPI-T10q3w

(n=32)PartB:Metastaticorlocallyadvanced,unresectableMELRibasAetal.ASCO2013.Abstract9009.31肺癌免疫治療進(jìn)展KEYNOTE-001：

NSCLC擴(kuò)大隊列研究設(shè)計(N=307)非隨機(jī)(N=33)PD-L1+2次治療非隨機(jī)(N=40)PD-L1+2次治療至少1次含鉑隨機(jī)(N=144)PD-L1+1次治療至少1次含鉑隨機(jī)(N=45)PD-L1+初治非隨機(jī)(N=45)PD-L1+1次治療至少1次含鉑Pembro10mg/kgq3wPembro10mg/kgq2wPembro10mg/kgq3wPembro10mg/kgq2wPembro10mg/kgq2wPembro10mg/kgq3wPembro2mg/kgq3wPembro2mg/kgq3wR(3:2)R*(1:1:1)*前11例患者隨機(jī)分入2mg/kgq3w和10mg/kgq3w組，剩余34例患者隨機(jī)接受10mg/kgq2w和10mg/kgq3w組****非隨機(jī)隊列的45例接受2mg/kgq3w的患者分析截止日期為2014年9月11日數(shù)據(jù)截止日期：2014年3月3日GaronEB,etal.2014ESMOAbstractLBA43.主要終點：ORR(RECISTv1.1[獨立中心評估])次要終點：免疫相關(guān)療效標(biāo)準(zhǔn)(irRC)[研究者評估]Pembrolizumab(MK3475)治療持續(xù)直至PD，不可接受的毒性或死亡32肺癌免疫治療進(jìn)展KEYNOTE-001：基線特征特征

N=262年齡，中位(范圍)，歲65(28-86)男性50%ECOGPS：0/1/缺失31%/68%/1%人種：白種/黑人或非裔美國人/亞裔/其他83%/4%/11%/2%鱗癌17%既往接受治療次數(shù)：0/>=117%/83%分期：M0/M1a/M1b/未知13%/28%/49%/11%腦轉(zhuǎn)移瘤史5%EGFR突變(N=250)16%KRAS突變(N=156)26%ALK基因重排(N=231)3%吸煙史：目前/曾經(jīng)/從不/未知5%/64%/28%/2%GaronEB,etal.2014ESMOAbstractLBA43.33肺癌免疫治療進(jìn)展KEYNOTE-001：

治療暴露與治療相關(guān)不良事件匯總4例患者(1.5%)發(fā)生輸注相關(guān)反應(yīng)發(fā)生率<1%的其他潛在免疫調(diào)節(jié)不良事件為結(jié)腸炎和低鈉血癥治療暴露N=262中位(范圍)治療時間(d)85.5(1-400)中位(范圍)劑量(n)5.5(1-23)治療相關(guān)不良事件總結(jié)(%)任何級別67%3-4級9%死亡0.4%終止3%不良事件發(fā)生率N=262任何級別3-5級治療相關(guān)不良事件(發(fā)生率≥5%)乏力20%<1%瘙癢9%0關(guān)節(jié)痛8%<1%食欲減退8%0腹瀉7%0甲狀腺功能減退6%0發(fā)熱6%0皮疹6%0惡心5%<1%其他關(guān)注的臨床不良事件(發(fā)生率≥1%)肺炎4%2%甲狀腺功能亢進(jìn)2%<1%GaronEB,etal.2014ESMOAbstractLBA43.34肺癌免疫治療進(jìn)展KEYNOTE-001：

腫瘤大小自基線最大變化*(%)

(RECISTv1.1，中心評估)*可評估患者為根據(jù)中心評估基線有可測量病灶且至少接受一次基線后腫瘤評估GaronEB,etal.2014ESMOAbstractLBA43.35肺癌免疫治療進(jìn)展KEYNOTE-001：抗腫瘤活性

(RECISTv1.1，中心評估)a包括確認(rèn)和未確認(rèn)緩解；b數(shù)據(jù)截止日期為2014年3月3日GaronEB,etal.2014ESMOAbstractLBA43.

NORR%(95%CI)總計23621(16-27)治療史236未經(jīng)治療4226(14-42)曾接受過治療19420(15-26)組織學(xué)230非鱗癌19123(17-29)鱗癌3918(8-34)吸煙史230目前/曾經(jīng)16527(20-34)從不659(4-19)

NORR%(95%CI)給藥方案2362Q3W633(4-78)10Q3W12621(14-29)10Q2W10421(14-30)PD-L1表達(dá)236陽性20123(18-30)陰性359(2-23)EGFR突變3614(5-30)KRAS突變3928(15-45)ALK基因重排617(0-64)36肺癌免疫治療進(jìn)展KEYNOTE-001：

抗腫瘤活性(irRC，研究者評估)a包括確認(rèn)和未確認(rèn)緩解；b數(shù)據(jù)截止日期為2014年9月11日GaronEB,etal.2014ESMOAbstractLBA43.額外45例接受2mg/kgq3w治療的患者中，ORRa為20%(95%CI:10%-35%)bNORR%(95%CI)總計26223(18-29)治療史262未經(jīng)治療4547(32-62)曾接受過治療21718(13-24)組織學(xué)258非鱗癌21223(17-29)鱗癌4425(13-40)吸煙史256目前/曾經(jīng)18227(21-34)從不7414(7-24)NORR%(95%CI)給藥方案2622Q3W667(22-96)10Q3W14122(16-30)10Q2W11522(15-30)PD-L1表達(dá)262陽性22225(19-31)陰性4013(4-27)EGRFR突變4112(4-26)KRAS突變4132(18-48)ALK重排633(4-78)37肺癌免疫治療進(jìn)展KEYNOTE-001：

至緩解時間&緩解持續(xù)時間a包括確認(rèn)和未確認(rèn)緩解GaronEB,etal.2014ESMOAbstractLBA43.38肺癌免疫治療進(jìn)展KEYNOTE-001：

生存期評估：初治vs.復(fù)治GaronEB,etal.2014ESMOAbstractLBA43.初治復(fù)治中位PFS(周)271024周PFS(%)5126初治復(fù)治中位OS(月)NR8.26個月OS(%)865939肺癌免疫治療進(jìn)展KEYNOTE-001：

生存期評估：不同劑量GaronEB,etal.2014ESMOAbstractLBA43.全組人群中位PFS(周)13.024周PFS(%)30全組人群中位OS(月)8.26個月OS(%)6440肺癌免疫治療進(jìn)展KEYNOTE-001：

PD-L1表達(dá)水平與緩解率GaronEB,etal.2014ESMOAbstractLBA43.41肺癌免疫治療進(jìn)展KEYNOTE-001：

生存期評估：PD-L1表達(dá)PD-L1強(qiáng)陽性：>=50%的腫瘤細(xì)胞PD-L1弱陽性：1-49%的腫瘤細(xì)胞染色陰性為PD-L1無表達(dá)GaronEB,etal.2014ESMOAbstractLBA43.PD-L1強(qiáng)陽性患者較弱陽性/陰性患者的PFS更長(HR=0.52;95%CI:0.33-0.80)PD-L1強(qiáng)陽性患者較弱陽性/陰性患者的OS更長(HR=0.59;95%CI:0.35-0.99)42肺癌免疫治療進(jìn)展KEYNOTE-001：

總結(jié)與結(jié)論在初治(ORR26%)和復(fù)治(ORR20%)晚期NSCLC患者中，所有劑量和方案都觀察到很好的抗腫瘤活性2mg/kgq3w劑量下，ORR為20%(irRC)緩解持久安全性及毒性可管理PD-L1強(qiáng)表達(dá)與緩解率(37%)、PFS(HR=0.52)、OS(HR=0.59)的改善相關(guān)在KEYNOTE-001研究額外入組的300例患者中將前瞻性驗證PD-L1的截點GaronEB,etal.2014ESMOAbstractLBA43.43肺癌免疫治療進(jìn)展4/49PD-L1IdentifiesPtsWithNSCLCMostLikelytoBenefitFromMK-3475(Pembrolizumab,Anti-PD-1)StrongPD-L1positivestainingwasconsidered≥50%oftumorcells,andweakwasdefinedasstainingbetween1%to49%ofpositivelystainingtumorcells.NegativehadnotumorstainingforPD-L1.ResponseRate(%)3/427/4615/4125/129GandhiL,etal.AACR2014.AbstractCT105.Reprintedwithpermission.RR-RECIST1.1504030201001937157Total1%-49%PD-L1staining≥50%PD-L1stainingPD-L1negativeResponseRate(%)4/5320/4428/146RR-irRC50403020100194688n/N:n/N:44肺癌免疫治療進(jìn)展OngoingMK-3475(Pembrolizumab,Anti-PD-1)

ClinicalTrialsinPatientsWithNSCLCLineofTherapyPhasePD-L1SelectionComparatorSingle-agentMK-34751stline;≥2ndline[1,2]I/IIBothNA2ndline[3]IIIYesDocetaxel1stline[4]IIIYesChemotherapyCombinationMK-3475NA[5]I/IINoSingleagent;+chemotherapy;+pemetrexed;+gefitinib;+erlotinib;+ipilimumab1.ClinicalT.NCT02085070.2.ClinicalT.NCT02129556.3.ClinicalT.NCT01905657.4.ClinicalT.NCT02142738.5.ClinicalT.NCT02039674.45肺癌免疫治療進(jìn)展PhaseIStudyofMPDL3280A

(Anti-PDL-1)inNSCLCMPDL3280A:anti–PD-L1antibodyengineeredforenhancedsafetyandefficacyPatientswithmetastaticsolidtumorsEGFRandKRASstatusassessedatbaselineStudydesign:MPDL3280AIVevery3wksx16cycles(≈1yr)Primaryendpoint:safetySecondaryendpoint:ORRbyRECISTv1.1BaselinedemographicsCharacteristicsn=85*Medianage,yrs(range)60(24-84)Sex,male/female,n(%)48(56)/37(44)ECOGPS,0/1,n(%)27(32)/58(68)Histology,n(%)Squamous20(24)Nonsquamous65(76)*Safetyevaluablepatients(n=85)withNSCLC.DatacutoffApril30,2013.?Systemicregimensadministeredinthemetastatic,adjuvantorneoadjuvantsetting.3%ofpatientshadnoprevioussystemicregimens.Characteristics,n(%)n=85*Previoussystemicregimens?1or236(42)≥347(55)SmokingstatusCurrent/previous68(80)Never17(20)HornL,etal.WCLC2013.AbstractMO18.Reprintedwithpermission.47肺癌免疫治療進(jìn)展PD-L1Status*(N=53)ORR,?%(n/N)PtsWithPD,%(n/N)

IHC3(n=6)83(5/6)17(1/6)IHC2and3(n=13)46(6/13)23(3/13)IHC1/2/3(n=26)31(8/26)38(10/26)Allpatients(IHC0/1/2/3and7patientswithdiagnosticunknown;

N=53)23

(12/53)40

(21/53)DurationofTreatmentandResponseWkHistologyIHCNSIHC0SIHC3NSIHC0NSIHC1NSIHC0SIHC2NSIHC3SIHC3NSIHC3NSIHC0NSIHC3NSIHC1*PD-LIstatusdeterminedusingproprietaryGenentechRocheIHC.?ORRincludesinvestigator-assessedunconfirmedandconfirmed(u/c)PRperRECIST1.1.Patientsfirstdosedat1-20mg/kgbyOctober1,2012.DatacutoffApril30,2013.MPDL3280A(Anti-PDL-1)inNSCLC:BestResponsebyPD-L1StatusandDOT/DORHornL,etal.WCLC2013.AbstractMO18.Reprintedwithpermission.0612182430364248546066727884Onstudy,ontreatment

Onstudy,posttreatment

Treatmentdiscontinued

Ongoingresponse

FirstresponseFirstPD48肺癌免疫治療進(jìn)展*ORRincludesinvestigator-assessedu/cPRbyRECIST1.1.Patientsfirstdosedat1-20mg/kgbyOctober1,2012.DatacutoffApril30,2013.Former/

CurrentSmokersNever

SmokersResponsebySmokingStatus(ORR*)SmokingStatus(NSCLC;n=53)PtsWithPR(%)EGFRMutantEGFRStatus(NSCLC;n=53)UnknownResponsebyEGFRStatus(ORR*)PtsWithPR(%)KRASStatus(NSCLC;n=53)ResponsebyKRASStatus(ORR*)PtsWithPR(%)KRASMutantUnknownEGFRWTEGFRMutantKRASWTKRASMutant11/431/109/401/68/271/10MPDL3280A(Anti-PDL-1)PhaseIa:

ResponsebySmokingandMutationalStatusHornL,etal.WCLC2013.AbstractMO18.Reprintedwithpermission.504030201005040302010050403020100Former/CurrentSmokersNeverSmokers26%10%23%17%30%10%51%30%19%76%13%11%81%19%KRASWTEGFRWT49肺癌免疫治療進(jìn)展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.AdverseEvent(n=85)TreatmentRelated,%(n)AnyGrade*Grade3/4?AnyAE66(56)11(9)Fatigue20(17)2(2)Nausea14(12)1(1)Decreasedappetite12(10)0Dyspnea9(8)1(1)Diarrhea8(7)0Asthenia7(6)0Headache7(6)0Rash7(6)0Pyrexia6(5)0Vomiting6(5)1(1)Upperrespiratorytractinfection5(4)0HornL,etal.WCLC2013.AbstractMO18.Reprintedwithpermission.50肺癌免疫治療進(jìn)展OngoingMPDL3280A(Anti-PDL-1)

ClinicalTrialsinPatientsWithNSCLCLineofTherapyPhasePD-L1SelectionComparatorSingle-agentMPDL3280A1stline;≥2ndline[1]IIYesNA1stline;≥2ndline[2]IIYesNA2ndline[3]IINoDocetaxel≥2ndline[4]IIINoChemotherapyCombinationMPDL3280AExpansion:EGFRmTKInaive[5]INo+erlotinibExpansion:KRASNSCLC[6]INo+cobimetinibNA[7]INo+chemotherapy;+be