肺癌免疫治療進展課件

肺癌免疫治療進展肺癌免疫治療進展FutureOutlookUpdateofcheckpointInhibitorsinlungcancertherapyCancerImmunotherapy123OutlineFutureOutlookUpdateofcheckpFutureOutlookUpdateofcheckpointInhibitorsinlungcancertherapyCancerImmunotherapy123OutlineFutureOutlookUpdateofcheckp

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)師高度關注，近年進步顯著，使得免疫治療成為更具期待的領域1896年coley毒素應用于臨床1899年放療治愈第1例病人1946年氮芥治療淋巴瘤獲得成功免疫治療放療化療靶向治療進入21世紀，分子靶向治療如火如荼

腫瘤免疫治療—攻克腫瘤的新希望

人類抗擊腫瘤的歷史1896eKeyeventsinthehistoryofcancerimmunotherapy1890s1stCAvaccinedeveloped(coley)1973discoveryofthedendriticcell(steinman)19761ststudywithBCGinbladderCA1978DiscoveryoftumorspecificmABs19851ststudywithadoptiveT-celltransferinCA1986IFNα(cytokine)approvedforCA1990sDiscoveryofroleofcheckpointsinCA1992Il-2(Cytokine)approvedforCA19971stmABapprovedforCA20101stcellularimmunotherapyapprovedforCA20111stcheckpointinhibitorapprovedforCA20142ndcheckpointinhibitorapprovedforCAEnthusiasmphase1976-1985Skepticismphase1986-1992Renaissancephase1997-eKeyeventsinthehistory189美國《Science》雜志:2013年六大值得關注的科學領域單細胞測序“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植物研究美國《Science》雜志:Breakthroughofyear2013

Science.2013Dec20;342(6165):1432-3Breakthroughofyear2013

ScieImmunity.39(1)25July2013,Pages1–10StimulatoryandInhibitoryFactorsintheCancer-ImmunityCycleImmunity.39(1)25July2013,PCTLA-4andPD-1/PD-L1checkpoint

blockadeforcancertreatmentCTLA-4andPD-1/PD-L1checkpoiCTLA-4andPD-1/PD-L1

CheckpointBlockadeforCancerTreatmentImmunecheckpointblockadeincludesagentstargetingthenegativeregulatorsCTLA-4andPD-1CTLA-4attenuatestheearlyactivationofnaiveandmemoryTcellsinthelymphnodesAgentstargetingCTLA-4includeipilimumabandtremelimumabIncontrast,PD-1modulatestheeffectorphaseofTcellactivityinperipheraltissuesviainteractionwithPD-L1andPD-L2AgentstargetingPD-1includenivolumabandMK-3475AgentstargetingPD-L1includeMPDL3280AandMEDI4736KyiC,etal.FEBSLett.2014;588:368-376CTLA-4andPD-1/PD-L1

CheckpoComparingCTLA-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-1haveseparatebutcomplimentaryrolesinimmuneresponsesComparingCTLA-4andPD-1CTLA-FutureOutlookUpdateofcheckpointInhibitorsinlungcancertherapyCancerImmunotherapy123OutlineFutureOutlookUpdateofcheckpCTLA-4CheckpointInhibitor肺癌免疫治療進展課件Anti-CTLA-4antibodiescaninduce

clinicalresponseinabroadvarietyofcancerAdaptedformLebbeetal.ESMO2008PresentedByLawrenceFongat2014ASCOAnnualMeetingBladderRenalEsophagealCNSColorectalGlioblastomaLeukemiaSoftTissueSarcomaAnti-CTLA-4antibodiescanindJClinOncol.2012Jun10;30(17):2046-54AnnOncol.2013Jan;24(1):75-83JClinOncol.2012Jun10;30(1JClinOncol.2012Jun10;30(17):2046-54IpilimumabincombinationwithPCasfirst-linetherapyinstageIIIB/IVNSCLCJClinOncol.2012Jun10;30(1Kaplan–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-rankP0.48ConcurrentlpiControlKaplan–MeierplotsforOSJClEvents/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.02ControlPhasedIpiControlConcurrentlpiEvents/patientsAdverseEventsJClinOncol.2012Jun10;30(17):2046-54AdverseEventsJClinOncol.20Follow-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)SCREENINGINDUCTIONMAINTENANCEFCA184-156: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)PlaceboQ3W2cycleCA184-156:PhaseIIITrialComAPhaseIIIStudyofNivolumabinCombinationwithYervoyinPatientswithAdvancedNon-SmallCellLungCancerAPhaseIIIStudyofNivolumabPD-1/PD-L1CheckpointInhibitors肺癌免疫治療進展課件PD-1andPD-L1antibodiesinphaseIIIdevelopmentPD-1andPD-L1antibodiesinpPhase1Nivolumab(anti-PD-1;BMS-936558,ONO-4538)multidoseregimenEligibility:advcancedmelanoma,NSCLC,RCC,CRC,orCRPCwithPDafter1-5systemictherapiesPhase1Nivolumab(anti-PD-1;BSelectAes(>1%)occuringinPtswithNSCLCtreatedwithNivolumab(N=129)Drug-relatedpneumonitis(anygrade)occurredin8NSCLCPts(6%)VS12Pts(4%)intheoverallstudypopulation-3Pts(2%)withNSCLChadgrade?pneumonitisSelectAes(>1%)occuringinPtEfficacyofNivolumabmonotherapy

inPtstreatedwithNSCLCEfficacyofNivolumabmonotheNivolumabincombinationwithPT-DCinadvancedNSCLCAntoniaSJ,etal.2014ASCOAbstract8113.NivolumabincombinationwithResultsandConclusions治療的前6周沒有發(fā)生劑量限制毒性3-4級治療相關不良事件發(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.ResultsandConclusions治療的前6周沒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.OngoingNivolumabClinical

TrPartsCtoF: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.PartsCtoF:AdditionalMELaKEYNOTE-001：

NSCLC擴大隊列研究設計(N=307)非隨機(N=33)PD-L1+2次治療非隨機(N=40)PD-L1+2次治療至少1次含鉑隨機(N=144)PD-L1+1次治療至少1次含鉑隨機(N=45)PD-L1+初治非隨機(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例患者隨機分入2mg/kgq3w和10mg/kgq3w組，剩余34例患者隨機接受10mg/kgq2w和10mg/kgq3w組****非隨機隊列的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：免疫相關療效標準(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KEYNOTE-001：

NSCLC擴大隊列研究設計(N=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.KEYNOTE-001：基線特征特征N=262年齡，中位(KEYNOTE-001：

治療暴露與治療相關不良事件匯總4例患者(1.5%)發(fā)生輸注相關反應發(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級治療相關不良事件(發(fā)生率≥5%)乏力20%<1%瘙癢9%0關節(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%其他關注的臨床不良事件(發(fā)生率≥1%)肺炎4%2%甲狀腺功能亢進2%<1%GaronEB,etal.2014ESMOAbstractLBA43.KEYNOTE-001：

治療暴露與治療相關不良事件匯總4例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.KEYNOTE-001：

腫瘤大小自基線最大變化*(%)

KEYNOTE-001：抗腫瘤活性

(RECISTv1.1，中心評估)a包括確認和未確認緩解；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)KEYNOTE-001：抗腫瘤活性

(RECISTv1.1KEYNOTE-001：

抗腫瘤活性(irRC，研究者評估)a包括確認和未確認緩解；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)KEYNOTE-001：

抗腫瘤活性(irRC，研究者評估KEYNOTE-001：

至緩解時間&緩解持續(xù)時間a包括確認和未確認緩解GaronEB,etal.2014ESMOAbstractLBA43.KEYNOTE-001：

至緩解時間&緩解持續(xù)時間a包括KEYNOTE-001：

生存期評估：初治vs.復治GaronEB,etal.2014ESMOAbstractLBA43.初治復治中位PFS(周)271024周PFS(%)5126初治復治中位OS(月)NR8.26個月OS(%)8659KEYNOTE-001：

生存期評估：初治vs.復治GaKEYNOTE-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(%)64KEYNOTE-001：

生存期評估：不同劑量GaronEKEYNOTE-001：

PD-L1表達水平與緩解率GaronEB,etal.2014ESMOAbstractLBA43.KEYNOTE-001：

PD-L1表達水平與緩解率GaroKEYNOTE-001：

生存期評估：PD-L1表達PD-L1強陽性：>=50%的腫瘤細胞PD-L1弱陽性：1-49%的腫瘤細胞染色陰性為PD-L1無表達GaronEB,etal.2014ESMOAbstractLBA43.PD-L1強陽性患者較弱陽性/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)KEYNOTE-001：

生存期評估：PD-L1表達PD-LKEYNOTE-001：

總結(jié)與結(jié)論在初治(ORR26%)和復治(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強表達與緩解率(37%)、PFS(HR=0.52)、OS(HR=0.59)的改善相關在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.KEYNOTE-001：

總結(jié)與結(jié)論在初治(ORR26%)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:4/49PD-L1IdentifiesPtsWithOngoingMK-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.OngoingMK-3475(Pembrolizumab,ExamplesofPD-L1NSCLC

SampleIHCStaining*PD-L1NegativePD-L1Positive*Clinicaltrialassay.StainingIntensity0+1+2+3+PD-L1Positivity,%02100100GandhiL,etal.AACR2014.AbstractCT105.Reprintedwithpermission.ExamplesofPD-L1NSCLC

SamplPhaseIStudyofMPDL3280A

(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.PhaseIStudyofMPDL3280A

(AnPD-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

FirstresponseFirstPDPD-L1Status*ORR,?PtsWithPD,*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%KRASWTEGFRWT*ORRincludesinvestigator-assMajorityofAEsweregrade1/2anddidnotrequireinterventionNoMTDordose-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.MajorityofAEsweregrade1/2OngoingMPDL3280A(Anti-PDL-1)

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