医学课件-肺癌免疫治疗进展

肺癌免疫治疗进展肺癌免疫治疗进展FutureOutlookUpdateofcheckpointInhibitorsinlungcancertherapyCancerImmunotherapy123Outline2Confidential2/21/2013FutureOutlookUpdateofcheckpFutureOutlookUpdateofcheckpointInhibitorsinlungcancertherapyCancerImmunotherapy123Outline3Confidential2/21/2013FutureOutlookUpdateofcheckp

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1896年coley毒素应用于临床1899年放疗治愈第1例病人1946年氮芥治疗淋巴瘤获得成功免疫治疗放疗化疗靶向治疗进入21世纪，分子靶向治疗如火如荼4Confidential2/21/2013

肿瘤免疫治疗—攻克肿瘤的新希望

人类抗击肿瘤的历史1896eKeyeventsinthehistoryofcancerimmunotherapy1890s1stCAvaccinedeveloped(coley)1973discoveryofthedendriticcell(steinman)19761ststudywithBCGinbladderCA1978DiscoveryoftumorspecificmABs19851ststudywithadoptiveT-celltransferinCA1986IFNα(cytokine)approvedforCA1990sDiscoveryofroleofcheckpointsinCA1992Il-2(Cytokine)approvedforCA19971stmABapprovedforCA20101stcellularimmunotherapyapprovedforCA20111stcheckpointinhibitorapprovedforCA20142ndcheckpointinhibitorapprovedforCAEnthusiasmphase1976-1985Skepticismphase1986-1992Renaissancephase1997-5eKeyeventsinthehistory189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美国《Science》杂志:6Breakthroughofyear2013

Science.2013Dec20;342(6165):1432-37Confidential2/21/2013Breakthroughofyear2013

ScieImmunity.39(1)25July2013,Pages1–10StimulatoryandInhibitoryFactorsintheCancer-ImmunityCycle8Immunity.39(1)25July2013,PCTLA-4andPD-1/PD-L1checkpoint

blockadeforcancertreatment9CTLA-4andPD-1/PD-L1checkpoiCTLA-4andPD-1/PD-L1

CheckpointBlockadeforCancerTreatmentImmunecheckpointblockadeincludesagentstargetingthenegativeregulatorsCTLA-4andPD-1CTLA-4attenuatestheearlyactivationofnaiveandmemoryTcellsinthelymphnodesAgentstargetingCTLA-4includeipilimumabandtremelimumabIncontrast,PD-1modulatestheeffectorphaseofTcellactivityinperipheraltissuesviainteractionwithPD-L1andPD-L2AgentstargetingPD-1includenivolumabandMK-3475AgentstargetingPD-L1includeMPDL3280AandMEDI4736KyiC,etal.FEBSLett.2014;588:368-37610Confidential2/21/2013CTLA-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-1haveseparatebutcomplimentaryrolesinimmuneresponses11Confidential2/21/2013ComparingCTLA-4andPD-1CTLA-FutureOutlookUpdateofcheckpointInhibitorsinlungcancertherapyCancerImmunotherapy123Outline12Confidential2/21/2013FutureOutlookUpdateofcheckpCTLA-4CheckpointInhibitor13Confidential2/21/201313Confidential2/21/2013Anti-CTLA-4antibodiescaninduce

clinicalresponseinabroadvarietyofcancerAdaptedformLebbeetal.ESMO2008PresentedByLawrenceFongat2014ASCOAnnualMeetingBladderRenalEsophagealCNSColorectalGlioblastomaLeukemiaSoftTissueSarcoma14Confidential2/21/2013Anti-CTLA-4antibodiescanindJClinOncol.2012Jun10;30(17):2046-54AnnOncol.2013Jan;24(1):75-8315Confidential2/21/2013JClinOncol.2012Jun10;30(1JClinOncol.2012Jun10;30(17):2046-54IpilimumabincombinationwithPCasfirst-linetherapyinstageIIIB/IVNSCLC16Confidential2/21/2013JClinOncol.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-rankP0.48ConcurrentlpiControl17Confidential2/21/2013Kaplan–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.02ControlPhasedIpiControlConcurrentlpi18Confidential2/21/2013Events/patientsAdverseEventsJClinOncol.2012Jun10;30(17):2046-5419Confidential2/21/2013AdverseEventsJClinOncol.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)20Confidential2/21/2013SCREENINGINDUCTIONMAINTENANCEFCA184-156: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)PlaceboQ3W2cycle21Confidential2/21/2013CA184-156:PhaseIIITrialComAPhaseIIIStudyofNivolumabinCombinationwithYervoyinPatientswithAdvancedNon-SmallCellLungCancer22Confidential2/21/2013APhaseIIIStudyofNivolumabPD-1/PD-L1CheckpointInhibitors23Confidential2/21/201323Confidential2/21/2013PD-1andPD-L1antibodiesinphaseIIIdevelopment24PD-1andPD-L1antibodiesinpPhase1Nivolumab(anti-PD-1;BMS-936558,ONO-4538)multidoseregimenEligibility:advcancedmelanoma,NSCLC,RCC,CRC,orCRPCwithPDafter1-5systemictherapies25Phase1Nivolumab(anti-PD-1;BSelectAes(>1%)occuringinPtswithNSCLCtreatedwithNivolumab(N=129)Drug-relatedpneumonitis(anygrade)occurredin8NSCLCPts(6%)VS12Pts(4%)intheoverallstudypopulation-3Pts(2%)withNSCLChadgrade¾pneumonitis26SelectAes(>1%)occuringinPtEfficacyofNivolumabmonotherapy

inPtstreatedwithNSCLC27EfficacyofNivolumabmonotheNivolumabincombinationwithPT-DCinadvancedNSCLCAntoniaSJ,etal.2014ASCOAbstract8113.NivolumabincombinationwithResultsandConclusions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%Nivo10+gem/cis鳞癌Nivo10+pem/cis非鳞癌Nivo10+pac/carb鳞+非鳞癌Nivo5+pac/carb鳞+非鳞癌N12151514ORR,n(%)4(33)7(47)7(47)7(50)mDOR(范围)，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为BOR,n(%)003(20)1(7)24周时PFS,%367138571年OS,%598759NAAntoniaSJ,etal.2014ASCOAbstract8113.AntoniaSJ,etal.2014ASCOAbstract8113.ResultsandConclusions治疗的前6周没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.NCT01454102.30OngoingNivolumabClinical

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.Abstract9009.31PartsCtoF:AdditionalMELaKEYNOTE-001：

NSCLC扩大队列研究设计(N=307)非随机(N=33)PD-L1+2次治疗非随机(N=40)PD-L1+2次治疗至少1次含铂随机(N=144)PD-L1+1次治疗至少1次含铂随机(N=45)PD-L1+初治非随机(N=45)PD-L1+1次治疗至少1次含铂Pembro10mg/kgq3wPembro10mg/kgq2wPembro10mg/kgq3wPembro10mg/kgq2wPembro10mg/kgq2wPembro10mg/kgq3wPembro2mg/kgq3wPembro2mg/kgq3wR(3:2)R*(1:1:1)*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：

NSCLC扩大队列研究设计(N=KEYNOTE-001：基线特征特征

N=262年龄，中位(范围)，岁65(28-86)男性50%ECOGPS：0/1/缺失31%/68%/1%人种：白种/黑人或非裔美国人/亚裔/其他83%/4%/11%/2%鳞癌17%既往接受治疗次数：0/>=117%/83%分期：M0/M1a/M1b/未知13%/28%/49%/11%脑转移瘤史5%EGFR突变(N=250)16%KRAS突变(N=156)26%ALK基因重排(N=231)3%吸烟史：目前/曾经/从不/未知5%/64%/28%/2%GaronEB,etal.2014ESMOAbstractLBA43.KEYNOTE-001：基线特征特征N=262年龄，中位(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治疗暴露N=262中位(范围)治疗时间(d)85.5(1-400)中位(范围)剂量(n)5.5(1-23)治疗相关不良事件总结(%)任何级别67%3-4级9%死亡0.4%终止3%不良事件发生率N=262任何级别3-5级治疗相关不良事件(发生率≥5%)乏力20%<1%瘙痒9%0关节痛8%<1%食欲减退8%0腹泻7%0甲状腺功能减退6%0发热6%0皮疹6%0恶心5%<1%其他关注的临床不良事件(发生率≥1%)肺炎4%2%甲状腺功能亢进2%<1%GaronEB,etal.2014ESMOAbstractLBA43.KEYNOTE-001：

治疗暴露与治疗相关不良事件汇总4例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：

肿瘤大小自基线最大变化*(%)

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.

NORR%(95%CI)总计23621(16-27)治疗史236未经治疗4226(14-42)曾接受过治疗19420(15-26)组织学230非鳞癌19123(17-29)鳞癌3918(8-34)吸烟史230目前/曾经16527(20-34)从不659(4-19)

NORR%(95%CI)给药方案2362Q3W633(4-78)10Q3W12621(14-29)10Q2W10421(14-30)PD-L1表达236阳性20123(18-30)阴性359(2-23)EGFR突变3614(5-30)KRAS突变3928(15-45)ALK基因重排617(0-64)KEYNOTE-001：抗肿瘤活性

(RECISTv1.1KEYNOTE-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%)bNORR%(95%CI)总计26223(18-29)治疗史262未经治疗4547(32-62)曾接受过治疗21718(13-24)组织学258非鳞癌21223(17-29)鳞癌4425(13-40)吸烟史256目前/曾经18227(21-34)从不7414(7-24)NORR%(95%CI)给药方案2622Q3W667(22-96)10Q3W14122(16-30)10Q2W11522(15-30)PD-L1表达262阳性22225(19-31)阴性4013(4-27)EGRFR突变4112(4-26)KRAS突变4132(18-48)ALK重排633(4-78)KEYNOTE-001：

抗肿瘤活性(irRC，研究者评估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：

至缓解时间&缓解持续时间a包括KEYNOTE-001：

生存期评估：初治vs.复治GaronEB,etal.2014ESMOAbstractLBA43.初治复治中位PFS(周)271024周PFS(%)5126初治复治中位OS(月)NR8.26个月OS(%)8659KEYNOTE-001：

生存期评估：初治vs.复治GaKEYNOTE-001：

生存期评估：不同剂量GaronEB,etal.2014ESMOAbstractLBA43.全组人群中位PFS(周)13.024周PFS(%)30全组人群中位OS(月)8.26个月OS(%)64KEYNOTE-001：

生存期评估：不同剂量GaronEKEYNOTE-001：

PD-L1表达水平与缓解率GaronEB,etal.2014ESMOAbstractLBA43.KEYNOTE-001：

PD-L1表达水平与缓解率GaroKEYNOTE-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：

生存期评估：PD-L1表达PD-LKEYNOTE-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.KEYNOTE-001：

总结与结论在初治(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:444/49PD-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.NCT02039674.45OngoingMK-3475(Pembrolizumab,ExamplesofPD-L1NSCLC

SampleIHCStaining*PD-L1NegativePD-L1Positive*Clinicaltrialassay.StainingIntensity0+1+2+3+PD-L1Positivity,%02100100GandhiL,etal.AACR2014.AbstractCT105.Reprintedwithpermission.46ExamplesofPD-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.47PhaseIStudyofMPDL3280A

(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

FirstresponseFirstPD48PD-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%KRASWTEGFRWT49*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.50MajorityofAEsweregrade1/2OngoingMPDL3280A(Anti-PDL-1)

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