CCO2014非小細(xì)胞肺癌進(jìn)展課件

CCO2014非小細(xì)胞肺癌進(jìn)展Non-Small-CellLungCancerforCliniciansWorkingWithintheVeteransHealthAdministrationCCO2014非小細(xì)胞肺癌進(jìn)展AboutTheseSlidesUsersareencouragedtousetheseslidesintheirownnoncommercialpresentations,butweaskthatcontent

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CCOmaterial,notthoseofClinicalCareOptions,LLC,theCMEproviders,orthecompaniesprovidingeducationalgrants.ThematerialsmaydiscussusesanddosagesfortherapeuticproductsthathavenotbeenapprovedbytheUnitedStatesFoodandDrugAdministration.Aqualifiedhealthcareprofessionalshouldbeconsultedbeforeusinganytherapeuticproductdiscussed.Readersshouldverifyallinformationanddatabeforetreatingpatientsorusinganytherapiesdescribedinthesematerials.CCO2014非小細(xì)胞肺癌進(jìn)展FacultyMillieDas,MD

ClinicalAssistantProfessorDivisionofOncology

DepartmentofMedicine

StanfordUniversity

Stanford,California

StaffPhysician

DivisionofOncology

DepartmentofMedicine

VAPaloAltoHealthCareSystem

PaloAlto,CaliforniaHeatherWakelee,MD

AssociateProfessorofMedicine,Oncology

DepartmentofMedicine/Oncology

StanfordUniversity

Stanford,CaliforniaCCO2014非小細(xì)胞肺癌進(jìn)展FacultyDisclosuresMillieDas,MD,hasnosignificantfinancialrelationshipstodisclose.HeatherWakelee,MD,hasdisclosedthatshehasreceivedconsultingfeesfromGileadSciencesandfundsforresearchsupportpaidtoStanfordUniversityfromAgennix,Celgene,Clovis,Exelixis,Genentech,EliLillyandCompany,Novartis,Pfizer,Regeneron,andRoche.CCO2014非小細(xì)胞肺癌進(jìn)展Introduction:

AdvancedNSCLCCCO2014非小細(xì)胞肺癌進(jìn)展LungCancerIncidenceandMortalityNewcasesin2013:228,19040%withstageIVdiseaseatpresentation(~90,000)~160,000deathsin2013,comparabletoprostate,pancreas,breast,andcoloncancercombined5-yearrelativesurvivalrate:13%overall(2%forpatientswithdistant-stage)diseaseNCI.Non-small-celllungcancertreatment(PDQ?).ACS.Cancerfacts&figures:2013.EstimatedCancerDeaths

bySite,2013OtherCancersLungCancer180,000160,000140,000120,000100,00080,00060,00040,00020,0000LungcancerProstatePancreasBreastColonCCO2014非小細(xì)胞肺癌進(jìn)展RiskFactorsforLungCancerSmoking91%men,80%women EnvironmentalfactorsSecond-handsmoke 3%to5% Radon 3%to5%Industrialpollution 0%to5%Radiationexposure rareCCO2014非小細(xì)胞肺癌進(jìn)展GuidelinesforLungCancerScreening1.USPSTF.ScreeningforLungCancer:RecommendationStatement.May2004.2.WenderR,etal.CACancerJClin.2013;63:107-117.3.BachPB,etal.JAMA.2012;307:2418-2429.4.NCCN.LungCancerScreeningGuidelines.V1.2014.5.JaklitschMT,etal.JThoracCardiovascSurg.2012;144:33-38.6.USPSTF.ScreeningforLungCancer:RecommendationStatement.August2013(Draft).OrganizationRecommendationYearUSPreventiveServicesTaskForce[1]TheevidenceisinsufficienttorecommendfororagainstscreeningwithLDCT,CXR,cytology,orthecombination2004AmericanCancerSociety[2]AmericanCollegeofChestPhysicians[3]AmericanSocietyforClinicalOncology[3]NationalComprehensiveCancerNetwork[4]

AmericanThoracicSociety[5]

USPreventiveServicesTaskForce(Draft)[6]1)AnnualLDCTscreeningshouldbeofferedinsettingsthatcandelivercomprehensivecaretopersonsaged55-74yrswhohavesmokedfor≥30pack/yrsandhavesmokedwithinthepast15yrs(withsomeorganizationsrecommendedscreeningupto80yrsofage)2)CTscreeningshouldnotbeperformedforindividualswhosmokedfor<30pack/yrs,areeitheryoungerthan55orolderthan74yrsofage,orwhoquitsmokingmorethan15yrsago;CTscreeningshouldalsonotbeperformedinindividualswithseverecomorbiditiesthatwouldprecludepotentiallycurativetreatmentand/orlimitlifeexpectancy2012-2013CCO2014非小細(xì)胞肺癌進(jìn)展NationalLungScreeningTrial:

TrialOverview53,345patientsscreenedandthenfollowedfor2years95%ofabnormalCTscanswere“falsepositives”20%relativemortalityreduction(P=.004)356vs443lungcancer–relateddeathsinLDCTvsCXRNumberneededtoscreentoprevent1lungcancerdeath:320Asymptomaticpatientswith≥30-pack/yearsmokinghistoryAge55-74years

(N=53,439)LDCTAnnualscreeningx3yrsCXRAnnualscreeningx3yrsNationalLungScreeningTrialResearchTeam,etal.NEnglJMed.2011;365:395-409.CCO2014非小細(xì)胞肺癌進(jìn)展NationalLungScreeningTrial:

SurvivalCurvesRelativereductioninall-causemortalityof6.7%(P=.02)1877deathsinLDCTgroup,2000inCXRgroupLungCancerMortalityAllMortalityNationalLungScreeningTrialResearchTeam,etal.NEnglJMed.2011;365:395-409.0123456781.000.990.980.970.960.950.940.930.920.910.90CTarmlungcancerCXRarmlungcancerCTarmall-causeCXRarmall-causeProbabilityofSurvival:

AllParticipantsYrsFromRandomizationCCO2014非小細(xì)胞肺癌進(jìn)展NationalLungScreeningTrial:QuestionsLungcancerscreeningnowrecommendedbyUSPSTF(draftstatementissuedsummer2013)[1]WillthisbeimplementedbytheVA?Apilotprogramisunderwayat8VAcentersWhattodowith95%of“benign”nodules?Adjustsizecriterionforintervention?Followvsbiopsyvsmorespecifictest1.USPSTF.ScreeningforLungCancer:RecommendationStatement.August2013(Draft).CCO2014非小細(xì)胞肺癌進(jìn)展ComplexitiesofLungCancerPathogenesisResultinDiverseHistologicSubtypesSCLC(~15%)NSCLCAdenocarcinoma(~45%)SCC(~25%)Largecell(~5-10%)LPA[formerlyBPA](~5-10%)NOS(~10-30%)SunS,etal.NatRevCancer.2007;7:778-790.

TravisWD,etal.JClinOncol.2013;31:992-1001.CCO2014非小細(xì)胞肺癌進(jìn)展NSCLC:AJCCStaging

EdgeSB,etal.AJCCCancerStagingManual.7thed.NewYork,NY:Springer;2010.P.253-270.LungCancerStaging:DifferencesBetweentheAJCCCancerStagingManual,6thand7thEditionsAJCC6thEditionAJCC7thEditionTdescriptorT1≤3cmT1a:≤2cm

T1b:>2cmbut≤3cmT23cmor:InvadesvisceralpleuraAtelectasisoflessthanentirelungProximalextentatleast2cmfromcarinaT2a:>3cmbut≤5cmT2b:>5cmbut≤7cm

Ortumors≤7cmwithinvasionofvisceralpleura,atelectasisoflessthanentirelung,proximalextentatleast2cmfromcarinaT3Tumorswithinvasionofchestwall,diaphragm,mediastinalpleuraTumors>7cmorwith:Directinvasionofchestwall,diaphragm,phrenicnerve,mediastinalpleura,parietalpericardium,mainbronchus<2cmfromcarina(withoutinvolvementofcarina)

TumornodulesinsamelobeasprimarytumorT4Tumorofanysizewith:

Invasionofmediastinum,heart,greatvessels,trachea,esophagusMalignantpleuralorpericardialeffusionsTumornodulesinthesamelobeastheprimaryTumorofanysizewith:

Invasionofmediastinum,heart,greatvessels,trachea,esophagusMetastatictumornodulesindifferentlobefromprimarytumorNdescriptorNochangesMdescriptorM1Distantmetastasis:metastatictumornodulesinadifferentlobefromtheprimarytumorSubdividedinto:M1a:Malignantpleuralorpericardialeffusionpleuralnodules,nodulesincontralaterallungM1b:DistantmetastasisChangesinstagingareshowninitalics.CCO2014非小細(xì)胞肺癌進(jìn)展AdvancedNSCLC:PrognosticFactorsFactorscorrelatedwithadverseprognosisPoorperformancestatusWeightlossof>10%MalegenderSquamouscellhistologyAdvancedagealonehasnotbeenshowntoinfluenceresponseorsurvivalwiththerapyNCI.Non-small-celllungcancertreatment(PDQ?).CCO2014非小細(xì)胞肺癌進(jìn)展ConsiderationsforFirst-lineTherapyPerformancestatusAgeOrganfunction,nutritionalstatusHemoptysisHistologyMolecularvariablesOtherCNSmetastasesPreviouschemotherapyinadjuvantorlocallyadvancedsettingCCO2014非小細(xì)胞肺癌進(jìn)展PathologicAssessmentofHistologyIsCriticaltoOptimizeTreatmentClassifypatientsassquamousornonsquamousAllpatientsthatdonothavebonafidesquamousNSCLCshouldbeconsiderednonsquamousSquamouscellsaretypicallyp63positiveandTTF1negativeAdenocarcinomasareTTF1positive(70%to90%)andgenerallyp63negativeDiLoretoC,etal.JClinPathol.1997;50:30-32.FabbroD,etal.EurJCancer.1996;32A:512-517.RekhtmanN,etal.ModPathol.2011;24:1348-1359.CCO2014非小細(xì)胞肺癌進(jìn)展First-lineTreatmentConsiderationsintheAbsenceofEFGRorALKBiomarkersHowwellestablishedisthehistologicdiagnosis?NonsquamousSquamousMixedOptimalchemotherapyregimenRoleoftargetedtherapiesAntiangiogenicAnti-EGFRCCO2014非小細(xì)胞肺癌進(jìn)展Advanced-stage,previouslyuntreatedNSCLCpatients(N=1725)Cisplatin75mg/m2onDay1+

Gemcitabine1250mg/m2onDays1and8

Six3-wkcyclesCisplatin75mg/m2onDay1+

Pemetrexed500mg/m2onDay1

Six3-wkcyclesScagliottiGV,etal.JClinOncol.2008;26:3543-3551.PhaseIIIStudy:Cisplatin/GemcitabinevsCisplatin/PemetrexedasFirst-lineTherapyStratifiedby:ECOGperformancestatus(0vs1)Diseasestage(IIIBvsIV)Brainmetastases(yesvsno)Sex(malevsfemale)Pathologicdiagnosis(histologicvscytologic)TreatmentcenterCCO2014非小細(xì)胞肺癌進(jìn)展Cisplatin/PemetrexedvsCisplatin/GemcitabineinAdvancedNSCLC:OSScagliottiGV,etal.JClinOncol.2008;26:3543-3551.SurvivalTime(Mos)inAllPatientsSurvivalProbabilityHR:0.94

(95%CI:0.84-1.05)C/P

C/GMedianSurvival10.3mos10.3mos1.00.90.80.70.60.50.40.30.20.100612182430CCO2014非小細(xì)胞肺癌進(jìn)展C/PvsC/GinAdvancedNSCLC:OSbyHistologySurvivalTime(Mos)inAllPatients

WithSquamousHistologySurvivalProbabilitySquamousNonsquamousSurvivalTime(Mos)inPatients

WithNonsquamousHistologySurvivalProbabilityScagliottiGV,etal.JClinOncol.2008;26:3543-3551.C/P

C/G

C/PvsC/GMedianSurvival11.8mos10.4mosAdjustedHR:0.81(95%CI:0.70-0.94)C/P

C/G

C/PvsC/GMedianSurvival9.4mos10.8mosAdjustedHR:1.23(95%CI:1.00-1.51)1.00.90.80.70.60.50.40.30.20.1030061218241.00.90.80.70.60.50.40.30.20.103006121824CCO2014非小細(xì)胞肺癌進(jìn)展MaintenanceTherapyforNon-ProgressiveDiseaseAfterInitialPlatinum-BasedCTPatientswithatleaststablediseaseafter4-6cyclesofCT,ECOGPS0-1ContinuationMaintenanceObservationRSwitchMaintenanceObservationREarly2ndLineTherapyObservationRbevacizumab,cetuximab,pemetrexeddocetaxel,pemetrexed,erlotinib/gefitinibNCCN.ClinicalPracticeGuidelinesinOncology:non-small-celllungcancer.V2.2014.Options:CCO2014非小細(xì)胞肺癌進(jìn)展SwitchMaintenanceTrialsStudySwitchAgentMedianPFS,MosMedianOS,

MosFidiasetal[1](N=566)ImmediatedocetaxelDelayeddocetaxel5.72.712.39.7JMEN[2](N=663)PemetrexedPlacebo4.32.613.410.6SATURN[3](N=1949)ErlotinibPlacebo2.82.612.011.0ATLAS[4](N=1145)Erlotinib+bevacizumabPlacebo+bevacizumab4.83.714.413.3INFORM[5](N=296)GefitinibPlacebo4.82.618.716.91.FidiasPM,etal.JClinOncol.2009;27:591-598.2.CiuleanuT,etal.Lancet.2009;374:1432-1440.

3.CappuzzoF,etal.LancetOncol.2010;11:521-529.4.JohnsonBE,etal.JClinOncol.2013;31:3926-3934.5.ZhangL,etal.LancetOncol.2012;13:466-475.CCO2014非小細(xì)胞肺癌進(jìn)展ContinuationMaintenanceTrials1.BelaniCP,etal.ASCO2010.Abstract7506.2.PérolM,etal.JClinOncol.2012;30:3516-3524.3.Paz-AresLG,etal.JClinOncol.2013;31:2895-2902.StudyContinuationAgentMedianPFS,MosMedianOS,MosBelanietal[1]Gemcitabine+BSCBSC7.47.78.09.3IFCT[2]GemcitabineErlotinibObservation3.82.91.912.111.410.8PARAMOUNT[3]Pemetrexed+BSCPlacebo+BSC4.42.813.911.0CCO2014非小細(xì)胞肺癌進(jìn)展BevacizumabinNonsquamousNSCLC:

KeyResultsE4599[1](N=878)AVAiL[2,3](N=1043)JO19907[4](N=180)OutcomePCbBPCbCGB

(7.5mg/kg)CGB

(15mg/kg)PlaceboPCbBPCbORR,%351537.834.621.660.731.0P<.001P<.0001P=.0002P=.001HRforPFS0.66(P<.001)0.75(P=.0003)0.85(P=.046)0.61(P=.009)MedianPFS,mos6.24.56.76.56.16.95.9HRforOS0.79(P=.003)0.93

(P=.42)1.03

(P=.76)0.99(P=.95)MedianOS,mos12.310.313.613.413.122.823.41.SandlerA,etal.NEnglJMed.2006;355:2542-2550.2.ReckM,etal.JClinOncol.2009;27:1227-1234.

3.ReckM,etal.AnnOncol.2010;21:1804-1809.4.NihoS,etal.LungCancer.2012;76:362-367.CCO2014非小細(xì)胞肺癌進(jìn)展PointBreakPhaseIIIStudy:Pem/BevvsBevasMaint.inNonsquamousNSCLCPrimaryendpoint:OSOtherendpoints:PFS,ORR,safety,QOL,PKPemetrexed/Carboplatin/Bevacizumabfor4cyclesPaclitaxel/Carboplatin/Bevacizumabfor4cyclesChemotherapy-naivepatientswithstageIIIB/IVnonsquamousNSCLC(N=904)Pemetrexed/BevacizumabBevacizumabPatientswithoutdiseaseprogressionPatelJD,etal.2012MultidisciplinarySymposiuminThoracicOncology.AbstractLBPL1..NCT00762034.Stratifiedbystage(IIIbvsIV),

PS(0vs1),sex,

measurablevsnonmeasurablediseaseCCO2014非小細(xì)胞肺癌進(jìn)展SurvivalPem+Cb+BevPac+Cb+BevMedianOS,mos12.613.4HR(95%CI;Pvalue)1.00(0.86-1.16;P=.949)Survivalrate,%1yr52.754.12yr24.421.2PatelJ,etal.2012ChicagoMultidisciplinarySymposiuminThoracicOncology.AbstractLBPL1.PointBreak:OSFromRandomization(ITT)CensoringrateforPem+Cb+Bev:27.8%;Pac+Cb+Bev:27.2%03691215182124273033363900.10.20.30.40.50.60.70.80.91.0MosFromInductionSurvivalProbabilityPem+Cb+Bev

Pac+Cb+BevCCO2014非小細(xì)胞肺癌進(jìn)展PatelJ,etal.2012ChicagoMultidisciplinarySymposiuminThoracicOncology.AbstractLBPL1.PointBreak:PFSFromRandomization(ITT)*PFSwithoutgrade4toxicity03691215182124273033360102030405060708090100MosFromInductionPFS(%)Pem+Cb+Bev

Pac+Cb+BevPem+Cb+BevPac+Cb+BevMedianPFS,mos6.05.6HR(95%CI;Pvalue)0.83(0.71-0.96;P=.012)TTPD,mos7.06.0HR(95%CI;Pvalue)0.79(0.67-0.94;P=.006)ORR,%34.133.0MedianG4PFS,*mos4.33.0HR(95%CI;Pvalue)0.74(0.64-0.86;P<.001)CCO2014非小細(xì)胞肺癌進(jìn)展AVAPERL:UpdatesonBevacizumab+PemetrexedMaintenanceTherapyPhaseIIItrialofCis/Pem/Bev(7.5mg/kg)every3weeksfor4cycles(N=376)NonprogressorsrandomizedtoreceivemaintenanceBev+Pem

(n=128)orBev(n=125)PFSfrominduction(primaryendpoint):10.2vs6.6months;HR:0.58(95%CI0.45-0.76);P<.001At58%ofevents,OS(Bev+PemvsBev):Frominduction:19.8vs15.9months;HR:0.88(95%CI:0.64-1.22);P=.32Fromrandomization:17.1v13.2months;HR:0.87(95%CI:0.63-1.21);P=.29RittmeyerA,etal.ASCO2013.Abstract8014.CCO2014非小細(xì)胞肺癌進(jìn)展ECOG5508:OngoingNSCLCPhaseIIIStudyExploringMaintenanceTherapyRandomizedphaseIIItrialinpatientswithstageIIIB/IVNS-NSCLCandPS0-1whoareeligibleforbevacizumabtherapyPaclitaxelCarboplatinBevacizumab(N=1236)Nonprogressors(n=864)BevacizumabPemetrexedBevacizumabPemetrexedPrimaryendpoint:OSSecondaryendpoints:PFS,RR,safety,PK.NCT01107626.CCO2014非小細(xì)胞肺癌進(jìn)展Bevacizumab:PatientSelection,TreatmentDuration,Maintenance,andContinuationBevacizumabincreasesRRandPFSwhenaddedtofirst-linechemotherapyforNSCLC;improvedOSin1phaseIIItrialCanusewithanticoagulants,brainmetastases;cautioninelderlyEncouragingdatasupportstandardpracticeofcontinuedmaintenancebevacizumabuntilPDOngoingE5508willaddressthesequestionsDatatosupportcarboplatin/paclitaxel/bevacizumabORcarboplatin/pemetrexed/bevacizumabORcarboplatin/pemetrexedasreasonablefirst-lineoptionsfornonsquamousNSCLCPredictiveandprognosticmarkersareindevelopmenttohelpguidepatientselection,butnonevalidatedtodateICAM,VEGFlevels,VEGFpolymorphisms,C/Afs...CCO2014非小細(xì)胞肺癌進(jìn)展LiT,etal.JClinOncol.2013;31:1039-1049.NSCLCasonediseaseEvolutionofNSCLCSubtypingtoaMultitudeofMolecular-definedSubsetsHistology-basedSubtypingSquamous34%Other11%Adenoca55%AdenocarcinomaSquamousCellCancerALKHER2BRAFPIK3CAAKT1MAP2K1NRASROS1RETEGFRKRASUnknownEGFRvIIIPI3KCAEGFRDDR2FGFR1AmpUnknownCCO2014非小細(xì)胞肺癌進(jìn)展MolecularTestingGuideline:EGFRandALKRecommendedforadenocarcinomas,mixedlungcancers;notforsquamous,small-cell,orlarge-cellcarcinomasPrimarytumorsandmetastaticlesionsequallysuitableDiscordancebetweenmutationstatusofprimarytumorandmetastasesappearsrare(inpreviouslyuntreatedpatients)MoleculartestingresultsforEGFRandALKshouldbeavailablewithin2weeksofspecimenreceiptPathologicsamplepreparationsusingheavymetalfixativesoracidicsolutionscompromisemoleculartestingeg,bonedecalcifyingsolutionsLindemanNI,etal.JThoracOncol.2013;8:823-859.CCO2014非小細(xì)胞肺癌進(jìn)展First-lineTreatmentWithEGFRTKIsvsChemotherapyinEGFR-MutatedPatientsStudyTreatmentNMedianPFS,MosMedianOS,MosMaemondo[1]Gefitinibvscarboplatin/

paclitaxel23010.8vs5.4(P<.001)30.5vs23.6(P=.31)Mitsudomi[2,3]Gefitinibvscisplatin/

docetaxel1779.2vs6.3(P<.0001)36vs39(P=.443)OPTIMAL[4,5]Erlotinibvscarboplatin/gemcitabine16513.7vs4.6(P<.0001)22.7vs28.9(P=.69)EURTAC[6]Erlotinibvsplatinum-basedchemotherapy1749.7vs5.2(P<.0001)19.3vs19.5(P=.87)LUX-Lung3[7]Afatinibvscisplatin/pemetrexed34511.1vs6.9(P=.001)Notreported1.MaemondoM,etal.NEnglJMed.2010;362:2380-2388.2.MitsudomiT,etal.LancetOncol.2010;11:121-128.3.MitsudomiT,etal.ASCO2012.Abstract7521.4.ZhouC,etal.LancetOncol.2011;12:735-742.5.ZhangC,etal.ASCO2012.Abstract7520.6.RosellR,etal.LancetOncol.2012;13:239-246.7.SequistLV,etal.JClinOncol.2013;31:3327-3334.CCO2014非小細(xì)胞肺癌進(jìn)展TargetingALKGeneTranslocationsTypicalphenotypeYoung,maleorfemale,never/scantsmokers(butnotalways)Adenocarcinoma±signetringmorphologyPoorresponsetoEGFRTKI;conventionalresponsetostandardchemotherapyNooverlapwithEGFRmutationgenotypeCamidgeDR,etal.LancetOncol.2012;13:1011-1019.CrizotinibinALK-PositiveNSCLC(N=133*)100806040200-20-40-60-80-100ChangeFromBaseline(%)PD

SD

PR

CR*Excludedpatientswithearlydeathbeforereimaging,nonmeasurablenontargetdisease,orindeterminateresponses.CCO2014非小細(xì)胞肺癌進(jìn)展SquamousCellLungCancer:AnUnmetNeedClinicallychallengingpopulation:older,comorbiditiesPlatinumdoubletsremainthestandardofcareGemcitabine-ortaxane-basedregimenscommonlyusedRoleofnab-paclitaxelnotyetclearAntiangiogenicstrategiesconsideredtootoxicPemetrexednolongerapprovedforuseinthissubsetNewstrategiesareneededforthislargegroupofpatients

35CCO2014非小細(xì)胞肺癌進(jìn)展PhaseIIIStudy:Carboplatin/Nab-PaclitaxelvsCarboplatin/PaclitaxelinAdvancedNSCLCPrimaryendpoint:ORRSecondaryendpoints:PFS,OS,safetyPatientswithstageIIIb/IVNSCLC,ECOGPS0-1,nopreviouschemotherapyformetastaticdisease(N=1050)Nab-Paclitaxel100mg/m2onDays1,8,15+CarboplatinAUC6onDay1NopremedicationPaclitaxel200mg/m2onDay1+CarboplatinAUC6onDay1Premedication:dexamethasone,antihistaminesStratifiedbystage(IIIbvsIV),

age(<70yrsvs>70yrs),sex,

histology(squamousvsnonsquamous),geographicregion21-daycyclesSocinskiMA,etal.JClinOncol.2012;30:2055-2062.CCO2014非小細(xì)胞肺癌進(jìn)展P=.005

RRR:1.3133%25%Independent

RadiologicReview(ITT)SocinskiMA,etal.JClinOncol.2012;30:2055-2062.Carboplatin/Nab-PaclitaxelvsCarboplatin/

PaclitaxelinAdvancedNSCLC:RRCarboplatin/nab-paclitaxel

Carboplatin/paclitaxelResponseRate(%)P<.001

RRR:1.680P=.808

RRR:1.03441%26%24%25%01020304050SquamousNonsquamousn=229n=221n=292n=310InteractionPvalueforhistology=.036n=521n=531CCO2014非小細(xì)胞肺癌進(jìn)展Carboplatin/Nab-PaclitaxelvsCarboplatin/

PaclitaxelinNSCLC:SafetyMostcommontreatment-relatedadverseevents,%Nab-P/C(n=514)P/C(n=524)Grade3Grade4Grade3Grade4PValuesforGrade3/4HematologicNeutropenia33143226<.001*Thrombocytopenia13572<.001?Anemia2256<1<.001?Febrileneutropenia<1<11<1NSNonhematologicFatigue4<16<1NSSensoryneuropathy3011<1<.001*Anorexia20<10NSNausea<10<10NSMyalgia<1020.011*Nohypersensitivityreactionsoccurredinthenab-P/Carmwithoutprophylacticpremedication,whereas3occurredintheP/Carm(grade1,2,and3,respectively).*Favorsnab-P/C.?FavorsP/C.SocinskiMA,etal.JClinOncol.2012;30:2055-2062CCO2014非小細(xì)胞肺癌進(jìn)展Conclusions:StandardofCareinPatientsWithoutIdentifiableDriverMutationsNonsquamousNSCLCPemetrexedortaxane-baseddoubletsBevacizumabinselectedpatients4-6cyclesConsiderationofmaintenancetherapyafter4-6cyclesSquamousNSCLCTaxane-orgemcitabine-baseddoublets4-6cyclesConsiderationofmaintenancetherapyafter4-6cyclesCCO2014非小細(xì)胞肺癌進(jìn)展2013:First-lineTreatmentof

Advanced/MetastaticNSCLC75%25%Non-SCCaSCCaPlatinum+

paclitaxel,docetaxel,

gemcitabine,or

vinorelbine,

nab-paclitaxelNohemoptysisAnyhemoptysis90%10%Carboplatin+paclitaxel

+bevacizumabor

platinum+pemetrexedPlatinum+pemetrexed,paclitaxel,docetaxel,orgemcitabineEGFRmutation+15%KRASornoother“actionable”mutation:80%EGFR-TKIEML4/ALK

ROS1CrizotinibOrchemotherapyMutationalanalysisOther

mutations

5%to10%ModifiedfromGandaraD,etal.ClinLungCancer.2009;10:392-394.CCO2014非小細(xì)胞肺癌進(jìn)展IFCT-0501:DoubletvsSingle-AgentChemotherapyinElderlyAdvancedNSCLCDoubletchemotherapy(carboplatin/paclitaxel)superiortosingle-agentchemotherapy(gemcitabineorvinorelbine)inelderlywithadvancedNSCLCQuoixE,etal.Lancet.2011;378:1079-1088.HR:0.64(95%CI:0.52-0.78;P<.0001)Doubletchemotherapy(177deaths)

Monotherapy(199deaths)1.00.80.60.40.200OS(%)6121824303642Duration(Mos)PatientsatRisk,n

Doublet

Monotherapy

SurvivalProbability

Doublet

Monotherapy225

226160

11792

5444.5

25.452

2532

1522.4

11.719

87

29.0

4.02

2Patientsaged70-89yrs,

stageIII/IVNSCLC,and

PS0-2

(N=451)CCO2014非小細(xì)胞肺癌進(jìn)展SalvageTherapyandEmergingTherapeuticApproachesCCO2014非小細(xì)胞肺癌進(jìn)展Second-line(orThird-line)TherapyECOGperformancestatus0-2(ifnotalreadygiven)DocetaxelPemetrexedErlotinib(EGFRWT),afatinib(EGFRmutant)GemcitabinePlatinumdoublet±bevacizumab±erlotinib(iferlotiniborcrizotinibfirst-linetherapyANDnonsquamoussubtype)ECOGperformancestatus3ErlotiniborbestsupportivecareNCCN.ClinicalPracticeGuidelinesinOncology:non-small-celllungcancer.v.2.2014.CCO2014非小細(xì)胞肺癌進(jìn)展OverviewofCurrentSecond-lineTreatmentNocombinationtherapyhasprovenbenefitoversingleagentsNumerousfactorsinvolvedinchoiceoftreatmentPrevioustherapyHistologyPerformancestatusOrganfunctionEGFRTKIsmaybean

optioncomparabletochemotherapy(EGFRWT)Lesstoxic;betterQoLSurvivalsimilaracrossallsubgroupsConsiderablecrossoveronallstudiesInmanycases,thequestionisnotwhetherapatientwillreceiveadrug,butwhenandinwhatsequenceCCO2014非小細(xì)胞肺癌進(jìn)展BlockadeofPD-1BindingtoPD-L1(B7-H1)andPD-L2(B7-DC)RevivesTCellsPD-L1expressionontumorcellsisinducedbyγ-interferonInotherwords,activatedTcellsthatcouldkilltumorsarespecificallydisabledbythosetumorsSznolM,etal.ClinCancerRes.2013;19:1021-1034.CCO2014非小細(xì)胞肺癌進(jìn)展Nivolumab(MDX-1106/ONO-4538):Anti-PD-1TargetedTherapyinNSCLCFullyhumanIgG4antihumanPD-1–blockingantibody[1]PD-1expressionontumor-infiltratinglymphocytesinNSCLCiscorrelatedwithdecreasedcytokineproductionanddecreasedeffectorfunction[2]PD-L1expressionnotedaspotentialbiomarkerinNSCLC[3,4]InNSCLCpatients(n=129)[5]:All-gradeAEs:71%inNSCLCvs75%intotalpopulation(N=306)Mostcommonincludedfatigue,diarrheaGrade3-4AEsoccurredin14%ofpatientswithNSCLCAll-gradepneumonitiswasnotedin8(6%)patientswithNSCLCDrug-relateddeaths(2)occurredinNSCLCpatientswithpneumonitis1.BrahmerJR,etal.JClinOncol.2010;28:3167-3175.2.ZhangY,etal.CellMolImmunol.2010;7:389-395.3.TopalianSL,etal.ASCO2012.AbstractCRA2509.4.TykodiSS,etal.ASCO2012.Abstract2510.5.BrahmerJR,etal.ASCO2013.Abstract8030.CCO2014非小細(xì)胞肺癌進(jìn)展ParameterNivolumabDose,mg/kg1310ORR,numberofpatients*(%)Squamous0n=184(22.2)n=185(23.8)n=21Nonsquamous1(5.6)n=185(26.3)n=197(18.9)n=37SD24wks,numberofpatients(%)Squamous4(26.7)1(5.6)3(14.3)Nonsquamous1(5.6)2(10.5)2(5.4)MedianOS,mosSquamous89.510.5Nonsquamous9.918.27.4*1patientofunknownhistologywhoreceived1mg/kghadanOR.ClinicalActivityofNivolumabbyHistology(EfficacyPopulation)BrahmerJR,etal.ASCO2013.Abstract8030.CCO2014非小細(xì)胞肺癌進(jìn)展OverallSurvivalforPatientsWithNSCLCTreatedWithNivolumabMonotherapyMedianOS(95%CI)–9.6months(7.8–12.4)1-yearOS–42%2-yearOS–14%BrahmerJR,etal.ASCO2013.Abstract8030.CCO2014非小細(xì)胞肺癌進(jìn)展MPDL3280AAnti-PD-L1AntibodyPhaseIa:EfficacySummary,InvestigatorAssessed

AllresponderscontinuedtorespondatlastassessmentRECIST1.1ResponseRate(ORR),%SD≥24Wks,%24-WkPFSRate,%Overallpopulation

(N=140)211645NSCLC(n=41)*221246Nonsquamous(n=31)191344Squamous(n=9)331144*1patienthadanundeterminedhistologystatus.Spigel,etal.ASCO2013.Abstract8008.CCO2014非小細(xì)胞肺癌進(jìn)展DocorGemFGFRi+DocorGemDocorGemFGFRAmplification,Mutation,FusionCDK4/6iDocorGemCyclinD1AmplificationorCDKN2loss+RBWTPI3KiDocorGemPI3KCAMutationBiomarkerProfiling(NGS/CLIA)HGFi+ErlotinibErlotinibMETExpression(IHCscore)PD-L1iBiomarkerNon-MatchMultiplePhaseII-IIIArmswith“Rolling”O(jiān)pening&ClosureMASTERLUNG-1(S1400):Biomarkersand2ndLineTherapyforSquamousCellNSCLCCCO2014非小細(xì)胞肺癌進(jìn)展ManagementofDiseaseSymptomsandAdverseEventsCCO2014非小細(xì)胞肺癌進(jìn)展ManagementofBrainMetastasesBrainmetastasesoccurin>30%ofpatientswithlungcancerManagementofpatientswithbrainmetastasesincludessurgicalresection,radiationtherapy,orsystemictherapyBrainmetastasesinpatientswhoharborEGFR-activatingmutationsarefrequentlyresponsivetotherapywitherlotinibandm