晚期非鳞状NSCLC无靶向驱动因素突变

ChandraP.Belani,MDPennStateHersheyCancerInstituteMiriamBecknerDistinguishedProfessorofMedicinePennStateHersheyCollegeofMedicineAdvancedNon-SquamousNSCLCNoTargetableDrivers/MutationsLungCancers,notLungCancerRethinkingtheIllnessAdenocarcinomas60%LargeCellCarcinomas2%(N=14,418)LungCancersPatientsPemetrexed+CisplatinGemcitabine+CisplatinAdenocarcinomas84713monthsCI0.71to0.9811monthsSquamousCell4739months11monthsCI1.0to1.5LargeCell15310monthsCI0.48to0.977monthsScagliottiJClinOncol2008ChemotherapySelectionbyHistologicType

Pemetrexedvs.

GemcitabinewithCisplatin

MedianSurvivalbyRegimenStratifiedby:DiseasestageDegreeofweightlossPriorradiotherapyMeasurablediseaseBevacizumab

15mg/kgIVq3wuntilprogressionofdiseaseorunacceptabletoxicityFirst-line

treatmentofpatientswithstageIIIBwithmalignantpleuraleffusion,orIV,orrecurrentNSCLC(N=878)Bev+PCq3w×6Bevacizumab15mg/kgpaclitaxel200mg/m2carboplatinAUC6PCq3w×6paclitaxel200mg/m2carboplatinAUC6

(nocrossoverpermitted)ProgressionofdiseaseorunacceptabletoxicityEndpoints:PrimaryOSSecondaryResponseratePFSToxicityAUC=areaunderthecurve;IV=intravenous;OS=overallsurvival;PFS=progression-freesurvival.SandlerA,etal.NEnglJMed.2006;355:2542-2550E4599PhaseIIITrialDesignCarboplatin-plus-PaclitaxelOnlyBevacizumab15mg/kg+Carboplatin–plus-PaclitaxelpEntered444434CR/PRRate15%35%<0.00011YrSurvival44%51%MedianSurvival10.3months12.3months0.007RandomizedphaseIIItrialin878patients–JUL01-APR04NopriortherapyforstageIIIB/IVlungcancersSandlerNEJM2006ECOG4599PhaseIIITrialofChemotherapy+/-BevacizumabinNSCLCs0.00.20.40.60.81.0ProportionSurviving0642481830122436HR=0.80;P=0.013Bev/PC12.3moPC 10.3mo

MedianSurvival1-yearsurvival51%vs44%2-yearsurvival23%vs15%Sandler.NEnglJMed.2006;355:24MonthsECOG4599:Chemotherapy+/-Bevacizumab

OverallSurvivalwPB

MedianPFS:5.4mo,DOC

MedianPFS:3.9mo,HRadj.=0.62[0.44-0.87]p=0.006

Common2ndlineNSCLCpopulationBevacizumabeligibleFastaccrualULTIMATE:WeeklyPaclitaxel/Bev.vs.Docetaxel

Second-LineNSCLC(Cortotetal,ASCO2016)wPB

Mediansurvival:9.9mo,DOC

Mediansurvival:11.4moHRadj.=1.18[0.81-1.72]p=0.40ORRfavourswPB(22.5%vs.5.4%)ToxicityprofiledifferentQoLequalinbotharmsOSdifferencenegatedbycrossover?WeeklyPBvs.Docetaxel

(Cortotetal,ASCO2016)Bevacizumab-eligiblepatientswhostartwithbevacizumabSHOULDKEEPGETTINGIT11*Analyzablepatients:aliveandwithoutPDthrough6cycles+21days.†Atotalof207patientscompletedatleast7cyclesofBVtreatment.Sandler,etal.Poster.IASLC.2011(abstrP3.216).PatientsinECOG4599

n=869Received≤6CyclesCP+BV

n=429CPn=440CP+BV

n=217†Analysispopulation*CP+BV

n=258(60%)Completed6CyclesCP

n=194(44%)CP

n=134E4599PatientDispositionand

AnalysisStrategyProportionProgressionFreeMonthsSinceTreatmentInitiation1.00.80.60.40.20.00.51yr:32%(n=82)4.581218243036421yr:17%(n=21)Induction

18wksBV/CPnonprogressorsCPnonprogressorsHR(adjusted)=0.64;

P<0.001Sandler,etal.PresentedatIASLC.2011(abstrP3.216)E4599Maintenance:PostinductionPFSProportionSurvivingMonthsSinceTreatmentInitiation1.00.80.60.40.20.00.54.581218243036421yr:75%(n=162)1yr:69%(n=92)Induction18wks2yr:34%(n=46)2yr:25%(n=17)BV/CPnonprogressorsCPnonprogressorsHR(adjusted)=0.75;

P=0.03Sandler,etal.PresentedatIASLC.2011(abstrP3.216)E4599Maintenance:PostinductionOSAvaALLevaluateswhetherbevacizumab+standardofcare(SOC)in2nd-andlaterlinesoftreatmentforNSCLCimprovesOSinpatientswhohavebeenpreviouslytreatedwithbevacizumabmaintenancePatientswithNSCLCmaybenefitfromcontinuedsuppressionofVEGFbybevacizumab14TrialRationale:DoesBevacizumabBeyondProgressionEnhanceSurvival*SOC2:Labelledagentsfor2nd-linetreatmentofNSCLC(erlotinib,pemetrexedanddocetaxel)†SOC3andbeyond:Choiceoflabelledagentsin3rd-lineandbeyondistheInvestigator’schoiceBevacizumabdosemustremainthesamethroughoutthetrialBeyondPD3,bevacizumabshouldbecontinuedthroughsubsequentlinesoftherapyatInvestigator’sdiscretion(intheabsenceofunacceptabletoxicityorconsentwithdrawal)Globaltrialconductedin~20countriesEnrollPrimaryendpoint:OSPD1SOC2*

+

bevacizumabSOC3†

+

bevacizumabSOC4

±

bevacizumabSOC2*SOC3†SOC4PD3Randomize1:1PD2StageIIIB/IVnon-squamousNSCLCtreatedwithplatinum-doublet(4-6cycles)+bevacizumabPLUS>2cyclesofbevacizumabmaintenanceN=600AvaALL

TrialDesignNon-squamousNSCLC(patientsdonotneedtobere-biopsiedatPD1)withPDfollowing1Ltreatmentwith4-6cyclesofbevacizumab+platinumdoublet-containingchemotherapyregimen,and>2cyclesofbevacizumab(monotherapy)maintenancetreatmentpriortoPD1Notreatmentinterruptionofbevacizumabtreatment>2consecutivecycles(42d)betweenthestartof1st-linetreatmenttod1ofC1of2nd-linetreatmentRandomizationwithin4weeksofPD1>1unidimensionallymeasurablelesionmeetingRECIST(v.1.1)criteriaPatientswithasymptomatictreatedbrainmetastasesareeligiblefortrialparticipation16Eligibility-KeyInclusionCriteriaPrimaryendpointOSN=939randomisedSocinskial#8004Istherea‘best’regimenforfirstlinetreatmentofnon-molecularlydefinedNSCLC?12.6vs.

13.4mOS,HR1.00NS;6.0vs

.5.6mPFS,HR=0.83,p=0.012fatigue,thrombocytopenia,anemiaonPem/Cb/BevPOINTBREAKSocinskial#8004Including29trialspublisedbetween2005-2015，n=5890 Meta-Analysis

BevacizumabplusTaxanevs.Non-TaxaneRegimensPFSOSAE：Taxane

vs.Non-TaxaneGrade3-5：59%vs.69%，P=0.10MetaAnalysis

BevacizumabplusTaxanevs.Non-TaxaneRegimens

JThoracOncol.2015;10:1142–1147ORRP=0.65P=0.06P=0.5P=0.61P=0.59P=0.40P=0.5P=0.66P=0.50NodifferenceinbothefficacyandsafetyTaxaneNon-TaxanePemtrexedGemcitabineNon-TaxanePemtrexedGemcitabineTaxaneNon-TaxanePemtrexedGemcitabineTaxaneCR,completeresponse;nsNSCLC,nonsquamousnon–smallcelllungcancer;PD,progressivedisease;PR,partialresponse;q3w,every3weeks;RECIST,ResponseEvaluationCriteriainSolidTumors;SD,standarddeviation.aRandomized,open-label,phaseIIIstudy;bDoseofbevacizumab=7.5mg/kg;doseofpemetrexed=500mg/m2;doseofcisplatin=75mg/m2.RECIST-relatedendpointsmeasuredfromthepreinductionphaseStratificationfactors:GenderSmokingstatusResponseatrandomizationPreviously

untreatedstageIIIB–IVnsNSCLCArmA:bevacizumabArmB:bevacizumab+pemetrexedBevacizumabb

+pemetrexedb

+cisplatinbCR/PR/SDperRECISTcFirst-lineinduction

4cycles,q3wRPDContinuationmaintenanceq3wuntilPDFollow-upPrimaryobjective:progression-freesurvivalSecondaryobjectives:Overallsurvival,responserate,diseasecontrolrate,durationofresponse,durationdiseasecontrol,safety,QOLN=376N=25367%N=125N=128Barlesietal,ESMO2011,abstract34LBAAVAPERL:TrialdesignAVAPERL:PFSfrominduction

Bev+Pem

10.2m(81events)

Bev

6.6m(104events)HR,0.50(0.37–0.69);P<.001

128 126 103 66 25 4 0 125 122 73 38 12 2 0 0 3 6 9 12 15 18ProportionProgressionFree((%ofpatients)时间(月)1007550250

Cont.maintenancebev+pem(n=128) Cont.maintenancebev(n=125)Bev+pemBevPtsatriskMedianfollow-uptime:11months(8months,excludinginduction).30%ofeventsatthetimeofanalysisforoverallsurvival.bev,bevacizumab;HR,hazardratio;NR,notreached;pem,pemetrexed;pts,patients.

Randomizedpts,Intent-to-treatpopulationBarlesietal,ESMO2011,abstract34LBAOverallsurvival(%ofpatients)1007550250

0 3 6 9 12 15 18 21

128 127 120 103 56 20 3 0 125 123 110 96 45 17 2 0Time(months)Bev+pem NR(34events)

Bev15.7months(42events)HR,

0.75(0.47–1.20);P=0.23PtsatriskBev+pemBevMedianfollow-uptime:11months(8months,excludinginduction).30%ofeventsatthetimeofanalysisforoverallsurvival.bev,bevacizumab;HR,hazardratio;NR,notreached;pem,pemetrexed;pts,patients.

Randomizedpts,Intent-to-treatpopulation

Cont.maintenancebev+pem(n=128) Cont.maintenancebev(n=125)Barlesietal,ESMO2011,abstract34LBAAVAPERL:OSfrominductionStageIIIB/IVNSCLCPS0-14priorcyclesofgem,doc,ortax+cisorcarb,withCR,PR,orSDRandomizationfactors:genderPSstagebesttumorresponsetoinductionnon-platinuminductiondrugbrainmetsPemetrexed500mg/m2(d1,q21d)+BSC(N=441)*PrimaryEndpoint=PFSPlacebo(d1,q21d)+BSC(N=222)**B12,folate,anddexamethasonegiveninbotharms2:1RandomizationDouble-blind,Placebo-controlled,Multicenter,PhaseIIITrialPhaseIIITrialofMaintenancePemetrexedinAdvancedNSCLCCiuleanu…Belani,Lancet374(9699):1432-40,2009Belanietal,JClinOncol28:7s,2010(suppl;abstr7506)OverallSurvivalbyHistologyPlacebo10.3mosPlacebo10.8mosNon-squamous(n=481)Squamous(n=182)HR=0.70(95%CI:0.56-0.88)p=0.002HR=1.07(95%CI:0.49–0.73)p=0.678SurvivalProbabilityTime(months)Time(months)Belanietal,J.ClinOncol28:7s,2010(suppl;abstr7506)Pemetrexed15.5mosPemetrexed9.9mosStageIIIB/IVBeveligibleNSCLCPS0-14priorcyclesofCarbTax+Bev(1236)

,withCR,PR,SD(864)Randomizationfactors:genderPSstagebesttumorresponsetoinductionPemetrexed500mg/m2(q21d)PrimaryEndpoint=OS*B12,folate,anddexamethasonegiveninPem.armsECOG5508PhaseIIIStudyDesignMaintenanceBev.Vs.Pem.Vs.Bev.+Pem.RANDOMIZEBevacizumab15mg/kg(q21d)Pemetrexed500mg/m2(q21d)Bevacizumab15mg/kg(q21d)Total1236patientswith864randomized(288/arm)Primaryendpoint:PFS(RECISTv1.1,independentreview)Secondaryendpoints:OS,tumorresponse,QoL,safetyExploratoryendpoint:biomarkerassessmentRChemotherapy-naïveStageIIIB/IVNSCLCorpostoperativerecurrenceNon-squamousActivatingEGFRmutations*Exon19

deletionExon21L858RAge≥20yearsPS0–1NobrainmetastasisE

monotherapyErlotinib150mgqd(n=75)EBcombinationErlotinib150mgqd+bevacizumab15mg/kg

q3w(n=75)PDPDStratificationfactors:sex,smokingstatus,clinicalstage,EGFR

mutationtype1:1*T790MexcludedAbstract8005:PresentedbyTerufumiKatoJO25567StudyDesignEBEMedian(months)16.09.7HR0.54(95%CI:0.36–0.79)Pvalue*0.00157572696460534938302013844077665744392924211812105210001.0EEBNumberatriskTime(months)4812261014182226162024280.20.40.60.8PFSprobability9.716.0EBE*log-rank

test,two-sidedAbstract8005:PresentedbyTerufumiKatoPrimaryendpoint:PFSbyindependentreviewEBgroupEgroupMedian(months)18.010.3HR0.41

(95%CI:0.24–0.72)EBEEEBNumberatrisk01.004040EEBNumberatriskEBE1.0003537Time(months)4812261014182226162024283833273936292412521982029221235261695109300Time(months)48122610141822261620242831272233282414832115202817123118131274197200.20.40.60.8PFSprobabilityPFSprobability0.20.40.60.8Exon19deletionExon21L858REBgroupEgroupMedian(months)13.97.1HR0.67

(95%CI:0.38–1.18)Abstract8005:PresentedbyTerufumiKatoPFSbyEGFRMutationType1/Mb10/Mb100/Mb0.1/Mb816438316100178228n

=

109119214020HematologicChildhoodCarcinogens??Courtesy:Gaddy

Getz

and

Mike

Lawrence,BroadInstitute,MIT.Squamous

Ce