抗血管生成的在NSCLC的应用

Whatistheoptimalclinicalapplicationsofanti-angiogenic-basedNSCLCstrategiestohelpmorepatientsinthemaintenanceandsecond-linesetting?

JohnHeymach,MD,PhDAssociateProfessorThoracic/HeadandNeckMedicalOncologyandCancerBiologyFourthAnnualSymposiumonPersonalizedTherapiesandBestClinicalPracticesforLungCancerLosAngeles,CASeptember17,2011DisclosuresAdvisoryboardsforGenentechandAstraZenecaResearchsupportfromAstraZenecaCase#156yowomanwith15pack-yearhistorypresentswithamalignantpleuraleffusion,mediatinaladenopathy,anda3-4smallCNSmetastases.Shehasbeenhavingmildheadachesrecently.Cytologyrevealsadenocarcinoma,TTF1+EGFRmutatationtestingcouldnotbeperformedfromcellblockandadditionalbiopsyrefused.SheisinitiallytreatedwithstereotacticXRTforherCNSlesionsandcomesforsystemictherapy.

WhichchemotherapyregimenisnotsupportedbyrandomizedphaseIIIdata?

Carbo/pacCarbo/pac/BVPem/cisPem/carbo/BVQuestion1Question#1SheisinitiallytreatedwithstereotacticXRTforherCNSlesionsandcomesforsystemictherapy.WhichchemotherapyregimenisnotsupportedbyrandomizedphaseIIIdata?Carbo/pacCarbo/pac/BVPem/cisPem/carbo/BVCase#1Sheisstartedontreatmentwithcarboplatin,paclitaxel,andBVx6cycles.Shehasapartialresponse,toleratestreatmentwell,andwantstobetreatedaggressively.WhichmaintenancetherapyispartofaregimenthathasbeenshowntoprolongOSinarandomizedphaseIIIstudy?

BVmonotherapyPemetrexedBV+PemBV+erlotinibAandBA,B,andDNomaintenancetherapyQuestion2Question#2WhichmaintenancetherapyispartofaregimenthathasbeenshowntoprolongOSinarandomizedphaseIIIstudy?BVmonotherapyPemetrexedBV+PemBV+erlotinibAandBA,B,andDNomaintenancetherapy

12mo. 24mo. 43.7% 16.9% 51.9% 22.1%

0.00.20.40.60.81.0ProbabilityPCPCB

P=0.007061218243036MonthsMedians:10.2,12.5HR:0.77(0.65,0.93)PhaseIIITrialofBevacizumab

inNon-SquamousNSCLC(ECOG4599)

Sandleretal,NEJM2006

OverallsurvivalDoesBVmaintenanceprovidebenefitinfirst-lineNSCLC?InECOG4599,60.1%completed6cyclesofCPBand48%receivedBVmaintenance.44%completed6cyclesofCPwithoutPD.Sandleretal,ProcWorldLungmeeting2011,posterP3.216BVmaintNomaintOS(m)4.42.8PFS(m)12.411.2OS(fromstartoftx)17.316.1JMEN:Outcomeinnon-squamoushistology

pemetrexedvsBSCforNSCLC

Ciuleanuetal,Lancet,2009PFS4.5vs2.6monthsHR0.44P<.0001OS15.5vs10.3monthsHR0.70P<.002ATLASstudydesignMillerVA,etal.JClinOncol2009;27(Suppl1):AbstractLBA8002Post-

progression

therapyUnblind

atPD1:1Bevacizumab(15mg/kg)+erlotinib(150mg)toPDBevacizumab+PlacebotoPDPrimaryendpointPFSinallrandomizedpatientsSecondaryendpointsOverallsurvivalSafetyExploratoryendpointsBiomarkeranalyses(IHC,FISH,EGFR&

K-Rasmutation)Eligibility

StageIIIB**/IVNSCLCECOGperformancestatus0–1Stratificationfactors

GenderSmokinghistory(nevervs

former/current)ECOGperformancestatus(0vs≥1)Chemotherapyregimen*Carbo/paclitaxel;cis/vinorelbine;carboor

cis/gemcitabine;carboorcis/docetaxel**IIIBwithpleuraleffusionNon-PDn=768(66%)4cyclesof

1st-linechemotherapy*+bevacizumabChemo-naïveadvanced

NSCLCN=1160ATLAS–progression-freesurvivalMillerVA,etal.JClinOncol2009;27(Suppl1):AbstractLBA8002373142582715630370178814320631No.ofpatientsatrisk:Bev+placeboBev+erlotinibProgression-freesurvival(months)0369121518210.00.20.40.60.81.0ProportionwithouteventHR=0.722(0.592–0.881)Log-rankp=0.0012

Bevacizumab+placebo(n=373)

Bevacizumab+erlotinib(n=370)ATLAS–updateonoverallsurvivalA40%crossoverrate(placebopatientstoreceiveEoncediseaseprogressed)andunderpowereddesignpreventedtrialfromreachingsignificanceforOSanalysis2-monthOSbenefitwasobservedintheBvandEmaintenancearmafteroccurrenceof57%eventsBiomarkeranalysisdataofATLASstudyareexpectedsoonKabbinavarFF,

etal.JClinOncol2010;28:15s(suppl;abstr7526)Datacut-offPatientswithevents,n/N(%)MedianOS(months)Bv+EvsBvHR(95%CI)18July2008

(pre-specified)228/743(31)14.4vs13.30.92(0.70–1.21)19June2009439/768*(57)15.9vs13.90.90(0.74–1.09)*25patientswererandomizedaftercut-offformainanalysisofPFSECOG5508:PhaseIIItrialofBV,Pem,orBV+PemasmaintenancetherapyinadvancedNSCLCCarbo/pac/BVQ3wx4cyclesEligibility-BVeligible-non-squam-chemonaive-noCNSmets

PI:S.Ramilingam;;trialNCT01107626RNon-PDBVInductionMaintenancePemBV+PemPrimaryendpoint:OSSecondary:PFSS130trial:PhaseIIItrialofCP+BvBvvsPemCarbo+BvPeminfirstlineNSCLCEligibility-BVeligible-non-squam-chemonaive-treatedbrainmetsSponsor:Lilly;from;trialNCT00948675RCarboplatinpaclitaxel+BV(15mg/kg)q3wBVPemCarboplatinpemetrexedInductionMaintenancePrimaryendpoint:PFSwithoutgrade4toxicitySecondary:PFS,ORR,DCR,toxicityPointBreak:phaseIIItrialofCP+BvBvvsPemCarbo+BvPem+BV(SandlervsPatel)infirstlineNSCLCEligibility-BVeligible-non-squam-chemonaive-treatedbrainmets

PIJ.Patel;Pateletal,ClinLungCancer,2009RCarboplatinpaclitaxel+BV(15mg/kg)q3wBVBV+PemCarboplatinpemetrexed+BV(15mg/kg)q3wInductionMaintenanceN~900Primaryendpoint:OS(superiority)Secondary:PFS,ORR,toxicityAVAPERL1:PhaseIIIBV+Pemasmaintenanceaftercis/pem/BVinductionas1stlinetherapyCisplatinPemetrexedBV(7.5mg/kg)Q3wx4cyclesEligibility-BVeligible-non-squam-chemonaive-noCNSmetsSponsor:Hoffman-LaRoche;;trialNCT00961415

RNon-PDBV(7.5mg/kg)InductionMaintenanceBV(7.5mg/kg)+PemetrexedPrimaryendpoint:PFSSecondary:RR,DCR,durationofresponse,OSCase#1continuedSheeventuallydevelopedshortnessofbreathfromarecurrentpleuraleffusion,andisfoundtohavemediastinaladenopathy.Abiopsyconfirmedthepresenceofadenocarcinoma.Mutationtestingdemonstratedanexon19deletioninEGFR.

Sheisgivenaprescriptionforerlotinib,butaskswhetherBVshouldberestartedaswell.Whichofthefollowingistrue?

InphaseIIItesting,theadditionofBVtoerlotinibprolongedPFSandimprovedresponseratesbutdidnotimproveOS.PatientswithmutantEGFRappeartoderivegreaterrelativebenefitfromBV+erlotinib(comparedtoerlotinibalone)thanthosewithwtEGFR.BothAandB.Noneoftheabove.Question3:Second-linetreatmentQuestion#3:second-linetreatmentSheisgivenaprescriptionforerlotinib,butaskswhetherBVshouldberestartedaswell.Whichofthefollowingistrue?InphaseIIItesting,theadditionofBVtoerlotinibprolongedPFSandimprovedresponseratesbutdidnotimproveOS.PatientswithmutantEGFRappeartoderivegreaterrelativebenefitfromBV+erlotinib(comparedtoerlotinibalone)thanthosewithwtEGFR.BothAandB.Noneoftheabove.RandomizedphaseIIIstudycomparingBV+erlotinibvserlotinib(BeTa)Herbstetal,Lancet377:1846-54,2011EB+EHRpOS(m)9.29.3.97(0.80-1.18)NSPFS(m)1.73.4.62(.52-.75)ORR(%)613.006N=636;peripheralsquamous,treatedCNSmetsallowedDidnotprolongOS(primaryendpoint)RandomizedphaseIIIstudycomparingBV+erlotinibvserlotinib(BeTa)Herbstetal,Lancet377:1846-54,2011PFSHR=0.62OSHR=0.97P=0.76RandomizedphaseIIIstudycomparingBV+erlotinibvserlotinib(BeTa):

greaterbenefitforBVinEGFRmutants?Herbstetal,Lancet377:1846-54,2011

HREGFRmutant: 0.44HRwtEGFR: 1.11ElevatedMETandHIF-1alevelsincelllineswithmutatedEGFRXuetal,Oncogene,2010RegulationofHIFandMETbyEGFRXuetal,Oncogene,201005001000150020002500VEGF(pg/3x105cells)---++-++-+-+--++-+-+++---++-++--EGFErlotinib(1mM)A549HCC827H1975H3255DifferentialRegulationofVEGFSecretioninHumanNSCLCCellsbyEGFRInhibitionMFFFXuetal,Oncogene,2010PhaseIIIstudyofBV+erlotinibvserlotinibinEGFRmut+patients

(CALGB31002/CHUGAIA+T)First-linechemo-naïveNSCLCStageIIIB/IVPresenceofEGFRmutation(L858R/exon19)TreatedbrainmetsokBV+ErlotinibErlotinibPrimaryendpoint:PFS(IRF)Secondaryendpoints:PFS(Inv),ORRQoLRandomizationSchemapresentedbyR.Lilenbaum,AstroChicagoLungSymposium2010Case#1:thirdlinetreatmentSheeventuallydevelopsPDaftertreatmentwitherlotinib.Sheistreatedwithpemetrexedbutdevelopsrenalinsufficiency.Docetaxelisrecommended.ShewantstoknowifthereisanyroleofaddingaVEGFinhibitortodocetaxel.WhichofthefollowinghasbeenfoundtobetrueinphaseIIItestingin2nd/3rdlineNSCLC?

BVprolongsPFS,ORR,andOSincombination

withdocetaxel.NoVEGFinhibitorhasbeenshowntoprolong

overallsurvivalincombinationwithdocetaxel.NoVEGFinhibitorhasbeenshowntoprovideclinicalbenefitincombinationwithdocetaxelinphaseIIItesting.BothBandC

Question4:third-linetreatmentQuestion#4:thirdlinetreatmentWhichofthefollowinghasbeenfoundtobetrueinphaseIIItestingin2nd/3rdlineNSCLC?BVprolongsPFS,ORR,andOSincombinationwithdocetaxel.NoVEGFinhibitorhasbeenshowntoprolongoverallsurvivalincombinationwithdocetaxel.NoVEGFinhibitorhasbeenshowntoprovideclinicalbenefitincombinationwithdocetaxelinphaseIIItesting.BothBandCRecurrent(stageIIIB/IV)NSCLCafter

failureoffirst-linechemotherapy

Totalrecruitment=1391patientsVandetanib100mg/d+docetaxel

75mg/m2(maxsix21-daycycles)

n=694Placebo+docetaxel75mg/m2

(maxsix21-daycycles)

n=697ZODIACVandetanib100mg/d+pemetrexed500mg/m2(every21days)

n=256Placebo+pemetrexed500mg/m2

(every21days)n=278LocallyadvancedormetastaticNSCLC(stageIIIB/IV)afterfailureoffirst-linetreatment

n=534ZEALZESTVandetanib300mg/dn=623Erlotinib150mg/dn=617Recurrent(stageIIIB/IV)NSCLC

afterfailureofatleastone

previouschemotherapyPriortreatmentwithcetuximab

orbevacizumabwaspermitted

n=1240DeBoerR,etal.JClinOncol2009;27(Suppl15):Abstract8010;NataleRB,etal.JClinOncol2009;27(Suppl15):Abstract8009;HerbstR,etal.JClinOncol2009;27(Suppl15):AbstractCRA80031:1RANDOMIZE1:1RANDOMIZE1:1RANDOMIZEPhaseIIIrandomizedvandetanibtrialsinNSCLCPFSinZODIACtrial69438017381402063069733813649175100Atrisk(n)VandetanibPlaceboHerbstR,etal,LancetOncol2010;11:604Time(months)0Progression-freesurvival00.10.20.30.40.50.60.70.80.91.03691215182124HR=0.79(0.70–0.90);P<0.001MedianPFS(m):Van4.0;Placebo3.2ORR:Van17%;Placebo10%,P<0.001Vandetanib100mg+docetaxelPlacebo+docetaxelVandetanibi