27.2018-12-4-2018非小細(xì)胞肺癌EGFR突變：優(yōu)化患者管理

CáncerdepulmónnomicrocíticoEGFRmutado:Optimizacióndelmanejodelpaciente

ManuelCoboDolsOncologiaMédicaHRegionalUniversitarioMálaga.IBIMA12-4-2018EGFRTKIsversusChemotherapyEvents/NMedianPFS(95%CI)12mPFS(95%CI)All57/10913.8m(10.3-21.3)56.7%(46.0-66.0)T790M+15/3716.0m(13.1-NE)72.4%(53.4-84.7)T790M-42/7210.5m(9.2-16.2)49.4%(36.6-61.0)StudyDesign

RecruitingSecondaryEndpointsStudyPeriodPrimaryEndpoint12ACCRURC1126(NCT01532089)USAPhasesIIIErlotinib+BecvsErlotinibEGFRMut(+)RecruitingPFSOSORRSafety2012–2017BEVERLY

(NCT02633189)Italy2015–2018OSQoLORRPhasesIIIErlotinib+BecvsErlotinibEGFRMut(+)NEJ026

(UMIN000017069)Japan2015–2018PhasesIIIErlotinib+BecvsErlotinibEGFRMut(+)ARTEMIS

(NCT02759614)China2016–2019PhasesIIIErlotinib+BecvsErlotinibEGFRMut(+)RecruitingRecruitingStatusStudyNo.PFSPFSPFSOSORRSafetyOSQoLORR

OngoingStudy:erlotinib+bevacizumabvs.erlotinibasfirst-linetreatmentIMPRESS.InexploratoryanalysisofT790Mnegative,theremaybePFSbenefittocontinuationofEGFRTKISoriaJC,etal.LancetOncol.2015;16:990-998.Erlotinib,Gefitinib,Afatinib(8-12m)PD:rebiopsyT790MOsimertinib(8-10m)EGFRdel19L858ROtherInitialbiopsyalso:liquidbiopsyMoketal.,PhaseIII(Aura3)(Osimertinibvs.CT)mPFS10.1vs.4.4mNEJM2016GirardN.Futureoncol2017PlasmaEGFRT790MPlasmafromAURAtrialsentforBEAMingPairedtumorandplasmaavailablefor216patientsOxnardetal,JCO,201618T790M+inplasma,nottumor111T790M+intumorandplasma47T790M+intumor,notplasma40patientsT790M-tumorandplasmaT790M+intumor:62%RR,10mPFST790M+inplasma:63%RR,10mPFSImmunotherapyinEGFR-MutantNSCLC*Dataforthepembrolizumabdoseswerepooled.CheckMate057KEYNOTE-010*OAKNivolumabDocetaxelPembrolizumabDocetaxelAtezolizumabDocetaxelReferencesinslidenotes.Pts,nUnstratifiedHR(95%CI)821.18(0.69-2.00)3400.66(0.51-0.86)1600.74(0.51-1.06)Events/Pts,n/NHR(95%CI)46/860.88(0.45-1.70)447/8750.66(0.55-0.80)Pts,n(%)HR(95%CI)85(10)1.24(0.71-2.18)628(74)0.69(0.57-0.83)MutantNotdetectedNotreportedMutantWildtypeMutantWildtype1.00.52.00.254.01.00.1101.00.22LBA2_PR:OsimertinibvsSoCEGFD-TKIasfirst-linetreatmentinpatientswithEGFRmadvancedNSCLC(FLAURA)KeyresultsRamalingamSetal.AnnOncol2017;28(suppl5):AbstrLBA2_PRMedianPFS,months(95%CI)18.9(15.2,21.4)10.2(9.6,11.1)HR0.46(95%CI0.37,0.57)p<0.0001OsimertinibSoCPFS1.00.60.40.20.003691215182124270.8Probabilityofprogression-freesurvivalTimefromrandomization,monthsNo.atriskOsimertinibSoC27926223321017813907126427723919715210778371020FavoursSoCSubgroupOverall(n=556) LogRank(primary) CoxPHSex Male(n=206) Female(n=350)Ageatscreening <65(n=298) ≥65(n=258)Race Asian(n=347) Non-Asian(n=209)Smokinghistory Yes(n=199) No(n=357)CNSmetastases Yes(n=116) No(n=440)WHOperformancestatus 0(n=228) 1(n=327)EGFRmutationatrandomisation# Exon19deletion(n=349) L858R(n=207)EGFRmutationbyctDNA?Positive(n=359)Negative(n=124)CentrallyconfirmedEGFRmutation§ Positive(n=500)Negative(n=6)?FLAURAdatacut-off:12June2017

Hazardratio<1impliesalowerriskofprogressiononosimertinib80mg.Sizeofcircleisproportionaltothenumberofevents

*ByInvestigatorassessment;#Localorcentraltest;?Resultmissingfor36patientsintheosimertinibarmand37patientsintheSoCarm;§Resultmissingfor21patientsintheosimertinibarmand29patientsintheSoCarm;?Subgroupcategorieswithlessthan20eventswereexcludedfromtheanalysis

CNS,centralnervoussystem;ctDNA,circulatingtumourDNA;EGFR,epidermalgrowthfactorreceptor;PFS,progression-freesurvival;SoC,standard-of-care;WHO,WorldHealthOrganization.Ramalingametal.Presentedat:ESMOCongressSep8-12,,2017;Madrid,Spain.PFS*acrosssubgroups0.10.20.30.40.60.8Hazardratio

(95%confidenceinterval)0.46(0.37,0.57)0.46(0.37,0.57)0.58(0.41,0.82)0.40(0.30,0.52)0.44(0.33,0.58)0.49(0.35,0.67)0.55(0.42,0.72)0.34(0.23,0.48)

0.48(0.34,0.68)0.45(0.34,0.59)0.47(0.30,0.74)0.46(0.36,0.59)0.39(0.27,0.56)0.50(0.38,0.66)

0.43(0.32,0.56)0.51(0.36,0.71)0.44(0.34,0.57)0.48(0.28,0.80)

0.43(0.34,0.54)NC(NC,NC)2.0PFShazardratioand95%confidenceinterval1.0Favoursosimertinib10.025Objectiveresponserate*FLAURAdatacut-off:12June2017Tickmarksindicatecensoreddata*Byinvestigatorassessment#Analysisperformedusingalogisticregressionstratifiedbyrace(AsianversusNon-Asian)andmutationtype(Exon19deletionversusL858R);?Responsedidnotrequireconfirmation;§CalculatedusingKaplan-MeierapproachCI,confidenceinterval;DoR,durationofresponse;ORR,objectiveresponserate;SoC,standard-of-care.Ramalinagmetal.Presentedat:ESMOCongressSep8-12,,2017;Madrid,Spain.DurationofresponseMedianDoR,months(95%CI)

17.2(13.8,22.0)8.5(7.3,9.8)Probabilityofremaininginresponse1.00.90.80.70.60.50.40.30.20.10.00369121518212427Timefromfirstresponse(months)No.atriskOsimertinibSoC2232102051801811361609512869823940171440001Osimertinib(n=279)SoC

(n=277)ORR(95%CI)80%(75,85)76%(70,81)Oddsratio#(95%CI)1.28(0.85,1.93);p=0.2335Completeresponse?,n(%)Partialresponse?,n(%)Stabledisease≥6weeks,n(%)Progression,n(%)Notevaluable,n(%)7(3)216(77)47(17)3(1)6(2)4(1)206(74)46(17)

14(5)

7(3)Estimatedremaininginresponse§,(95%CI)12months18months

64%(58,71)49%(41,56)

37%(31,44)19%(13,26)OsimertinibSoC26Keyresults(cont.)RamalingamSetal.AnnOncol2017;28(suppl5):AbstrLBA2_PRNo.atriskOsimertinibSoC279276269253243232015487427726325223721820012664102924OSinterimanalysis1.00.60.40.20.003691215182124270.830ProbabilityofoverallsurvivalTimefromrandomization,monthsHR0.63(95%CI0.45,0.88)p=0.0068??Ap-valueof<0.0015wasrequiredforstatisticalsignificanceatcurrentmaturityMedianoverallsurvivalNotreachedOsimertinibSoCNotreachedLBA2_PR:OsimertinibvsSoCEGFD-TKIasfirst-linetreatmentinpatientswithEGFRmadvancedNSCLC(FLAURA)GirardN.Futureoncol2017PacienteTumorEdadPSComorbilidadCercaníadomiciloahospitalApoyofamiliarSintomática/asintomáticoCargatumoralLocalización/NomtsPosibilidadantiangiogénicos?MtsSNCSubtipomutaciónDecisióndetratamientoenprimeralínea.FactoresatenerencuentaAfatinibinNSCLCPtsWithUncommomEGFRMutationsYangJC,etal.LancetOncol.2015;16:830-838.OutcomeAfatinibGroup1(n=38)*AfatinibGroup2(n=14)??AfatinibGroup3(n=23)?ChemotherapyGroup(n=25)§ORR,%(95%CI)71.1(54.1-84.6)14.3(1.8-42.8)8.7(1.1-28.0)24(9.4-45.1)MedianDOR,mos(95%CI)11.1(4.1-15.2)8.2(4.1-12.4)7.1(4.2-10.1)--Diseasecontrol,%(95%CI)84.2(68.7-94.0)64.3(35.1-87.2)65.2(42.7-83.6)--MedianPFS,mos(95%CI)10.7(5.6-14.7)2.9(1.2-8.3)2.7(1.8-4.2)8.2(5.2-10.8)MedianOS,mos(95%CI)19.4(16.4-26.9)14.9(8.1-24.9)9.2(4.1-14.2)30.2(13.0-42.3)*Consistsofptswithallpointmutationsorduplicationsinexons18-21.?ConsistsofptswithdenovoT790Mmutations.?Consistsofptswithexon20insertions.§Consistsofptswithmutationsfallingintogroups1/2/3(n=18/3/2).CohortnUncommonMutationsGroup138Pointmutationsorduplicationsinexons18-21(L861Q,G719S,G719A,G719C,S768I,rareothers)aloneorincombinationwitheachotherGroup214DenovoT790Mmutationsinexon20aloneorincombinationwithothermutationsGroup323Exon20insertionsPacientesconPS2ómayorJuanO.TherapeuticAdvancesinMedicalOncology2017Pacientesunfit,suelenser30%deloscasosEnsayosconafatinib,dacometiniboosimertinib,nohanreclutadoptsPS2Elrestodeestudios,conerlotinibygefitiniblaproporcióndeptsPS2fuepeque?a(exceptoenelEURTACconerlotinibsereclutaron14%deptsconPS2)[Roselletal.LancetOncol2012]..-PacientesPS2:lomásrecomendadogefitinibyerlotinib.MásdatosAfatinibydacometinibsonmástóxicosSólounestudioprospectivofaseIIcongefitinibquereclutó30ptsconmutacióndeEGFR,inelegibleparaquimioterapia.22ptsdeellosteníanPS?3,y68%deellos,elPSregresóa(chǎn)PS1enelcursode1mes,conunaRGdel&%%PFS6,5mesesySGde18,8mesesTenerencuentaeltipodecomorbilidad(Ej.Problemasintestinalescrónicos,TKIs2ogeneraciónmenosrecomendados.Hepática:mástoxicidadcongefitinib,etc)Erlotinibygefitinibtienenmásinteracciónfarmacológica.gefitinibyerlotinibtienenunpotencialimportantedeinteracciónconotrosfármacos.SecomportancomoinductoresoinhibidoresdeenzimasrelacionadasconloscitocromosJuanO.TherapeuticAdvancesinMedicalOncology2017Pacientesunfit-ancianosdependientes/polimedicadosPFSbenefitinAURA3patientswithCNSmetastasesatbaselineWithCNSmetastasesWithoutCNSmetastasesPopulation:intent-to-treatProgression-freesurvivaldefinedastimefromrandomisationuntildateofobjectivediseaseprogressionordeath.ProgressionincludeddeathsintheabsenceofRECISTprogression.

Tickmarksindicatecensoreddata.CNSmetastasesdeterminedprogrammaticallyfrombaselinedataofCNSlesionsite,medicalhistory,and/orsurgery,and/orradiotherapy.

Probabilityof

progression-freesurvival1.00.80.60.40.20No.atriskOsimertinibPlatinum-pemetrexed0369121518935180324692741424000MonthsOsimertinib(n=93)Platinum-pemetrexed(n=51)MedianPFS,months(95%CI)8.5(6.8,12.3)4.2(4.1,5.4)HR0.32

(95%CI0.21,0.49)Probabilityof

progression-freesurvival1.00.80.60.40.20036912151818689160611163561133659100MonthsOsimertinib(n=186)Platinum-pemetrexed(n=89)MedianPFS,months(95%CI)10.8(8.3,12.5)5.6(4.2,6.8)HR0.40

(95%CI0.29,0.55)Moketal.NEJM2017Osimertinib(n=22)#SoC(n=19)MedianbestpercentagechangefrombaselineinCNStargetlesionsize:-64%(range-100%to+20%)MedianbestpercentagechangefrombaselineinCNStargetlesionsize:-45%(range-100%to+20%)StablediseasePartialresponseProgressivediseaseBestchangefrombaselineintargetlesionsize(%)-100-80-60-40-20020-100-80-60-40-20020Bestchangefrombaselineintargetlesionsize(%)NotevaluableStablediseasePartialresponseCompleteresponseFLAURA:CNSRESPONSE*:CNSEVALUABLEFORRESPONSESETRRRRRRRRRRRRRRRRRPriorbrainradiotherapyRPriorbrainradiotherapy36PresentedbyJVansteenkisteatESMOAsia2017,17–19November2017,SingaporeProferredPaperSession1,AbstractLBA5.AnnOncol2017;28(suppl_10):mdx729.007Osimertinibaunnoaprobadoen1olíneadeCPNMavanzadoconmutaciónEGFRFlaura.CNSPFS:CNSFULLANALYSISSET.OsimertinibistherecomendationinptswithSNCmetastases*Progressioneventsthatdidnotoccurwithin2scheduledvisits(plusvisitwindow)ofthelastevaluableassessment(orrandomisation)werecensoredandthereforeexcludedinthenumberofevents;#Ap-valueof<0.0015wasrequiredforstatisticalsignificanceatcurrentmaturity

CI,confidenceinterval;CNS,centralnervoussystem;HR,hazardratio;NC,notcalculable;PFS,progression-freesurvival;SoC,standard-of-careFLAURAdatacut-off:12June2017MedianCNSPFS,months(95%CI) NC(16.5,NC) 13.9

(8.3,NC)HR0.48

(95%CI0.26,0.86)p=0.014Osimertinib(n=61)SoC(n=67)Medianfollow-upforCNSPFS,months12.47.0Totalnumberofevents(CNSprogressionordeath),%3045PtswithCNSprogressionotherthandeath,%*2039ProgressioninnewCNSlesions,%1230CNSPFSwasnominallystatisticallysignificantCNSPFSanalysiswasthirdinthehierarchicalstatisticaltestingstrategyand,asOSdidnotreachformalstatisticalsignificance(HR0.63[95%CI0.45,0.88];p=0.0068),#CNSPFScouldnotbeformallytestedforstatisticalsignificanceOsimertinib(N=61)SoC(N=67)0.20.40.60.81.00.00369121518212427Timefromrandomisation(months)Probabilityofprogression-freesurvivalNo.atriskOsimertinibSoCPresentedbyJVansteenkisteatESMOAsia2017,17–19November2017,SingaporeProferredPaperSession1,AbstractLBA5.AnnOncol2017;28(suppl_10):mdx729.007Osimertinibaunnoaprobadoen1olíneadeCPNMavanzadoconmutaciónEGFRFirstlineSecondlineThirdandsucessivelinesFirstgenerationTKIErlotinibOrgefitinibSecondgenerationTKIAfatinib

TKI+angiangiogenicErlotinib+bevacizumabThirdgenerationTKIOsimertinibChemoterapy9-10m15-30%nopossible2oline11-13mAfatinSecondgenerationTKIDacometinib14,7mDacomet16merl+bevE+BT790M-ultsens10merl+bevE+BT790M+ultsens16merl+bev18,9mosimertinibOsimertT790M-ultsensOsimertT790M+ultsens??????????????????????????5,5-6m25-30%T790Mnotdetected:NotPossiblebiopsy.LiquidbiopsyfalsenegativeOsiT790M+QTT790M-9-10m5,5mOsiT790M+QTT790M-9-10m5,5mOsiT790M+QTT790M-9-10m5,5mOsiT790M+QTT790M-9-10m5,5mOsi+GefitT790M+C797Strans9-10mQTNoMutat5,5mQTT790M+C797SCisQTNoMutat5,5mQTNoMutat5,5mQTNoMutat5,5mQTNoMutat5,5mQTNoMutat5,5m5,5mInmunoth??mInmunoth??mInmunoth??mInmunoth??mInmunoth??mInmunoth??mInmunoth??mInmunoth??mInmunoth??mInmunoth??mInmunoth??msequentialTKI2-4msequentialTKI2-4msequentialTKI2-4msequentialTKI2-4mNazartinib??mSequentialcronogramaCRITICALQUESTION.Whenappoved,OsimertinibforallpatientsinfirstlineEGFRmut,ORsequencehassenseinasubgroupofpatients?FirstlineSecondlineThirdandsucessivelinesFirstgenerationTKIErlotinibOrgefitinibSecondgenerationTKIAfatinib

TKI+angiangiogenicErlotinib+bevacizumabThirdgenerationTKIOsimertinibChemoterapy9-10m15-30%nopossible2oline11-13mAfatinSecondgenerationTKIDacometinib14,7mDacomet16merl+bevE+BT790M-ultsens10merl+bevE+BT790M+ultsens16merl+bev18,9mosimertinibOsimertT790M-ultsensOsimertT790M+ultsens??????????????????????????5,5-6m25-35%T790Mnotdetected:NotPossiblebiopsy.LiquidbiopsyfalsenegativeSequentialcronogramaWhichisthemorerecomendabletreatmentinfirstlineEGFRmut???IsbasedonPFSorisbasedintheoverallsurvivalofthecompletepotentialsequence?Osimertinib:uptofirst?PresentedBySanjayPopatat2017ASCOAnnualMeeting.-Addmediansurvivals:WRONGThisisnotbiologicalreal.Itisplaywithnumbers.-“Osimertinibfirstline:noothertargettherapiesinsucessivelines.Best,usesequence:WRONG.Ifthetreatmentisclearlybenefit,thismustbethefirstlineSubsequenttherapiespost-afatinibamongpatientswithEGFRM+NSCLCinLUX-Lung3,6and7Single-

agent

CTOther?1st-gen

TKImonotherapy*AnysubssystemictreatmentPlatinum-

based

CTSecond-line

treatment394(71%)252(46%)39(7%)49(9%)54(10%)Third-linetreatment265(48%)48(9%)104(19%)75(14%)38(7%)Fourth-linetreatment156(28%)27

(5%)50

(9%)49

(9%)30

(5%)Any-line

treatment394(71%)277(50%)181(33%)186(34%)DiscontinuedafatinibattimeofanalysisPatientswithcommonEGFRmutations

randomisedtoafatinibn=579n=553121

(22%)*Erlotinib,gefitinibandicotinib;?Includes:platinum-based,single-agentandotherCTcombinationtherapies;osimertinib,afatinib,HM61713androciletinibmonotherapies;erlotinib-,gefitinib-,icotinib-andafatinib-containingcombinations;immunecheckpointinhibitors;and‘other’therapiesSequistLetal.,ESMO2017poster#1349Datacut-off(LL3&6:25March2016;LL7:05December2016)29%ofpatientsnotReceivedsubsequenttherapyfordifferentenreasons:Thispatientsloosethechancetoreceived2olinetherapyagainstT790MmutNon-SheddingDNAsSheddingDNAsVessels,TissueBarriersTissueBiopsyLiquidBiopsyTumorHeterogeneityAllEGFRmutcontainactEGFRmutButonlysomecontainresistantT790MNotalltumorcellsshedDNAtobloodPresentedby:JamesChih-HsinYang,MD,PhD.NationalTaiwanUniversityNotalwaysLiquidbiopsydetectT790M.67-75%falsenegativeThesepatientsloosechancetoreceivedOsimertinibinsecondlineL781Qnotreatmentoption1.ThressKS,etal.NatMed.2015;21:560-562.2.NiederstMJ,etal.ClinCancerRes.2015;21:3924-3933.

3.HidakaNetal.,LungCancer,20174.Ho,C-Cetal.,JTO.12(3):567-572,20175.BersanelliMetal.JThoracOncol.2016;11:e121-123.6.KimTM,etal.JThoracOncol.2015;10:1736-1744.

7.PlanchardDetal.AnnalsofOnc2015;26:2073-2078.

8.LiLetal.Oncotarget.2017.9.OuS-HIetal.LungCancer2017:228-23110.PiotrowskaZetal.,ASCO201711.ErcanD.etal.,CanRes2015,21:3913-3923UnknowndrivernotreatmentoptionUnknowndriver

Rechallengewith3rdgenTKImightbebeneficialInvestigationalcompoundsunknowndrivernotreatmentoptionBRAFV600EBRAFinhibitorC797S/T790Mcis(mostfrequent)3:notreatmentoptionC797S/T790Mtrans2:combinationofTKIsC797S/T790Mwt:Retainedsensitivityto1stand2nd-genTKIs11MechanismsofAcquiredResistancetoOsimertinib:DriverMutation,PotentialTargetedTherapyOptionLostT790M:48%PotentialStrategiesatOsimertinibresistance:

AdaptedformNiederstetal.CCR2015.PreclinicaldataEGFRmNSCLCSensitiveEGFRmutSensitiveEGFRmT790M-C797S+First,SecondGenerationTKISensitiveEGFRmT790M+

C797S+

TransThirdGenerationOsimertinibResistance:Re-biopsySensitiveEGFRmut,T790MSensitiveto1-2GTKIsSensitiveto1G+3GTKISensitiveEGFRmT790M+

C797S+CisResistanttoTKIs_Chemo

29%Mostfrequent20%AllelicdispositionCourtesyN.Reguart9/12GenomiclandscapeofEGFRC797SinlungcancerctDNA,PresentedbyZofiaPiotrowskaAlterationPatients(%)EGFRamplification29(48%)METamplification10(16%)BRAFV600E(with/withoutBRAFamplification)3(5%)PIK3CAmutation(with/withoutPIK3CAamplification)9(15%)PIK3CAamplificationalone2(3%)BRAFamplificationalone9(15%)CCNE1amplification9(15%)KRASamplification,mutationorboth5(8%)MYCamplification6(10%)Fusions(EML4-ALK,NCOA4-RET,CCDC6-RET,STRN-ALK,TPM3-NTRK1,LMNA-NTRK1)5(8%)AdjacentEGFRmutations(L792,F795,G796,L798,Q791,P794)8(13%)Frequencyofco-occurringmutationsinC797S+samples51/61(84%)ptshadatleastonebonafideresistancemechanismco-occurringwithC797SPiotrowskaZ.IASLC2017TokioThequestion:AlthoughosimertinibinfirstlineincreasePFSbecausetargetcloneswithT790MfromthebeguiningORRELAPSETHEAPARITIONOFT790MASTHEFIRSTRESISTANCEMECHANISM,couldinducemoreagressivefenotypesintheprogessionandshorttheoverallsurvivalinmanypatients?Rosenbloometal./BiochimicaetBiophysicaActa1867(2017)69–83.-Competitionbetweensensitiveandresistantstrains.Thefitnesslandscapeofdrug-resistantstrains,aswellasthetimingofdrugresistancemutations,candeterminetheoutcomeoftherapy.SometimesthetwosubcloneshaveequalfitnessintheabsenceofdrugORsometimestheresistantsubclonepaysafitness“cost”andislessfitthanthesensitiveclone.-C:Thedrugresistancemutationoccursearly,allowingtheresistantclonetogrowtoalargesizebythetimetherapybegins.Asaresult,theslightdecreaseintumorsizecausedbytherapymaygoundetected,andthetumormaybedeemedintrinsicallyresistanttotherapy.D:Thedrugresistancemutationoccurslate,andtheresistantcloneissmallatthetimeoftreatment.Substantialtimemaypassbeforethetumorregrows.Thetumorisdeemedtoacquireresista