2018非小细胞肺癌EGFR突变优化患者管理

CncerdepulmnnomicrocticoEGFRmutado:Optimizacindelmanejodelpaciente,ManuelCoboDolsOncologiaMdicaHRegionalUniversitarioMlaga.IBIMA12-4-2018,EGFRTKIsversusChemotherapy,OngoingStudy:erlotinib+bevacizumabvs.erlotinibasfirst-linetreatment,IMPRESS.InexploratoryanalysisofT790Mnegative,theremaybePFSbenefittocontinuationofEGFRTKI,SoriaJC,etal.LancetOncol.2015;16:990-998.,Moketal.,PhaseIII(Aura3)(Osimertinibvs.CT)mPFS10.1vs.4.4mNEJM2016,GirardN.Futureoncol2017,PlasmaEGFRT790M,PlasmafromAURAtrialsentforBEAMingPairedtumorandplasmaavailablefor216patients,Oxnardetal,JCO,2016,18T790M+inplasma,nottumor,111T790M+intumorandplasma,47T790M+intumor,notplasma,40patientsT790M-tumorandplasma,T790M+intumor:62%RR,10mPFS,T790M+inplasma:63%RR,10mPFS,ImmunotherapyinEGFR-MutantNSCLC,*Dataforthepembrolizumabdoseswerepooled.,CheckMate057,KEYNOTE-010*,OAK,Nivolumab,Docetaxel,Pembrolizumab,Docetaxel,Atezolizumab,Docetaxel,Referencesinslidenotes.,1.0,0.5,2.0,0.25,4.0,1.0,0.1,10,1.0,0.2,2,LBA2_PR:OsimertinibvsSoCEGFD-TKIasfirst-linetreatmentinpatientswithEGFRmadvancedNSCLC(FLAURA),Keyresults,RamalingamSetal.AnnOncol2017;28(suppl5):AbstrLBA2_PR,MedianPFS,months(95%CI),18.9(15.2,21.4),10.2(9.6,11.1),HR0.46,(95%CI0.37,0.57)p0.0001,Osimertinib,SoC,PFS,1.0,0.6,0.4,0.2,0.0,0,3,6,9,12,15,18,21,24,27,0.8,Probabilityofprogression-freesurvival,Timefromrandomization,months,No.atrisk,Osimertinib,SoC,279,262,233,210,178,139,0,71,26,4,277,239,197,152,107,78,37,10,2,0,25,FavoursSoC,SubgroupOverall(n=556)LogRank(primary)CoxPHSexMale(n=206)Female(n=350)Ageatscreening65(n=298)65(n=258)RaceAsian(n=347)Non-Asian(n=209)SmokinghistoryYes(n=199)No(n=357)CNSmetastasesYes(n=116)No(n=440)WHOperformancestatus0(n=228)1(n=327)EGFRmutationatrandomisation#Exon19deletion(n=349)L858R(n=207)EGFRmutationbyctDNAPositive(n=359)Negative(n=124)CentrallyconfirmedEGFRmutationPositive(n=500)Negative(n=6),FLAURAdatacut-off:12June2017Hazardratio1impliesalowerriskofprogressiononosimertinib80mg.Sizeofcircleisproportionaltothenumberofevents*ByInvestigatorassessment;#Localorcentraltest;Resultmissingfor36patientsintheosimertinibarmand37patientsintheSoCarm;Resultmissingfor21patientsintheosimertinibarmand29patientsintheSoCarm;Subgroupcategorieswithlessthan20eventswereexcludedfromtheanalysisCNS,centralnervoussystem;ctDNA,circulatingtumourDNA;EGFR,epidermalgrowthfactorreceptor;PFS,progression-freesurvival;SoC,standard-of-care;WHO,WorldHealthOrganization.Ramalingametal.Presentedat:ESMOCongressSep8-12,2017;Madrid,Spain.,PFS*acrosssubgroups,0.1,0.2,0.3,0.4,0.6,0.8,Hazardratio(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),2.0,PFShazardratioand95%confidenceinterval,1.0,Favoursosimertinib,10.0,26,Objectiveresponserate*,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.,Durationofresponse,MedianDoR,months(95%CI)17.2(13.8,22.0)8.5(7.3,9.8),Probabilityofremaininginresponse,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0.0,0,3,6,9,12,15,18,21,24,27,Timefromfirstresponse(months),No.atriskOsimertinibSoC,Osimertinib,SoC,Keyresults(cont.),RamalingamSetal.AnnOncol2017;28(suppl5):AbstrLBA2_PR,No.atrisk,Osimertinib,SoC,279,276,269,253,243,232,0,154,87,4,277,263,252,237,218,200,126,64,1,0,29,24,OSinterimanalysis,1.0,0.6,0.4,0.2,0.0,0,3,6,9,12,15,18,21,24,27,0.8,30,Probabilityofoverallsurvival,Timefromrandomization,months,HR0.63,(95%CI0.45,0.88)p=0.0068,Ap-valueof0.0015wasrequiredforstatisticalsignificanceatcurrentmaturity,Medianoverallsurvival,Notreached,Osimertinib,SoC,Notreached,LBA2_PR:OsimertinibvsSoCEGFD-TKIasfirst-linetreatmentinpatientswithEGFRmadvancedNSCLC(FLAURA),GirardN.Futureoncol2017,Paciente,Tumor,Edad,PS,Comorbilidad,Cercanadomiciloahospital,Apoyofamiliar,Sintomtica/asintomtico,Cargatumoral,Localizacin/NmtsPosibilidadantiangiognicos?,MtsSNC,Subtipomutacin,Decisindetratamientoenprimeralnea.Factoresatenerencuenta,AfatinibinNSCLCPtsWithUncommomEGFRMutations,YangJC,etal.LancetOncol.2015;16:830-838.,*Consistsofptswithallpointmutationsorduplicationsinexons18-21.ConsistsofptswithdenovoT790Mmutations.Consistsofptswithexon20insertions.Consistsofptswithmutationsfallingintogroups1/2/3(n=18/3/2).,PacientesconPS2mayor,JuanO.TherapeuticAdvancesinMedicalOncology2017,Pacientesunfit,suelenser30%deloscasosEnsayosconafatinib,dacometiniboosimertinib,nohanreclutadoptsPS2Elrestodeestudios,conerlotinibygefitiniblaproporcindeptsPS2fuepequea(exceptoenelEURTACconerlotinibsereclutaron14%deptsconPS2)Roselletal.LancetOncol2012.-PacientesPS2:lomsrecomendadogefitinibyerlotinib.MsdatosAfatinibydacometinibsonmstxicosSlounestudioprospectivofaseIIcongefitinibquereclut30ptsconmutacindeEGFR,inelegibleparaquimioterapia.22ptsdeellostenanPS3,y68%deellos,elPSregresaPS1enelcursode1mes,conunaRGdel28(suppl_10):mdx729.007,Osimertinibaunnoaprobadoen1lneadeCPNMavanzadoconmutacinEGFR,Flaura.CNSPFS:CNSFULLANALYSISSET.OsimertinibistherecomendationinptswithSNCmetastases,*Progressioneventsthatdidnotoccurwithin2scheduledvisits(plusvisitwindow)ofthelastevaluableassessment(orrandomisation)werecensoredandthereforeexcludedinthenumberofevents;#Ap-valueof0.0015wasrequiredforstatisticalsignificanceatcurrentmaturityCI,confidenceinterval;CNS,centralnervoussystem;HR,hazardratio;NC,notcalculable;PFS,progression-freesurvival;SoC,standard-of-careFLAURAdatacut-off:12June2017,MedianCNSPFS,months(95%CI)NC(16.5,NC)13.9(8.3,NC),CNSPFSwasnominallystatisticallysignificantCNSPFSanalysiswasthirdinthehierarchicalstatisticaltestingstrategyand,asOSdidnotreachformalstatisticalsignificance(HR0.6395%CI0.45,0.88;p=0.0068),#CNSPFScouldnotbeformallytestedforstatisticalsignificance,No.atriskOsimertinibSoC,PresentedbyJVansteenkisteatESMOAsia2017,1719November2017,SingaporeProferredPaperSession1,AbstractLBA5.AnnOncol2017;28(suppl_10):mdx729.007,Osimertinibaunnoaprobadoen1lneadeCPNMavanzadoconmutacinEGFR,Firstline,Secondline,Thirdandsucessivelines,FirstgenerationTKIErlotinibOrgefitinib,SecondgenerationTKIAfatinib,TKI+angiangiogenicErlotinib+bevacizumab,ThirdgenerationTKIOsimertinib,Chemoterapy,9-10m,15-30%nopossible2line,11-13mAfatin,SecondgenerationTKIDacometinib,14,7mDacomet,16merl+bev,E+BT790M-ultsens,10merl+bev,E+BT790M+ultsens,16merl+bev,18,9mosimertinib,OsimertT790M-ultsens,OsimertT790M+ultsens,?,?,5,5-6m,25-30%T790Mnotdetected:NotPossiblebiopsy.Liquidbiopsyfalsenegative,Osi+GefitT790M+C797Strans,9-10m,QTT790M+C797SCis,Sequentialcronograma,CRITICALQUESTION.Whenappoved,OsimertinibforallpatientsinfirstlineEGFRmut,ORsequencehassenseinasubgroupofpatients?,Firstline,Secondline,Thirdandsucessivelines,FirstgenerationTKIErlotinibOrgefitinib,SecondgenerationTKIAfatinib,TKI+angiangiogenicErlotinib+bevacizumab,ThirdgenerationTKIOsimertinib,Chemoterapy,9-10m,15-30%nopossible2line,11-13mAfatin,SecondgenerationTKIDacometinib,14,7mDacomet,16merl+bev,E+BT790M-ultsens,10merl+bev,E+BT790M+ultsens,16merl+bev,18,9mosimertinib,OsimertT790M-ultsens,OsimertT790M+ultsens,?,?,5,5-6m,25-35%T790Mnotdetected:NotPossiblebiopsy.Liquidbiopsyfalsenegative,Sequentialcronograma,WhichisthemorerecomendabletreatmentinfirstlineEGFRmut?IsbasedonPFSorisbasedintheoverallsurvivalofthecompletepotentialsequence?,Osimertinib:uptofirst?,PresentedBySanjayPopatat2017ASCOAnnualMeeting,.-Addmediansurvivals:WRONGThisisnotbiologicalreal.Itisplaywithnumbers,.-“Osimertinibfirstline:noothertargettherapiesinsucessivelines.Best,usesequence:WRONG.Ifthetreatmentisclearlybenefit,thismustbethefirstline,Subsequenttherapiespost-afatinibamongpatientswithEGFRM+NSCLCinLUX-Lung3,6and7,Single-agentCT,Other,1st-genTKImonotherapy*,Anysubssystemictreatment,Platinum-basedCT,Second-linetreatment,394(71%),252(46%),39(7%),49(9%),54(10%),Third-linetreatment,265(48%),48(9%),104(19%),75(14%),38(7%),Fourth-linetreatment,156(28%),27(5%),50(9%),49(9%),30(5%),Any-linetreatment,394(71%),277(50%),181(33%),186(34%),Discontinuedafatinibattimeofanalysis,PatientswithcommonEGFRmutationsrandomisedtoafatinib,n=579,n=553,121(22%),*Erlotinib,gefitinibandicotinib;Includes:platinum-based,single-agentandotherCTcombinationtherapies;osimertinib,afatinib,HM61713androciletinibmonotherapies;erlotinib-,gefitinib-,icotinib-andafatinib-containingcombinations;immunecheckpointinhibitors;andothertherapies,SequistLetal.,ESMO2017poster#1349,Datacut-off(LL3LL7:05December2016),29%ofpatientsnotReceivedsubsequenttherapyfordifferentenreasons:Thispatientsloosethechancetoreceived2linetherapyagainstT790Mmut,Non-SheddingDNAs,SheddingDNAs,Vessels,TissueBarriers,TissueBiopsy,LiquidBiopsy,TumorHeterogeneity,AllEGFRmutcontainactEGFRmutButonlysomecontainresistantT790M,NotalltumorcellsshedDNAtoblood,Presentedby:JamesChih-HsinYang,MD,PhD.NationalTaiwanUniversity,NotalwaysLiquidbiopsydetectT790M.67-75%falsenegative,ThesepatientsloosechancetoreceivedOsimertinibinsecondline,L781Qnotreatmentoption,1.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.,CanRes2015,21:3913-3923,Unknowndrivernotreatmentoption,UnknowndriverRechallengewith3rdgenTKImightbebeneficial,Investigationalcompounds,unknowndrivernotreatmentoption,BRAFV600EBRAFinhibitor,C797S/T790Mcis(mostfrequent)3:notreatmentoption,C797S/T790Mtrans2:combinationofTKIsC797S/T790Mwt:Retainedsensitivityto1stand2nd-genTKIs11,MechanismsofAcquiredResistancetoOsimertinib:DriverMutation,PotentialTargetedTherapyOption,LostT790M:48%,PotentialStrategiesatOsimertinibresistance:,AdaptedformNiederstetal.CCR2015.Preclinicaldata,EGFRmNSCLC,SensitiveEGFRmut,First,SecondGenerationTKI,ThirdGenerationOsimertinibResistance:Re-biopsy,SensitiveEGFRmut,T790M,Sensitiveto1-2GTKIs,Sensitiveto1G+3GTKI,ResistanttoTKIs_Chemo,29%,Mostfrequent,20%,Allelicdisposition,CourtesyN.Reguart,9/12,GenomiclandscapeofEGFRC797SinlungcancerctDNA,PresentedbyZofiaPiotrowska,Frequencyofco-occurringmutationsinC797S+samples,51/61(84%)ptshadatleastonebonafideresistancemechanismco-occurringwithC797S,PiotrowskaZ.IASLC2017Tokio,Thequestion:AlthoughosimertinibinfirstlineincreasePFSbecausetargetcloneswithT790MfromthebeguiningORRELAPSETHEAPARITIONOFT790MASTHEFIRSTRESISTANCEMECHANISM,couldinducemoreagressivefenotypesintheprogessionandshorttheoverallsurvivalinmanypatients?,Rosenbloometal./BiochimicaetBiophysicaActa1867(2017)6983,.-Competitionbetweensensitiveandresistantstrains.Thefitnesslandscapeofdrug-resistantstrains,aswellasthetimingofdrugresistancemutations,candeterminetheoutcomeoftherapy.SometimesthetwosubcloneshaveequalfitnessintheabsenceofdrugORsometimestheresistantsubclonepaysafitness“cost”andislessfitthanthesensitiveclone.-C:Thedrugresistancemutationoccursearly,allowingtheresistantclonetogrowtoalargesizebythetimetherapybegins.Asaresult,theslightdecreaseintumorsizecausedbytherapymaygoundetected,andthetumormaybedeemedintrinsicallyresistanttotherapy.D:Thedrugresistancemutationoccurslate,andtheresistantcloneissmallatthetimeoftreatment.Substantialtimemaypassbeforethetumorregrows.Thetumorisdeemedtoacquireresistanceduringtherapy,.-EDrugresistancemutationsoccurmultipletimesbeforetherapy,butcannotgrowsubstantiallyduetothefitnesscost.Ifaresistancemutationoccursnearthetimethattreatmentbegins,eliminationofdrug-sensitivecellsreleasestheresistantsubclonefromcompetition,allowingittogrow.,Startof1-2generationTKI,T790Mclone,T790Mbeforetreatmentmaybedetectedbyultrasensitivemethodsbothinsolidorliquidbiopsy:Probablythiswouldbethepopulationwithmorebenefittoosimertinibfromthefirstline,Startof3generationTKI,Future,AzumaK,etal.JTO2017RemonJ,etal.ClinLung