EGFR抑制剂专题知识

EpidermalGrowthFactorReceptor(EGFR)InhibitorsDr.M.Jayanthi第1页Introduction第2页CellularSignallingPathwaysVitalforcellcycleprogression,growth,differentiation&death.GrowthFactors–ThekeystoneAdelicatebalancebetweenactivatingandinhibitorysignalsneedstobemaintainednormallyAlterationinthisbalance-Dysregulatedcellularproliferation&survivalofabnormalcells.第3页Gene

TranscriptionG0G1PrimingSG2MCellCycleGrowthFactors+GrowthFactors&CellCycleReceptors第4页EpidermalGrowthFactorReceptor(EGFR)第5页Breast14%-91%Colon25%-77%LungCancer40%-80%(Nonsmallcell)Ovarian35%-70%Pancreatic30%-50%Head&Neck80%-95%EGFRExpressionRateTumour第6页SomeLandmarksinEGFRSignallingStanleyCohenHumanEGF(1970’s)IsolationandcloningofEGFR(1980’s).LinkbetweenEGFRandmalignanttransformationofcellsdemonstratedEGFinmice(1960’s)Mendelsohnetal.,BlockingEGFRsignallingtotreatcancerMurinemonoclonalantibodiestargetingEGFR-TK→Human:murinechimericversionMorethan20anti-EGFRagentsindevelopment第7页TKTKTKerbB1

HER1EGFRerbB2HER2neuerbB3HER3erbB4HER4Nospecific

ligands-

oftenactsas

dimerpartnerHeregulinsNRG2NRG3Heregulinsβ-cellulinEGF,TGFa,

bCellulinAmphiregulin,HB-EGFHumanEpidermalGrowthFactorReceptorFamily

第8页TKIntracellularDomainTransmembraneDomainExtracellularDomainEGFRStructure第9页TKTKTKTKerbB1

HER1EGFRerbB2HER2neuerbB3HER3erbB4HER4EGFRHomoDimerisationEGFRStimulation&dimerisation第10页TKTKTKerbB1

HER1EGFRerbB2HER2neuerbB3HER3erbB4HER4HeteroDimerisationRiskforcancerEGFRstimulationcont…第11页TKEGFRFunctioninNormalCellTKATPATPCellProliferationAntiapoptosisAngiogenesisGeneTranscriptionCellCycleProgression+第12页TKTKEGFRsignaltransductionintumourcellsSurvival

(anti-apoptosis)PI3-KSTAT3AKTPTENMEKGenetranscriptionMAPKProliferation/

maturationChemotherapy/

radiotherapy

resistanceAngiogenesisMetastasispYpYRASRAFSOSGRB2pYG1SMG2第13页MMPαβγPyk2SrcRasMAPKCa++PPerbBLigandGeneTranscription+++HB-EGFSteroidhormoneSteroidhormonereceptorGproteinOthermechanismsofEGFRstimulation第14页EGFR-VariantIIIEGFR–WildTypeNoextracellulardomainPresentLigandcannotbindCanbindTKconstitutivelyactiveTKactivatedbyligandbindingCannotdimeriseCandimeriseNotfoundinnormalcellsFoundnormallyMorepropensityforcancerUpregulationleadstocancerHowEGFRvariantdiffersfromthewildtype第15页TKGenetranscriptionCellCycleProgressionCellProliferationMetastasisAntiApoptosisCancerATPEGFRvariant第16页NormalCellCancerousCellUpRegulationMutationConsequenceofproliferationofEGFRreceptors第17页EGFR–Agoodtargetforlungcancer

(nonsmallcell)Highlevelofreceptorexpressioncomparedwithhealthytissue.EGFR-Keyroleintumourcellgrowth&function.EGFRinhibitioncaninhibitdownstreamactivity.EGFRinhibitorshavenoseveretoxicity.第18页RationaleforEGFRInhibitorsinHead&NeckcancerEGFRexpressedin>90%ofhead&neckcancers.EGFRoverexpressionassociatedwithdecreasedsurvival.IncreasedEGFRexpressionisanearlyeventincarcinogenesis&evenpresentinpremalignantlesions.InhibitionofEGFR–TKslowsthegrowthofxenografttumourmodelsofhead&neck.第19页TKTKTKTKStrategiestoinhibitEGFRsignaling----EGFRtyrosine

kinaseinhibitorsAnti-EGFRmAbsAnti-ligand

mAbsBispecific

AbsImmuneeffectorcellATP第20页DrugsAvailableGefitinibErlotinibHighlyselective,potent&reversibleEGFRTyrosineKinaseInhibitorCetuximab–MonoclonalAntiEGFRantibodyH447MDX210BispecificAntiEGFRantibodylinkedtoAntiCD64第21页IndicationsMonotherapyinadvancedstageofNSCLCGefitinib&Erlotinib:

Gefitinib250mgO.D.oralErlotinib150mgO.D.oralCetuximab400mg/m2i.v.→200mg/m2i.v.wklyCetuximabMetastaticcolorectalcancerwith/withoutIrinotecanDose第22页SideEffectsSkinrashDiarrhoea(EGFR–TKIs)Fever(EGFR–mAb)Interstitiallungdisease–1%(onlyforGefitinib)

Discontinuationratesduetoadverseeffectsareverylowunlikechemotherapy.

第23页DrugInteractionsEGFR–TKInhibitorsmetabolisedbyCYP3A4.Inhibitors/inducersofCYP3A4canalterdruglevels.WarfarininteractionshaveoccurredinclinicaltrialsofGefitinib.ConcomitantadministrationwithwarfarinrequiresmonitoringofPT,INR.第24页AdvantagesofEGFRInhibitorsOrallyeffectiveBetterqualityoflife.Canbeusedasmonotherapy.Noneedforpremedicationordosemonitoring.Nohematologicaltoxicity.Potentialforlongtermtreatment.Reducedresistancetoradiationorhormonetherapy第25页CurrentStatusGefitinibFDAApprovedonMay,2023forLungcancer-NSC(AcceleratedApprovalProgramme)

ErlotinibFDAApprovedonNov,2023forLungcancer–NonSmallCell(AAP)

CetuximabFDAApprovedonFeb,2023foradvancedcolorectalcancer第26页ClinicalTrials第27页ParameterIDEALIIDEALIIDesign

RandomizeddoubleblindParallelGroup,multicenter

Randomizeddoubleblindparallelgroup,multicenterProtocolMonotherapyMonotherapyNofpatients209216CancerAdvancedNSCLC;1-2priorChemotherapycyclesAdvancedNSCLC;>2priorChemotherapycyclesDose/regimen250or500mg/day250or500mg/dayAdverseeffectsGI,RashGI,RashActivityCR/PR18%&19%,CR/PR/SD54%&51OS7.6&7.9mnthsat250&500mg/dCR/PR12%&9%,CR/PR/SD42%&36%;OS6.5&5.9mnthsat250&500mg/dGefitinibPhaseIITrials第28页ParameterINTACTIINTACTIIDesign

RandomizeddoubleblindPlacebocont.,multicenter

Randomizeddoubleblindplacebocont.,multicenterProtocolCombination–gemcitabine&cisplatinCombination-Carboplatin&PaclitaxelNofpatients10931037CancerAdv.NSCLCChemotherapynaïvestageIII/IVAdv.NSCLC;ChemotherapynaïvestageIII/IVDose/regimenStd.chemoplus250or500mg/dayStd.chemoplus250or500mg/dayAdverseeffectsDiarrhoea,RashDiarrhoea,RashActivityNodifferenceinoverallsurv.,Prog.Freesurv.,ortimetoworseningsymptomsNodifferenceinoverallsurv.,Prog.Freesurv.,ortimetoworseningsymptomsGefitinibPhaseIIITrials第29页ParameterIProtocolMonotherapyMonotherapyNofpatients12457CancerHead&neckCarefractorytochemo-/radiotherapyAdvancedNSCLrefractorytoplatinumbasedtherapyDose/regimen150mg/day150mg/dayAdverseeffectsDiarrhoea,RashDiarrhoea,RashActivity

PR6%;PR/SD46%CR/PR12%,CR/PR/SD51%;OS8.4mnths

Design

OpenlabelOpenlabelIIErlotinib–PhaseIITrials第30页OutcomeswithTargetedTherapyProgression-freesurvivalQualityoflifeResponsetotreatmentSafetyOverallSurvival第31页UnansweredQuestionsPatientselectionHowlongpatientsshouldbetreatedTimingandsequencingofcombinationtherapyUseinvariousstagesofdiseaseAppropriatemarkersforresponseManaginguniqueadverseevents

→ILD→LivertoxicityBestuseinothersolidtumours第32页OngoingTrials…DifferenttreatmentschedulesforuseincombinationchemotherapyInothermalignancies–Breast,Prostate,Head&Neck,Colonassingle/combinationtherapyStrategiesCombiningEGFRIwithRadiotherapy/SurgeryorothernoveltargetedagentsliketrastuzumabIdentifysubsetofpeoplewhowillbenefitfromTKISkinrashes,MutationinTK,KRAS第33页Conclusion第34页Conclusion…EGFRinhibitors-adefiniteroleintreatmentofcancerCombinationchemotherapy–FurtherstudiesneededImprovesQOLwithminimaladverseeffectsCanbeadministeredatoptimalbiologicaldosePotentialforuseinmultipletumors第35页RoleinearlystageofcancerneedstobeassertainedSurvivalnotsignificantlyprolongedCostly

Conclusion…第36页Reference第37页ReviewArticles1.SolerR.P.HER1/EGFRTargeting:Refiningthestrategy.Oncologist2023;9:58–67.2.HerbstR.S,FukuokaM,BaselgaJ.Gefitinib–anoveltargetedapproachtotreatingcanver.Naturerevcancer2023;4:956–65.3.StrausbergR.L,SimpsonA.J.G,OldL.J,RigginsG.J.Oncogenomicsandthedevelopmentofnewcancertherapies.Nature2023;429:469–74.4.NobleM.E.M,EndicottJ.A,JohnsonL.N.Proteinkinaseinhibitors:Insightsintodrugdesignfromstructure.Science2023;303:1800–05.5.GloverK.Y,SolerR.P,PapadimitradopoulouV.A.AreviewofsmallmoleculeEpidermalGrowthFactorReceptorspecifictyrosinekinaseinhibitorsindevelopmentfornonsmallcelllungcancer.Sem.Oncol.2023;31suppl:83–92.6.JanmaatM.L,GiacconeG.SmallmoleculeEpidermalGrowthFactorReceptortyrosinekinaseinhibitors.Oncologist2023;8:576–86.第38页ReviewArticles–cont…7.YanoS,NishiokaY,GotoH,SoneS.Molecularmechanismofangiogenesisinnonsmallcelllungcancerandtherapeuticstragetingrelatedmolecules.Cancersci.2023;94:479–85.8.Vlahovic