EGFR抑制剂专题知识培训讲义课件

IntroductionCellularSignallingPathwaysVitalforcellcycleprogression,growth,differentiation&death.GrowthFactors–ThekeystoneAdelicatebalancebetweenactivatingandinhibitorysignalsneedstobemaintainednormallyAlterationinthisbalance-Dysregulatedcellularproliferation&survivalofabnormalcells.Gene

TranscriptionG0G1PrimingSG2MCellCycleGrowthFactors+GrowthFactors&CellCycleReceptorsEpidermalGrowthFactorReceptor(EGFR)Breast14%-91%Colon25%-77%LungCancer40%-80%(Nonsmallcell)Ovarian35%-70%Pancreatic30%-50%Head&Neck80%-95%EGFRExpressionRateTumourSomeLandmarksinEGFRSignallingStanleyCohenHumanEGF(1970’s)IsolationandcloningofEGFR(1980’s).LinkbetweenEGFRandmalignanttransformationofcellsdemonstratedEGFinmice(1960’s)Mendelsohnetal.,BlockingEGFRsignallingtotreatcancerMurinemonoclonalantibodiestargetingEGFR-TK→Human:murinechimericversionMorethan20anti-EGFRagentsindevelopmentTKTKTKerbB1

HER1EGFRerbB2HER2neuerbB3HER3erbB4HER4Nospecific

ligands-

oftenactsas

dimerpartnerHeregulinsNRG2NRG3Heregulinsβ-cellulinEGF,TGFa,

bCellulinAmphiregulin,HB-EGFHumanEpidermalGrowthFactorReceptorFamily

TKIntracellularDomainTransmembraneDomainExtracellularDomainEGFRStructureTKTKTKTKerbB1

HER1EGFRerbB2HER2neuerbB3HER3erbB4HER4EGFRHomoDimerisationEGFRStimulation&dimerisationTKTKTKerbB1

HER1EGFRerbB2HER2neuerbB3HER3erbB4HER4HeteroDimerisationRiskforcancerEGFRstimulationcont…TKEGFRFunctioninNormalCellTKATPATPCellProliferationAntiapoptosisAngiogenesisGeneTranscriptionCellCycleProgression+TKTKEGFRsignaltransductionintumourcellsSurvival

(anti-apoptosis)PI3-KSTAT3AKTPTENMEKGenetranscriptionMAPKProliferation/

maturationChemotherapy/

radiotherapy

resistanceAngiogenesisMetastasispYpYRASRAFSOSGRB2pYG1SMG2MMPαβγPyk2SrcRasMAPKCa++PPerbBLigandGeneTranscription+++HB-EGFSteroidhormoneSteroidhormonereceptorGproteinOthermechanismsofEGFRstimulationEGFR-VariantIIIEGFR–WildTypeNoextracellulardomainPresentLigandcannotbindCanbindTKconstitutivelyactiveTKactivatedbyligandbindingCannotdimeriseCandimeriseNotfoundinnormalcellsFoundnormallyMorepropensityforcancerUpregulationleadstocancerHowEGFRvariantdiffersfromthewildtypeTKGenetranscriptionCellCycleProgressionCellProliferationMetastasisAntiApoptosisCancerATPEGFRvariantNormalCellCancerousCellUpRegulationMutationConsequenceofproliferationofEGFRreceptorsEGFR–Agoodtargetforlungcancer

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

kinaseinhibitorsAnti-EGFRmAbsAnti-ligand

mAbsBispecific

AbsImmuneeffectorcellATPDrugsAvailableGefitinibErlotinibHighlyselective,potent&reversibleEGFRTyrosineKinaseInhibitorCetuximab–MonoclonalAntiEGFRantibodyH447MDX210BispecificAntiEGFRantibodylinkedtoAntiCD64IndicationsMonotherapyinadvancedstageofNSCLCGefitinib&Erlotinib:

Gefitinib250mgO.D.oralErlotinib150mgO.D.oralCetuximab400mg/m2i.v.→200mg/m2i.v.wklyCetuximabMetastaticcolorectalcancerwith/withoutIrinotecanDoseSideEffectsSkinrashDiarrhoea(EGFR–TKIs)Fever(EGFR–mAb)Interstitiallungdisease–1%(onlyforGefitinib)

Discontinuationratesduetoadverseeffectsareverylowunlikechemotherapy.

DrugInteractionsEGFR–TKInhibitorsmetabolisedbyCYP3A4.Inhibitors/inducersofCYP3A4canalterdruglevels.WarfarininteractionshaveoccurredinclinicaltrialsofGefitinib.ConcomitantadministrationwithwarfarinrequiresmonitoringofPT,INR.AdvantagesofEGFRInhibitorsOrallyeffectiveBetterqualityoflife.Canbeusedasmonotherapy.Noneedforpremedicationordosemonitoring.Nohematologicaltoxicity.Potentialforlongtermtreatment.ReducedresistancetoradiationorhormonetherapyCurrentStatusGefitinibFDAApprovedonMay,2003forLungcancer-NSC(AcceleratedApprovalProgramme)

ErlotinibFDAApprovedonNov,2004forLungcancer–NonSmallCell(AAP)

CetuximabFDAApprovedonFeb,2004foradvancedcolorectalcancerClinicalTrialsParameterIDEALIIDEALIIDesign

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/dGefitinibPhaseIITrialsParameterINTACTIINTACTIIDesign

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.,ortimetoworseningsymptomsGefitinibPhaseIIITrialsParameterIProtocolMonotherapyMonotherapyNofpatients12457CancerHead&neckCarefractorytochemo-/radiotherapyAdvancedNSCLrefractorytoplatinumbasedtherapyDose/regimen150mg/day150mg/dayAdverseeffectsDiarrhoea,RashDiarrhoea,RashActivity

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

Design

OpenlabelOpenlabelIIErlotinib–PhaseIITrialsOutcomeswithTargetedTherapyProgression-freesurvivalQualityoflifeResponsetotreatmentSafetyOverallSurvivalUnansweredQuestionsPatientselectionHowlongpatientsshouldbetreatedTimingandsequencingofcombinationtherapyUseinvariousstagesofdiseaseAppropriatemarkersforresponseManaginguniqueadverseevents

→ILD→LivertoxicityBestuseinothersolidtumoursOngoingTrials…DifferenttreatmentschedulesforuseincombinationchemotherapyInothermalignancies–Breast,Prostate,Head&Neck,Colonassingle/combinationtherapyStrategiesCombiningEGFRIwithRadiotherapy/SurgeryorothernoveltargetedagentsliketrastuzumabIdentifysubsetofpeoplewhowillbenefitfromTKISkinrashes,MutationinTK,KRASConclusionConclusion…EGFRinhibitors-adefiniteroleintreatmentofcancerCombinationchemotherapy–FurtherstudiesneededImprovesQOLwithminimaladverseeffectsCanbeadministeredatoptimalbiologicaldosePotentialforuseinmultipletumorsRoleinearlystageofcancerneedstobeassertainedSurvivalnotsignificantlyprolongedCostly

Conclusion…ReferenceReviewArticles1.SolerR.P.HER1/EGFRTargeting:Refiningthestrategy.Oncologist2004;9:58–67.2.HerbstR.S,FukuokaM,BaselgaJ.Gefitinib–anoveltargetedapproachtotreatingcanver.Naturerevcancer2004;4:956–65.3.StrausbergR.L,SimpsonA.J.G,OldL.J,RigginsG.J.Oncogenomicsandthedevelopmentofnewcancertherapies.Nature2004;429:469–74.4.NobleM.E.M,EndicottJ.A,JohnsonL.N.Proteinkinaseinhibitors:Insightsintodrugdesignfromstructure.Science2004;303:1800–05.5.GloverK.Y,SolerR.P,PapadimitradopoulouV.A.AreviewofsmallmoleculeEpidermalGrowthFactorReceptorspecifictyrosinekinaseinhibitorsindevelopmentfornonsmallcelllungcancer.Sem.Oncol.2004;31suppl:83–92.6.JanmaatM.L,GiacconeG.SmallmoleculeEpidermalGrowthFactorReceptortyrosinekinaseinhibitors.Oncologist2003;8:576–86.ReviewArticles–cont…7.YanoS,NishiokaY,GotoH,SoneS.Molecularmechanismofangiogenesisinnonsmallcelllungcancerandtherapeuticstragetingrelatedmolecules.Cancersci.2003;94:479–85.8.VlahovicG,Crawford