EGFR和昔妥西单抗总论

EGFROverview

EGFRcriticallyregulatestumorcellcycleprogression,repair,andsurvival,andisinvolvedintumormetastasisBindingofspecificligandstoEGFR(eg,EGF,TGF-a)activatesthereceptorandtriggerssignaltransductioncascadesthataffectcellproliferationManyhumancancersexpressEGFRonthecellsurfaceInhibitionofEGFRontumorcellsmayinhibitthegrowthorprogressionofEGFR-expressingtumorsRoleofEpidermalGrowthFactor

Receptor(EGFR)inHumanCancerMetastasisProliferation/MaturationSurvival/ApoptosisAngiogenesisMAPKMEKGenetranscriptionCell-cycleprogressionPI3-KRASRAFSOSGRB2PTENAKTSTATpYpYKKpYEGFRSignalTransductionMG1SG2CourtesyofJoséBaselgaTumorTypePercentageofTumors

ExpressingEGFR(range)ReferencesColorectal 25-82%Salomon(1995);Messa(1998)Goldstein(2001),Cunningham(2003)HeadandNeck80-100%Salomon(1995);Grandis(1996)Pancreatic30-95%Salomon(1995);Uegaki(1997)

Abbruzzese(2001)NSCLC40-81%Fujino(1996);Rusch(1997);

Fontanini(1998);Gatzemeier(2003)RenalCarcinoma50-90%Salomon(1995);Yoshida(1997)Breast14-91%Klijn(1992);Beckman(1996);

Bucci(1997);Walker(1999)Ovarian35-70%Bartlett(1996);Fischer-Colbrie(1997)Glioma40-63%Salomon(1995);Watanabe(1996);

Rieske(1998)Bladder31-48%Salomon(1995);Chow(1997)EGFRExpressionin

SelectedHumanTumorsEGFRExpression:

ClinicalSignificanceAbbreviations:DFS,disease-freesurvival;OS,overallsurvival;

NSCLC,non-small-celllungcancerTumorTypePrognosisSurvivalRiskof

MetastasesReferencesColorectalPoorIncreasedMayer(1993)Hemming(1992)HeadandNeckPoorDecreasedDFSDecreasedOSGrandis(1998)Maurizi(1996)PancreaticPoorDecreasedOSDong(1998)Yamanaka(1993)NSCLCPoorPoorDecreasedOSIncreasedVolm(1998)Veale(1993)Ohsaki(2000)Pavelic(1993)BreastPoorSainsbury(1985)BladderPoorNeal(1985)UseofImmunohistochemistry(IHC)toDetectEGFRExpressioninTumorsIHCdetectsexpressionofEGFRproteinonsurfaceoftumorcells,withdirectvisualizationofthetargetReagentsandequipmentarecommonlyavailableIHCiswidelyusedinclinicalstudiesStandardizedmethodsarebeingdevelopedRationaleforEGFRBlockadeEGFRisexpressedinasignificant%ofallsolidtumorsEGFRhasmultiplemechanismsofactionincluding:PromotinggrowthoftumorcellsAidinginrepair/survivalfortumorcellsdamagedbyCT/RTPlayinganimportantroleinangiogenesisPlayingacriticalroleininvasionandmetastasesEGFRexpressionisanindicatorofpoorprognosis,decreasedsurvival,andincreasedmetastasesTumorsthatexpressEGFRhaveahighlevelofunmetmedicalneed

SignaltransductionSignaltransductionCelldeathMAbsTKIsToxinconjugatesAntisenseProtein

synthesisKKKKLigandKKTKIKKLigandLigandLigandEGFR-targetingApproachesCourtesyofJoséBaselgaPPPPligandLigand

binding

blockedReceptor-MAb

internalizationEGFR-targetingMAbligandligandligandEGFRTyrosine

kinaseExtracellular

domainCell

membraneIntracellular

domainSignaltransduction

cascade

blockedOther

enzyme

or

adaptorGeneactivation,

Cell

cycle

progressionEGFRInhibitionViaMonoclonal

Antibodies

Blocking

LigandBindingLigand(EGF,TGF-α)PPPPEGFRExtracellular

domainCell

membraneIntracellular

domainSignaltransduction

cascade

blockedOther

enzyme

or

adaptorGeneactivation,

Cell

cycle

progressionTyrosine

kinase

inhibitorTyrosine

kinaseEGFRInhibitionVia

Tyrosine

Kinase

InhibitorsEGFROverview-ConclusionsEGFRmayplayacriticalroleinregulatingtumorcellgrowth,repairandsurvival,angiogenesis,invasion,andmetastasisEGFRisexpressedinasignificantpercentageofhumantumorsandiscorrelatedwithpoorprognosis,decreasedsurvival,and/orincreasedmetastasisAgentsdesignedtoblockEGFRactivityarepostulatedto:InhibitphosphorylationandsignaltransductionResultinmultipleantitumormechanisms

EnhancechemotherapyandradiotherapyantitumoreffectsOngoingtrialsareevaluatingtheclinicalutilityofEGFRinhibitorsforthetreatmentofEGFR-expressingcancersCetuximab-PreclinicalData

Whatiscetuximab?Properties

CetuximabIgG1monoclonalantibodyAbsolutespecificityforEGFR

anditsheterodimersBindstoEGFRwithhighaffinityPreventsligandbindingtoEGFRStimulatesreceptorinternalizationanddegradationBlocksreceptordimerization,tyrosinekinasephosphorylation,andsignaltransductionCetuximab-PreclinicalDataCetuximab-MechanismofActionOverview

MechanismsofAction(1)

CetuximabBlocksreceptordimerization,tyrosinekinasephosphorylation,andsignaltransductionPreventsrepairandsurvivaloftumorcellsdamagedbytheeffectsofchemotherapyandradiotherapyPotentiatesapoptosisInhibitscellcycleprogressionDownregulates

angiogenicgrowthfactorsInhibitsinvasion/metastasisElicitsADCCresponseCourtesyofJoséBaselga(modified)MetastasisProliferation/MaturationCellRepair/SurvivalAngiogenesisMAPKMEKGenetranscriptionCell-cycleprogressionPI3-KRASRAFSOSGRB2PTENAKTSTATpYpYKKpYMG1SG2XXXXYXMechanismsofAction(2)

CetuximabInhibitionofSignalTransductionCetuximabAct-ERK2TotalERK2Act-EGFR 0 0.2 2 20 200cetuximab(nM)180KD145KDEGFRvIIIEGFRCHO-EGFRvIIICHO-wtEGFRControlCetuximabandEGFRvIIICHO(-)CHO-EGFRvIII-4(+)Cetuximabimmunoprecipitationofcellextractspreparedfrom35S-labeledCHO-transfectantsCetuximabcellsurfacestainingofEGFRvIIItransfectedcellsCetuximab-PreclinicalDataCetuximab-InductionofApoptosisBrunsCJ,etal.Clin

CancerRes.2000;6:1936-1948ControlGemcetuximabcetuximab+GemIncreasedApoptosisin

PancreaticTumorEndotheliumTreatedWithCetuximabandGemcitabineCetuximab-PreclinicalDataCetuximab–InhibitionofCellCycleProgressionInhibitionofTumorGrowth(1)

CetuximabOverholserJP,etal.Cancer2000;89:74-82SubcutaneoushumanpancreaticcarcinomaBxPC-3tumorscetuximab(17mg/kg)cetuximab(33mg/kg)Saline(control)***P<0.00107142128504249566370Meantumorvolume(mm3)200400600800100012001400160018000DaysaftertumorimplantationDaysaftertumorimplantationMeantumorvolume(mm3)010203040506070050010001500huIgG1controlcetuximab1.0mgendtreatmentSK-RC-29renalcellcarcinomaxenograftsPrewettM,etal.ClinCancerRes.1998;4:2957-2966InhibitionofTumorGrowth(2)

CetuximabDaysaftertumorimplantation0102030405060708090Fractionsurviving0.00.81.0cetuximabhuIgG1P<0.001RCCCaki-1renalcellascitestumorsIncreasedSurvival

CetuximabPrewettM,etal.ClinCancerRes.1998;4:2957-2966Cetuximab-PreclinicalDataCetuximab–DownregulationofangiogenicgrowthfactorsBrunsCJ,etal.Clin

CancerRes.2000;6:1936-1948ControlGemcetuximabcetuximab+GemVEGFIL-8CD31InhibitionofAngiogenesisinL3.6pl

PancreaticTumorsbyCetuximabandGemcitabineCetuximab-PreclinicalDataCetuximab–InhibitionofInvasion/MetastasisTreatment

Group

SalineGemcitabinecetuximabcetuximab+GemcitabineTumor

Incidence

10/1010/105/100/9MedianTumor

Volume,mm3

(range)538.7(253.7–859.6)152.4(58.8–364.5)0.3(0–13.4)0(0)Liver

Metastasis

5/103/102/100/9Reg.LN

Metastasis

10/106/108/101/9BrunsCJ,etal.Clin

CancerRes.2000;6:1936-1948InhibitionofInvasion/Metastasis

CetuximabandGemcitabineOrthotopicL3.6plpancreatictumorsCetuximab-PreclinicalDataCetuximab–PreclinicalcombinationStudiesCetuximab-PreclinicalDataCetuximabincombinationwithCTXDaysaftertumorimplantation05101520253035404550550100200300400500600700800900100011001200cetuximab+5-FUcetuximabSaline5-FUMeantumorvolume(mm3)HumanpancreaticcarcinomaBxPC-3xenograftsOverholserJP,etal.Cancer2000;89:74-82InhibitionofTumorGrowth

Cetuximaband5-FUCetuximab-PreclinicalDataCetuximabincombinationwithRTXcetuximab+10Gy10501001502002500100200300400cetuximab10GyControl%ofOriginalTumorVolume(300mm3-baseline)Time(days)A431humanepidermoidcarcinomaSalehMN,etal.CancerBiotherRadiopharm.1999;14:451-463.EnhancedAntitumorActivity

CetuximabandRadiationTherapyCetuximab-PreclinicalDataCetuximab–PreclinicalConclusionsPreclinicalConclusionsEGFRplaysacriticalroleinregulatingtumorcellgrowth,repairandsurvival,angiogenesis,invasion,andmetastasisEGFRisexpressedinasignificantpercentageofhumantumorsEGFRiscorrelatedwithpoorpatientprognosis,decreasedsurvival,and/orincreasedmetastasisAgentsthatblockEGFRactivityinhibitphosphorylationandsignaltransductionmayenhancechemotherapyandradiationtherapyantitumoreffectsresultinmultipleantitumormechanismsEGFRblockingagentsmayleadtoeffectivetherapiesforEGFR-expressingcancersCetuximab–ClinicalDataSafety&TolerabilityAcne-likeRash

CetuximabThemostcommontoxicityreportedinclinicaltrialsofcetuximabisaself-limitingacne-likerashSterile,nonsuppurativeCharacterizedasmultiplepustularlesionslocatedontheface,neck,andtrunkGenerallyappearsduringthefirst3weeksoftherapyandimproveswhileptsareontreatmentResolvesspontaneouslyuponcessationoftreatmentwithoutscarringGrade3/4Hypersensitivity

Reactions

CetuximabSevere(grade3/4)hypersensitivityreactionshavebeenreportedin2-4%ofpatientsSevereanaphylactoidreactionsoccurpredominantlyduringthefirstinfusionIncaseofanaphylactoidreactionsstandardmedicaltreatmentshouldbeusedCetuximabClinicalTrialExperienceOver1500patientshavebeentreatedwithcetuximabtodateinavarietyoftumortypesusingvariouscombinations.Tumor ERBITUXTreatment StudyNumbersColorectal plusirinotecan 9923,007Colorectal single-agent 0141,007,027Colorectal +/-irinotecan/5-FU/FA 0038,009,010Colorectal +/-oxaliplatin/5-FU/FA 021SCCHN plusradiation* 9607SCCHN plusradiation 006SCCHN plusradiation/cisplatin 9813SCCHN pluscisplatin* 9608,9503SCCHN

pluscisplatin 9816,001SCCHN pluscisplatin E5397SCCHN pluscisplatin/5-FU 008SCCHN singleagent 016NPC pluscarboplatin 003*Dose-rangingstudies

Cetuximab-Clinical

Experience(1)Tumor ERBITUXTreatment StudyNumberPancreatic plusgemcitabine 9814NSCLC pluscarboplatin/paclitaxel 9932NSCLC pluscarboplatin/gemcitabine 9925NSCLC plusdocetaxel 0036NSCLC +/-vinorelbine/cisplatin 011EGFR-expr.tumors singleinfusion* 9401EGFR-expr.tumors multipleinfusion* 9502,

BMS004/005Renalcell multipleinfusion 9710Prostate plusdoxorubicin* 9504Breast pluspaclitaxel* 9605EGFR-expr.tumors plusirinotecan 012*Dose-rangingstudies

Cetuximab-ClinicalExperience(2)Cetuximab–ClinicalData

Cetuximab–InColorectalCancer(CRC)ColorectalCancerOverview940,000newcasesannuallyForth-leadingcauseofcancerdeath

(490,000peryear)UnresectablediseaseisuniformlyfatalChemotherapyaffordsonlymodest

clinicalbenefitMetastaticColorectalCancer

Irinotecanin5-FUFailureMediansurvival9.2monthsMedianTTP4.1months1-yearsurvival36%CunninghamD,etal.Lancet.1998;352:1413–1418VonHoffDD.ProcASCO.1997;16:803aMediansurvival9.0monthsMedianTTP4.0months1-yearsurvival13%MetastaticColorectalCancer

CurrentFront-lineTherapy

Irinotecan/5-FU/LeucovorinSaltzL,etal.NEJM.2000;343:905-914DouillardJ-Y,etal.Lancet.2000;355:1041-1047TournigandC,etal.ProcAmSocClinOncol;2001;20(494)KohneC-H,etal.ProcAmSocClinOncol;2003;22(1018)Responserate35–57%Timetoprogression7–8.4monthsMediansurvival14.8-20.1months5-yearsurvival<1%AdvancedColorectalCancer

CombinationofOxaliplatin(OXAL),

5-Fluorouracil(5-FU),andIrinotecan(CPT-11)GoldbergRM,etal.;interimanalysis;ProcASCO2002;21:abstract511IFL(N=264)FOLFOX4(N=267)Oxaliplatin+CPT-11(N=264)Responserate29%38%28%MedianTTP(months)Mediansurvival(months)1-yearsurvival58%71%65%MetastaticColorectalCancer

CurrentFront-lineTherapy

Oxaliplatin/5-FU/LeucovorinDeGramont,etal.JClinOncol2000;18(16):2938-47Giacchetti,etal.JClinOncol2000;18(1):18(1):136-47TournigandC,etal.ProcAmSocClinOncol;2001;20(494)Grothey,etal.ProcAmSocClinOncol;2002;21:(512)Responserate49-56%Timetoprogression7.8–9.0monthsMediansurvival16.2–21.3monthsMetastaticColorectalCancer

CurrentFront-lineTherapywith

infusional5-FU/FAincombinationeitheroxaliplatinoririnotecan

DeGramont,etal.JClin

Oncol2000;18(16):2938-47Giacchetti,etal.JClin

Oncol2000;18(1):18(1):136-47Grothey,etal.ProcASCO2002;21:abstractno.512DouillardJ-Y,etal.Lancet.2000;355:1041-1047KohneCHetal.ProcASCO2003;abstractno1018Responserate~39–56%Timetoprogression~7–9monthsMediansurvival~17–21monthsResultsofrandomizedphaseIIIstudiesColorectalCancer

ConclusionsColorectalcancerremainsamajorcauseofcancerdeathStandardagentsare5-FU,leucovorin,andirinotecan/oxaliplatinNewcombinationregimenscontainingoxaliplatinin1stlinetherapyofmetastaticCRCshowpromisingresultsCurrentlythereisnoeffectivetherapyforirinotecan-and/oroxaliplatin-refractorycolorectalcancerThereisaclear,unmetmedicalneedforactivetherapiesafter5-FUandirinotecanoroxaliplatinfailureCetuximab–Clinicaldata

Cetuximab–IncombinationwithIrinotecanCetuximabPhaseIIClinicalSummary:CetuximabPlusIrinotecaninColorectalCancerSaltzL,etal.ProcASCO

2001;20:abstract

no.7*EGFRexpressing(≥1+)byimmunohistochemistryCetuximabPlusIrinotecaninCRC

ScheduleCetuximabat400/250mg/m2x6weeks

plus

Irinotecanat125mg/m2weeks1–4

or

Irinotecanat350mg/m2weeks1&4AbsenceofprogressionAdditionaltherapyuntildiseaseprogressionTreatmentgroup2

ProgressivediseaseTreatmentgroup1

StablediseaseMetastaticEGFR-expressing*colorectalcancerrefractorytostandardchemotherapy(irinotecanand5-FU)SaltzL,etal.ProcASCO

2001;20:abstract

no.7CetuximabPlusIrinotecaninCRC

PatientInclusionCriteriaMetastaticorrecurrentCRCPatientsrefractorytostandardchemotherapy(irinotecanand5-FU)Patientswithstablediseaseafterreceivinganirinotecan-containingregimenDocumentedEGFRexpression(≥1+)byimmunohistochemistryAllprioririnotecandosemodificationsweremaintainedNointerveningtherapySaltzL,etal.ProcASCO

2001;20:abstract

no.7CetuximabPlusIrinotecaninCRC

PatientCharacteristics(1)72%ofallpatientsscreenedforthistrialdemonstratedEGFR-expressionwithinthetumors120patientswithmetastaticorrecurrentCRCrefractorytostandardchemotherapy(irinotecanand5-FU)18patientswithmetastaticorrecurrentCRCwithstablediseaseafterreceivinganirinotecan-containingtherapySaltzL,etal.ProcASCO

2001;20:abstract

no.7CetuximabPlusIrinotecaninCRC

PatientCharacteristics(2)Medianage,yrs 56(range,26-83)MedianKPS 90(range,60-100)Timefromirinotecanfailure: Median: 30days Mean: 54daysSaltzL,etal.ProcASCO

2001;20:abstract

no.7CetuximabPlusIrinotecaninCRC

EfficacyResults(120PtsRefractoryto

StandardChemotherapy*)

PR21

(17%;95%C.I.11%-25%)SD37

(31%;minimumduration12weeks)Overalldisease

control(PR+SD)58(48%)Mediandurationofresponse(n=21)84days*Irinotecanand5-FUSaltzL,etal.ProcASCO

2001;20:abstract

no.7CetuximabPlusIrinotecaninCRC

ToxicityHypersensitivityreactionGr3 2% Gr4 1%Acne-likerash Gr1-2 53% Gr3 8%SaltzL,etal.ProcASCO

2001;20:abstract

no.7PhaseI/IIClinicalSummary:

CetuximabinCombinationwith5-FU/FAinPatientsWithEGFR-ExpressingMetastaticCRCLutzMetal.ProcAnnOncol.2002,Suppl.5:Abstract265PDCetuximabCetuximab+Infusional5-FU+FACetuximab:400mg/m21stinfusion,250mg/m2wklyIrinotecan:80mg/m2

FA:500mg/m2

Lowdose5-FU:1,500mg/m224hinf.SchemaHighdose5-FU:2,000mg/m224hinf.++LutzMetal.ProcAnnOncol.2002,Suppl.5:Abstract265PDCetuximab+Infusional5-FU+FA21patientswithEGFR-expressingtumorsMedianage=61years(range36-68years)MedianbaselineKPS=100(range70-100)Amedianof6treatmentcyclesweregiveninthelow-dose5-FUgroup,and4inthehigh-dose5-FUgroup2/6patientsinthelow-dosegroupand7/13patientsinthehigh-dosegrouphaddosemodificationsduringtheirfirstcycleoftreatmentPatientCharacteristicsLutzMetal.ProcAnnOncol.2002,Suppl.5:Abstract265PDCetuximab+Infusional5-FU+FASelectedsideeffectsLow-dose5-FUHigh-dose5-FUEvaluablepts613Diarrheagrade1/23(50%)8(62%)Diarrheagrade3/40(0%)3(23%)Rashgrade1/25(83%)11(85%)Rashgrade3/41(17%)2(15%)LutzMetal.ProcAnnOncol.2002,Suppl.5:Abstract265PDCetuximab+Infusional5-FU+FAEfficacyResultsAllptsLow-doseHigh-dosen19613CR2(11%)11PR12(63%)48RR14(74%)5(83%)9(69%)SD4(21%)13PD1(5%)-1LutzMetal.ProcAnnOncol.2002,Suppl.5:Abstract265PDCetuximab+Infusional5-FU+FACetuximabplusinfusional5-FU/FAissafeandfeasibleinEGFR-expressingmetastaticCRCThehigh-dose5-FUcombinationregimenwasassociatedwithahigherincidenceoftreatmentdelaysordosereductionsCetuximabplusinfusional5-FU/FAshowspromisingactivityinmetastaticCRCwitharesponserateof74%ConclusionsLutzMetal.ProcAnnOncol.2002,Suppl.5:Abstract265PDCetuximaband

IrinotecaninCRC

ResponseasaFunctionofSkinRashIMCL9923/CRC:irinotecan+cetuximabinirinotecan-refractorypatientsNoRashN=26n(%)Grade1N=43n(%)Grade2N=34n(%)Grade3N=17n(%)ObjectiveResponseRate1(3.8)6(14.0)8(23.5)12(70.6)MedianSurvival(d)P<0.0001124193320395SaltzLBetal.ProcAmSocOncol.2003,abstract817CetuximabPhaseIIClinicalSummary:

CetuximabwithIrinotecan,BolusFluorouracil,andLeucovorininColorectalCancerRosenbergAH,etal.ProcAmSocClinOncol.2002;21:135a.Abstract536.CetuximabPlus

IFLinCRCCetuximab400mg/m2initialdose,200mg/m2IV

Irinotecan125mg/m2IV

Leucovorin20mg/m2IV

5-FU500mg/m2IV

DosingScheduleWeeks123456TherapyIFL+CIFL+CIFL+CIFL+CCCC=cetuximab;IFL=irinotecan,5-FU,andleucovorinRosenbergAH,etal.ProcAmSocClinOncol.2002;21:135a.Abstract536.CetuximabPlus

IFLinCRCCharacteristicPatient,n(%)Gender

Male

Female

15(51.7)

14(48.3)Race

White

Black

Asian

Indian

26(89.7)

1(3.4)

1(3.4)

1(3.4)ECOGPS

0

1

12(41.4)

17(58.6)PatientCharacteristicsRosenbergAH,etal.ProcAmSocClinOncol.2002;21:135a.Abstract536.CetuximabPlus

IFLinCRC10Dehydration10Asthenia21Acne28Neutropenia28DiarrheaCetuximab+IFL

(%ofpatients)ToxicitySelectedGrade3/4ToxicitiesNR20NR5423IFLAlone*

(%ofpatients)NR=notreported.

*AsreportedinCAMPTOSAR®fullprescribinginformation.RosenbergAH,etal.ProcAmSocClinOncol.2002;21:135a.Abstract536.CetuximabPlus

IFLinCRCPR=partialresponse,MR=minimalresponse,SD=stabledisease,PD=progressivediseasePR,n(%)14(48.3)SD,n(%)12(41.3)PD,n(%)2(5.9)Notassessable,n(%)1(3.4)EfficacyResultsRosenbergAH,etal.ProcAmSocClinOncol.2002;21:135a.Abstract536.CetuximabPlus

IFLinCRCCetuximabcanbeaddedsafelytotheirinotecan,

5-FU,leucovorinregimenThemajorityofpatientsrequireddoseadju