晚期大肠癌的个体化治疗

IndividualizedTreatmentsforAdvancedColorectalCancer:TheKRASStorySUMMARYTargetedtherapieshaveimprovedclinicaloutcomeofmCRCNeedjudicioususeoftheseagents:when,howManyquestionsremainingHowtoovercomethehighcost►Treatmentsneedtobeindividualized:biomarkersandgeneticsignaturesStoryforGIatASCO20081stbiomarkerforindividualizedtherapyforcolorectalcancer:KRASstatuspredictsresponsiveness(orlackofresponsiveness)toEGFRtargetedtherapiesAdvancesintheTreatmentofColorectalCancer198019851990199520002005CapecitabineOxaliplatinCetuximabBevacizumabIrinotecan5-FUPanitumumabMedianSurvivalBSC:4-6months5FU:10-14months5FU/OX/Iri:~20months+targetedtherapy:>30months?SomeHistoricalData

EGFRTargetedTherapies

inCRC

Cetuximab&PanitumumabBOND1:RandomizedPivotal

TrialinMetastaticColorectalCancerRANDOMIZECetuximab+irinotecanCetuximab(initialdose,400mg/m2thenweeklyinfusion250mg/m2)+irinotecan(sameasprestudytherapy)(n=218)N=329PatientswithmCRCwhoprogressedduringorwithin3moafteririnotecanEGFR+CRCHistaminereceptorantagonistpremedicationgivenbeforeatleastthefirstcetuximabinfusion.Cetuximab

(initialdose,400mg/m2thenweeklyinfusion250mg/m2)(n=111)CunninghamD,etal.NEnglJMed.2004;351:337-345.0510152025012345622.9%5.7mo4.2mo10.8%ObjectiveResponseRateMedianDurationofResponse

Cetuximabwithirinotecan(n=218)Cetuximabasasingleagent(n=111)CetuximabRandomizedPivotal

Trial:ResponseRatesP=0.007CunninghamD,etal.NEnglJMed.2004;351:337-345.RANDOMIZEN=1298PatientswithCRCwhoprogressedon5FU,Oxaliplatin,GFR+IrinotecanCetuximab+IrinotecanJonkeretal.AACR2007.Abstract3556.EPIC:Cetuximab+IrinotecanvsIrinotecanas2nd-lineTherapyEPICStudyEfficacyData

Cetuximabisactivein2ndline,irinotecannaïvepts

Lackofoverallsurvival:cross-overeffect?CRYSTAL:PhaseIIITrialofFOLFIRI+/-CetuximabinFirst-linemCRCRANDOMIZEFOLFIRI+cetuximab(608)First-linemCRCFOLFIRI(609)CutsemetaI,etal.ASCO2007.4000.CRYSTALEfficacyDataCetuximab+FOLFIRI(N=608)Irinotecan(N=609)PValuePFS8.98<0.036ResponseRate(%)46.9%38.7%<0.005

CetuximabimprovesRR,PFSin1stline,incombinationwithFOLFIRIPhaseIIIStudy:PanitumumabvsBestSupportiveCarePeetersM,etal.AACR2006.AbstractCP-1.RANDOMIZEPanitumumab

(6mg/kgq2wk)+BSC(n=231)N=463Patientsthird-linemCRCEGFRexpressionrequiredOptionalpanitumumabcrossoverstudy(n=174)Bestsupportivecare(n=232)PDPDStratificationbasedonECOGscore,geographicregionPanitumumabImprovesPFSoverBestSupportiveCarePFSlongerwithpanitumumabvsBSCHR,0.54(95%CI,0.44-0.66;P<0.000000001)*P<0.0001. PeetersM,etal.AACR2006.AbstractCP-1.Panitumumab(n=231)BSC(n=232)PR,n(%)19(8)*0(0)SD,n(%)64(28)24(10)Mediandurationresponse,wk(range)17(4+-40+)n/aOnlyasmallportionofpatientsrespondedtoEGFRtargetedtherapies

MajorityofpatientssufferedthesideeffectsandhighcostwithoutbenefitsDilemmaWhatmayhelpselectthesepatients?EGF/EGFRPathwayProliferationApoptosisResistanceTranscriptionShcPI3KRafMEKK-1MEKMKK-7JNKERKRasmTORGrb2AKTSos-1EGFRPhaseIIIStudy:PanitumumabvsBestSupportiveCareKRASMutationPredictsNoBenefitfromPanitumumabCRYSTAL:PhaseIIITrialofFOLFIRI+/-CetuximabinFirst-linemCRCRANDOMIZEFOLFIRI+cetuximab(608)First-linemCRCFOLFIRI(609)CutsemetaI,etal.ASCO2007.4000.CRYSTAL:PFSinPatientsWiththeKRASMutation00.20.40.60.81.004812MosPFSEstimate16Cetuximab+FOLFIRIFOLFIRIKRASmutation(n=192)HR:1.07;P=.47261014MedianPFScetuximab+FOLIFIRI:7.6mosMedianPFSFOLIFIRI:8.1mos0.10.30.50.70.9VanCutsemE,etal.ASCO2008.Abstract2.Reproducedwithpermission.CRYSTAL:PFSinPatientsWith

WTKRAS00.20.40.60.81.004812Mos18Cetuximab+FOLFIRIFOLFIRIWTKRAS(n=348):HR:0.68;P=.017261014MedianPFScetuximab+FOLIFIRI:9.9mosMedianPFSFOLIFIRI:8.7mos0.10.30.50.70.9161-yrPFSrate:43%VanCutsemE,etal.ASCO2008.Abstract2.Reproducedwithpermission.1-yrPFSrate:25%PFSEstimateCRYSTAL:InitialandRetrospectiveResultsITTPopulationK-rasWildTypeK-rasMutationFOLFIRIFOLFIRIFOLFIRIWithERBITUXNoERBITUXWithERBITUXNoERBITUXWithERBITUXNoERBITUX#ofPatients59959917217610587OverallResponseRate47%39%p=0.00459%43%p=0.00336%40%p=0.46MedianPFS8.9mos8.0mosHazardRatio:0.85p=0.059.9mos8.7mosHazardRatio:0.68p=0.027.6mos8.1mosHazardRatio:1.07p=0.75KRASStatusandEfficacyofFirst-LineFOLFOX±Cetuximab:OPUSGenomicDNAwasisolatedfromarchivedtumormaterialKRASmutationstatusofcodons12/13wasdeterminedusingasensitive,quantitativePCR-basedassayPopulationwithtissueavailableforKRASanalysis

(n=233)wasrepresentativeofoverallITTpopulation

(n=337)intermsofdemographicsandefficacyparametersKRASmutationsdetectedin42%(99/233)ofevaluablesamplesBokemeyerC,etal.ASCO2008.Abstract4000.OPUS:InitialandRetrospectiveResultsITTPopulationK-rasWildTypeK-rasMutationFOLFOXFOLFOXFOLFOXWithERBITUXNoERBITUXWithERBITUXNoERBITUXWithERBITUXNoERBITUX#ofPatients16916861735247OverallResponseRate46%36%p=0.00661%37%p=0.0133%49%p=0.11MedianPFS7.2mos7.2mosHazardRatio:0.93p=NSS7.7mos7.2mosHazardRatio:0.57p=0.025.5mos8.6mosHazardRatio:1.83p=0.02CAIRO2SummaryCetuximab+bevacizumab/capecitabine/oxaliplatindecreasedPFSwithoutaffectingOSAlthoughmanageable,cetuximab+bevacizumab/chemotherapyincreasesskintoxicityanddiarrhea

adverseeventsTreatmentdiscontinuationduetotoxicitydidnotdifferbetweenarmsNegativeinteractionbetweenanti-VEGFandanti-EGFRcannotbediscountedPuntCJ,etal.JClinOncol.2008;26(May20suppl):abstrLBA4011.IsKRASindependentfromskinrashasapredictorforresponse?

CandoseescalationovercomeKRASmutant-type?KRASandEfficacy

ofIrinotecanandCetuximabinmCRC:EVERESTPatientswithirinotecan-refractorymetastaticcancerCetuximab400mg/m2initialdosethen

250mg/m2/wk+Irinotecan

180mg/m2Q2WControlStandardCetuximabregimen(250mg/m2/wk)(n=23)DoseEscalationCetuximabdoseincreasesof50mg/m2Q2Wuptomaximum

500mg/m2/wk(n=31)Nonrandomized

StandardCetuximabregimen(250mg/m2/wk)SCREENINGDay22Randomized:

skintoxicitygrade0/1Noteligibleforrandomization:skintoxicity

grade2/3AllpatientscontinuedtoreceiveirinotecanTreatmentuntilprogression,unacceptabletoxicityorwithdrawalofconsentSkinandtumorbiopsyatbaseline,Week3,andatmaximumcetuximabdoseindose-escalationarmTejparS,etal.ASCO2008.Abstract4001.EVEREST:PFS(ITTPopulation)00.20.40.60.81.00200400600DaysPFSEstimate800P<.0001KRASmutantWTKRASKRASmutationpresent83days(95%CI:75.9-90.2)173days(95%CI:141.3-204.7)TejparS,etal.ASCO2008.Abstract4001.Reproducedwithpermission.EVEREST:PFSbyTreatmentGroupandKRASStatus0.00.20.40.60.81.002004006008000.00.20.40.60.81.002004006008000.00.20.40.60.81.00200400600800DaysDaysDaysKRASmutantWTKRASControlKRASmutationpresentP=.014KRASmutantWTKRASDoseEscalationKRASmutationpresentKRASmutantWTKRASNonrandomizedKRASmutationpresentP<.001P=.020TejparS,etal.ASCO2008.Abstract4001.Reproducedwithpermission.PFSEstimatePFSEstimatePFSEstimateEVERESTSUMMARYDoseescalationofcetuximabdidincreaseresponserateAmongpatientswithoutrashreceiving,KRASstatusstillpredictedresponsetocetuximabAmongpatientsreceivingescalateddoseofcetuximab(torash),KRASMTstilldidnotrespondHigherdosedidnotovercomeKRASstatusSkinrashandKRASareindependentpredictorsSUMMARYofKrasDataKrasstatusisapredictivemarkerforEGFRtargetedtherapyPatientswithwild-typeKrasmaybenefitfromEGFRtargetedtherapyPatientswithmutantKrasmayNOTbenefitfromEGFRtargetedtherapyCetuximabmayhavedetrimentaleffectsinpatientswithmutantKrasWheneverconsideringtouseEGFRtargetedtherapy,Krasstatusshouldbetested.QuestionsRaisedbyKRASDataWhattodowithcurrenttrialsinvolvingEGFRtargeted-agents?WhattodoforpatientswithmutatedKRAS?Anyotherpredictivemarkers?Developmorereliable,affordabl