AnewtreatmentparadigmformCRCProfessorofMedicineAssociateDirector,ClinicalResearchUSCNorrisComprehensiveCancerCenterLosAngeles,CAAnewtreatmentparadigmformAnti-EGFRantibodiesinmCRCAnti-EGFRantibodiesinmCRCComparisonofcetuximabandbevacizumabBleedingpossible,wound-healingcomplicationsNocomplicationsPerioperativeHypertension,thromboemboliceventsAcne-likeskinrash

Specificsideeffect+?++RRwithFOLFOX+++RRwithFOLFIRIFirstlineSecond/thirdlineRegistered?YesSingle-agentactivityVEGFproteinEGFreceptorAntibodyBevacizumabCetuximabCharacteristicComparisonofcetuximabandbePhaseIIICRYSTALstudy:StudydesignStratificationfactors:RegionECOGperformancestatusPopulations:Randomizedpatients(n=1217)Safetypopulation(n=1202)ITTpopulation(n=1198)FOLFIRIIrinotecan(180mg/m2)+5-FU(400mg/m2bolus+2400mg/m2

as46-hcontinuousinfusion)+LV(every2weeks)ERBITUX+FOLFIRIERBITUX(IV400mg/m2onday1,then250mg/m2weekly)

+irinotecan(180mg/m2)+5-FU(400mg/m2bolus+2400mg/m2

as46-hcontinuousinfusion)+LV(every2weeks)

REGFR-expressingmCRCVanCutsemE,etal.ASCO2007(AbstractNo.4000)PhaseIIICRYSTALstudy:StudyStudyendpointsPrimaryendpointPFStime(asassessedbyblindedindependentreview)SecondaryendpointsORR(independentlyreviewed)DCR(CR+PR+SD)OSQualityoflife(EORTCQLQ-C30)SafetyVanCutsemE,etal.ECCO2007(AbstractNo.3001)StudyendpointsPrimaryendpoin1.00.80.90.00.10.20.30.40.50.60.702468101214161820Primaryendpoint:PFS(ITTpopulation)PFSestimateVanCutsemE,etal.ASCO2007(AbstractNo.4000)PFStime(months)1-yearPFSrate:

23%vs34%FOLFIRI(n=599)ERBITUX+FOLFIRI(n=599)PFSITT:HR=0.85;p=0.048mPFSERBITUX+FOLFIRI:8.9monthsmPFSFOLFIRI:8.0months1.00.80.90.00.10.20.30.40.50.6IndependentassessmentofresponseVanCutsemE,etal.ECCO2007(AbstractNo.3001)39%47%Responserate(%)p=0.0038aaCochran–Mantel–HaenszeltestIndependentassessmentofrespKRASanalysis:ObjectiveandmethodologyToretrospectivelyinvestigatetheimpactoftheKRASmutationstatusoftumorsonPFSandRRinthefirst-linetreatmentofmCRCwithFOLFIRI±ERBITUXEfficacyanalysesrepeatedonKRASevaluablepopulationGenomicDNAisolatedfromarchivedtumormaterialParaffin-embedded,formalin-fixedtissueKRASmutationstatusofcodons12/13determinedusingquantitativePCR-basedassayVanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2)KRASanalysis:ObjectiveandmKRASevaluablepopulation587subjectsanalysedforKRASmutationstatus540(45%)subjects:KRASevaluablepopulation348(64.4%)KRASwild-type192(35.6%)KRASmutant171subjectswithevents(49.1%)GroupA:105(54.7%)GroupB:87(45.3%)101subjectswithevents(52.6%)1198subjects(ITT)GroupA:172(49.4%)GroupB:176(50.6%)FOLFIRIERBITUX+FOLFIRIVanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2)KRASevaluablepopulation587sPatientdemographicsatbaselineaccordingtoKRASstatusVanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2)PatientdemographicsatbaseliITTandKRASevaluablepopulation:ComparabilityITTpopulation(n=1198)HR=0.85

MedianPFS:ERBITUX+FOLFIRI8.9monthsvsFOLFIRI8.0monthsKRASpopulation(n=540)HR=0.82MedianPFS:ERBITUX+FOLFIRI9.2monthsvsFOLFIRI8.7months1.0PFSestimateTime(Months)0.50.40.30.20.10.60.70.80.90.0802461012141618200.51.00.40.30.20.10.60.70.90.0802461012141618200.8Time(Months)PFSestimateERBITUX+FOLFIRIFOLFIRIVanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2)ITTandKRASevaluablepopulatFirst-lineERBITUX+FOLFIRI:

CorrelationofKRASstatuswithefficacyFirst-linetreatment:ERBITUX(6weeksmonotherapy),followedbyERBITUX+FOLFIRI(n=52)TaberneroJetal,ASCOGI2008First-lineERBITUX+FOLFIRI:RelatingKRASstatustoefficacy

Primaryendpoint:PFS–KRASwild-type0.00.10.20.30.40.50.60.70.80.91.0024681012141618MonthsProgression-freesurvivalestimateERBITUX+FOLFIRIFOLFIRIKRASwild-type(n=348)HR=0.68;p=0.017

mPFSERBITUX+FOLFIRI:9.9months

mPFSFOLFIRI:8.7months1-yearPFSrate25%vs43%VanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2)RelatingKRASstatustoefficaRelatingKRASstatustoefficacy

Primaryendpoint:PFS–KRASmutantKRASmutant(n=192)HR=1.07;p=0.75

mPFSERBITUX+FOLFIRI:7.6months

mPFSFOLFIRI:8.1months0246810121416MonthsERBITUX+FOLFIRIFOLFIRI0.00.10.20.30.40.50.60.70.80.91.0Progression-freesurvivalestimateVanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2)RelatingKRASstatustoefficaRelatingKRASstatustoefficacy:PFSERBITUX+FOLFIRI

HR=0.63(p=0.007)

MedianPFS:Wild-type(n=172)9.9months

vsmutant(n=105)7.6monthsFOLFIRI

HR=0.97(p=0.87)

MedianPFS:Wild-type(n=176)8.7months

vsmutant(n=87)8.1months0.51.00.40.30.20.10.00.60.70.80.9802461016PFSestimateTime(months)ERBITUX+

FOLFIRIwild-typeERBITUX+

FOLFIRImutant12140.51.00.40.30.20.10.00.60.70.80.9Time(months)FOLFIRIwild-typeFOLFIRImutant8024610161214PFSestimateVanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2)RelatingKRASstatustoefficaRelatingKRASstatustoefficacy

Secondaryendpoint:Responsep=0.0025aFOLFIRIERBITUX

+FOLFIRIaCochran-Mantel-Haenszel(CMH)testKRASwild-type(n=348)KRASmutant(n=192)p=0.46aFOLFIRIERBITUX

+FOLFIRIVanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2)RelatingKRASstatustoefficaRelatingKRASstatustooutcome:

Mostcommongrade3/4adverseeventsaTherewasnograde4acne-likerashVanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2)RelatingKRASstatustooutcomConclusions:CRYSTALstudyAddingERBITUXtoFOLFIRIinmCRCleadstoasignificantincreaseinPFS(HR=0.85;p=0.048)ThebenefitofERBITUX+FOLFIRIisgreaterinpatientswithKRASwild-typetumors:PFS(HR=0.68;p=0.017)Responserate59%vs43%(p=0.0025)Thegrade3/4adverse-eventprofilewassimilarintheKRASwild-typeandmutantpopulationsConclusions:CRYSTALstudyAddiOPUS:StudydesignPrimaryendpointOverallconfirmedresponserate

(asassessedbyindependentreview)SecondaryendpointsPFStimeOStimeRateofcurativesurgeryformetastasesSafetyERBITUX+FOLFOX4a400mg/m2initialIVinfusion(day1)then250mg/m2weekly+oxaliplatin85mg/m2+5-FU/LVevery2weeksFOLFOX4aOxaliplatin85mg/m2+5-FU/LVevery2weeksEGFR-detectablemCRCRStratificationby:

ECOGPS0/1,2BokemeyerC,etal.JClinOncol2008;26(Suppl.abstract4000)aTreatmentuntilprogression,symptomaticdeteriorationorunacceptabletoxicityOPUS:StudydesignPrimaryendPhaseIIOPUStrial:KRASanalysisObjectiveToretrospectivelyinvestigatetheimpactoftheKRASmutationstatusoftumorsontheresponserateandPFSinthefirst-linetreatmentofmCRCwithFOLFOX±ERBITUXBokemeyerC,etal.JClinOncol2008;26(Suppl.abstract4000)PhaseIIOPUStrial:KRASanalKRASevaluablepopulation233(69%)subjects:KRASevaluablepopulation134(58%)KRASwild-type99(42%)KRASmutantGroupA:52(53%)GroupB:47(47%)337subjects(ITT)GroupA:61(46%)GroupB:73(54%)FOLFOXERBITUX+FOLFOXBokemeyerC,etal.JClinOncol2008;26(Suppl.abstract4000)KRASevaluablepopulation233(PatientdemographicsatbaselineBokemeyerC,etal.JClinOncol2008;26(Suppl.abstract4000)PatientdemographicsatbaseliKRASwild-type:n=134(58%)KRASmutant:n=99(42%)p=0.011p=0.16RoleofKRASstatusinresponserateBokemeyerC,etal.JClinOncol2008;26(Suppl.abstract4000)37614933KRASwild-type:n=134(58%)KRARelatingKRASstatustoefficacy

Secondaryendpoint:PFS–KRASwild-type0.51.00.40.30.20.10.00.60.70.80.9802461012MonthsKRASwild-type:HR=0.57;p=0.016

mPFSERBITUX+FOLFOX:7.7months

mPFSFOLFOX:7.2monthsProgression-freesurvivalestimateFOLFOXERBITUX+FOLFOXBokemeyerC,etal.JClinOncol2008;26(Suppl.abstract4000)RelatingKRASstatustoefficaRelatingKRASstatustoefficacy

Secondaryendpoint:PFS–KRASmutantKRASmutantHR=1.83;p=0.0192

mPFSERBITUX+FOLFOX:5.5months

mPFSFOLFOX:8.6monthsFOLFOXERBITUX+FOLFOX0.51.00.40.30.20.10.00.60.70.80.9802461012MonthsProgression-freesurvivalestimateBokemeyerC,etal.JClinOncol2008;26(Suppl.abstract4000)RelatingKRASstatustoefficaRelatingKRASstatustoefficacy:

Progression-freesurvival0.51.00.40.30.20.10.00.60.70.80.9802461012PFSestimateTime(months)ERBITUX+

FOLFOXwild-typeERBITUX+

FOLFOXmutant0.51.00.40.30.20.10.00.60.70.80.9802461012Time(months)FOLFOXwild-typeFOLFOXmutantERBITUX+FOLFOX

HR=0.45;p=0.0009

mPFSCet+FOLFOXwild-type(n=61):7.7months

mPFSCet+FOLFOXmutant(n=52):5.5monthsFOLFOX

HR=1.40;p=0.1655

mPFSFOLFOXwild-type(n=73):7.2months

mPFSFOLFOXmutant(n=47):8.6monthsPFSestimateBokemeyerC,etal.JClinOncol2008;26(Suppl.abstract4000)RelatingKRASstatustoefficaMostcommongrade3/4AEsaTherewasnograde4acne-likerashBokemeyerC,etal.JClinOncol2008;26(Suppl.abstract4000)Mostcommongrade3/4AEsaTherConclusions:OPUSstudyTheadditionofERBITUXtoFOLFOXincreasedtheresponserateby10%(46%vs36%)InpatientswithKRASwild-typetumors,additionofERBITUXtoFOLFOXresultedinasignificantandrelevantimprovementin:Responserate(61%vs37%;p=0.011)PFS(HR=0.57;p=0.016)Conclusions:OPUSstudyTheadd1.VanCutsemE,etal.JClinOncol2008;26(AbstractNo.2);2.BokemeyerC,etal.JClinOncol2008;26(AbstractNo.4000)ERBITUX+CTinKRASwild-type:ConsistentresultsResponserate(%)5937010203040506070CRYSTAL1(n=348)OPUS2

(n=134)4361FOLFIRIFOLFOXERBITUX+FOLFIRIERBITUX

+FOLF0XCRYSTAL–KRASwild-type:HR=0.68p=0.01732%riskreduction

forprogressionOPUS–KRASwild-type:HR=0.57p=0.01643%riskreduction

forprogression0.00.10.20.30.40.50.60.70.80.91.0024681012141618Time(months)PFSestimate0.00.10.20.30.40.50.60.70.80.91.0024681012Time(months)PFSestimate1.VanCutsemE,etal.JClinERBITUXinpretreatedmCRCERBITUXinpretreatedmCRCEvidenceofcorrelationbetweenKRASwild-typeandEGFRinhibitorefficacyinchemorefractoryCRC:ResponseNCICCTGCO.17KarapetisC,etal.WCGIC2008June2810:45SessionXVIIEvidenceofcorrelationbetweeRoleofKRASmutationsinpredictingresponse,progression-freesurvivalandoverallsurvivalinirinotecan-refractorypatientstreatedwithcetuximabplusirinotecanforametastaticcolorectalcancer:Analysisof281individualdata

frompublishedseries

AbstractO-018–WorldCongressGICancer–Barcelona2008

DiFioreF(1),VanCutsemE(1),Laurent-PuigP(2),SienaS(3),FrattiniM(4),DeRoockW(1),LievreA(2),Sartore-BianchiA(3),BardelliA(5),TejparS(1)

(1)DigestiveOncologyUnit,UniversityHospitalGasthuisberg,Leuven-Belgium;(2)InstitutNationaldelaSantéetdelaRechercheMédicaleU775,UniversitéParis-Descartes,Paris-France;(3)DivisioneOncologiaMedicaFalck,OspedaleNiguardaCa’Granda,Milan-Italy;(4)InstituteOfPathology,Locarno-Switzerland;(5)LaboratoryofMolecularGeneticsInstituteforCancerResearchandTreatment,UniversityofTorinoMedicalSchool,Torino-Italy

RoleofKRASmutationsinpredResponsetocetuximab-IrinotecanaccordingtoKRASstatus(n=281)DiFioreF,VanCutsemEetal,WCGICBarcelona,AnnOncol,2008abstractO-018MetaanalysisinchemorefractoryCRCResponsetocetuximab-Irinotec6MetaanalysisinchemorefractoryCRCPFSaccordingtoKRASstatusDiFioreF,VanCutsemEetal,WCGICBarcelona,AnnOncol,2008abstractO-0186MetaanalysisinchemorefractoOSaccordingtoKRASstatusMetaanalysisinchemorefractoryCRCDiFioreF,VanCutsemEetal,WCGICBarcelona,AnnOncol,2008abstractO-018OSaccordingtoKRASstatusMetOverallsurvivalaccordingtoKRASmutationandskintoxicityTime(months)1.000.750.500.250.000102030p=0.000815.6months(95%CI:10.9–22)10.7months(95%CI:8.3–16.3)5.6months(95%CI:2.8–10.6)Survivalprobability2goodprognosticfactors(wild-typeandgrade2/3skintoxicity)

0goodprognosticfactors(KRASmutantandgrade0/1skintoxicity)1goodprognosticfactor(wild-typeorgrade2/3skintoxicity)LièvreA,etal.JClinOncol2008OverallsurvivalaccordingtoNCICCO.17:randomizedphaseIIItrialEGFRtestingbyIHC

DiseaseprogressionorUnacceptabletoxicityStratification:CenterECOGPS(0or1vs2)REGISTERRANDOMIZE1:1ERBITUX+BSCBSCaloneFailedorintoleranttoallrecommendedtherapiesJonkerD,etal.NEnglJMed2008NCICCO.17:randomizedphaseIERBITUX+BSCCENSOREDBSCCENSOREDSubjectsatriskERBITUX+BSC2872171367837144000BSC285197854426128210Proportionalive00.10.20.30.40.50.60.70.80.91.0Months0369121518212427

HR0.77(95%CI:0.64,0.92)Stratifiedlog-rankp=0.0046JonkerD,etal.NEnglJMed2008NCICCTGCO.17:OverallSurvivalERBITUX+BSCCENSOREDBSCCENSORERBITUX+BSCCENSOREDBSCCENSOREDProportionprogression-free00.10.20.30.40.50.60.70.80.91.0Months03691215

HR0.68(95%CI:0.57–0.80)Stratifiedlog-rankp<0.0001JonkerD,etal.NEnglJMed2008NCICCTGCO.17:ProgressionFreeSurvivalERBITUX+BSCCENSOREDBSCCENSORNCICCTGCO.17

K-RasAnalysisGenomicDNAextractedfromFFPETslidesorsectionsAssessedbybidirectionalsequencingforcodon12/13mutationsNodifferencebetweenK-rasmutatedandWTpatientsre:demographics,previoustreatmentorothervariablesN=572randomized:ITTsubsetN=394:K-rasassessedsubset(69%)N=164(42%)mutantN=230(58%)wild-typeKarapetisCetal,WCGICBarcelona,2008NCICCTGCO.17K-RasAnalysisGComparisonofITTandK-rasassessedsubsets*betweenmutatedandwild-typeK-RASgroupsfromchi-squaretestforcategoricalvariablesandt-testforcontinuousvariables.KarapetisCetal,WCGICBarcelona,2008ComparisonofITTandK-rasasNCICCTGC0.17:

PrimaryendpointoverallsurvivalTotalstudypopulation(ITTanalysis)K-rasassessedsubsetKarapetisCetal,WCGICBarcelona,2008NCICCTGC0.17:

PrimaryendpoNCICCTGC0.17:PFSintheMutantK-rasSubgroupHR0.9995%CI(0.73,1.35)Logrankp-value:0.96KarapetisCetal,WCGICBarcelona,2008NCICCTGC0.17:PFSintheMuNCICCTGC0.17:PFSintheK-rasWild-TypePatientsHR0.4095%CI(0.30,0.54)Logrankp-value:<0.0001KarapetisCetal,WCGICBarcelona,2008NCICCTGC0.17:PFSintheK-rNCICCTGC0.17:OverallsurvivalinK-rasMutantpatientsHR0.9895%CI(0.70,1.37)Logrankp-value:0.89KarapetisCetal,WCGICBarcelona,2008NCICCTGC0.17:OverallsurvivNCICCTGC0.17:OverallsurvivalinK-rasWild-TypepatientsHR0.55

95%CI(0.41,0.74)Logrankp-value:<0.0001KarapetisCetal,WCGICBarcelona,2008NCICCTGC0.17:Overallsurviv

NCICCTGC0.17:OverallSurvivalbyK-rasStatusinBSCARMHR1.0195%CI(0.74,1.37)Logrankp-value:0.97KarapetisCetal,WCGICBarcelona,2008

NCICCTGC0.17:OverallSurv

NCICCTGC0.17:OverallSurvivalbyK-rasStatusinBSCARMHR1.0195%CI(0.74,1.37)Logrankp-value:0.97NOPROGNOSTICIMPACTOFK-rasSTATUSKarapetisCetal,WCGICBarcelona,2008

NCICCTGC0.17:OverallSurvConclusions:pretreatedmCRCInpretreatedpatientswithmCRC,ERBITUXshowssignificantlyincreasedsurvivalbenefitaswellasaPFSbenefitinpatientswithKRASwildtypetumorsErbituxincombinationwithirinotecanismoreactivethanErbituxmonotherapyinirinotecanrefractorypatients.Thebenefitisstatisticallysignificant,butalsoclinicalrelevantConclusions:pretreatedmCRCInCrosstrialcomparison00.20.40.60.81024681012141618TimefromRandomisation(Months)ProportionAliveBSCinNCICCO17ErbituxinNCICCO17ERBITUXwithwildtypeinNCICCO17Erbitux+IriinBondERBITUX+Iriwithwildtypeinpretreatedpatients4.5m6.1m8.6m9.5m>10mCrosstrialcomparison00.20.40Resectionrateofmetastasesand

tumorresponseStudiesincludingallpatientswithmCRC(solidline)(r=0.74;p<0.001) Studiesincludingselectedpatients

(livermetastasesonly,noextrahepaticdisease)(r=0.96;p=0.002)PhaseIIIstudiesincludingallpatientswithmCRC(dashedline)(r=0.67;p=0.024)Folprecht,etal.AnnOncol2005;16:1311–1319Resectionrateofmetastasesa54%SurvivalafterprimaryorsecondaryresectionoflivermetastasesProportionSurvivingSurvivalTime(years)98765432101.9.8.7.6.5.4.3.2.1029%34%50%34%27%Resectable

(n=425)Initiallynonresectable

(n=95)Bismuthetal,199654%SurvivalafterprimaryorsCRYSTALTrial:

SurgerywithCurativeIntent*CMHtestn=599/groupn=599/groupn=134/n=122p=0.0034*oddsratio3.0[95%CI:1.4-6.5]FOLFIRIaloneERBITUX+FOLFIRINoresidualtumorinpatientswithlivermetastasesITTpopulationLiver-limiteddiseasepopulationVanCutsemetal,ASCO2007CRYSTALTrial:

SurgerywithCOncoSurgicalstrategiesinlivermetastases

frompalliativetocurative…PalliativeCurativeSurvivalTimeOncoSurgicalstrategiesinlivConclusionsKRASisthefirstmolecularmarkerusedtoselectatargetedtherapyincombinationwithastandardchemotherapyregimenERBITUXbringsaneweraoftailoredtherapytotreatmentofmCRCERBITUXincombinationwithastandardfirst-linetreatmentforpatientswithmCRCisanimportantnewoptioninpatientswithKRASwild-typetumorsConclusionsKRASisthefirstmAnewtreatmentparadigmformCRCProfessorofMedicineAssociateDirector,ClinicalResearchUSCNorrisComprehensiveCancerCenterLosAngeles,CAAnewtreatmentparadigmformAnti-EGFRantibodiesinmCRCAnti-EGFRantibodiesinmCRCComparisonofcetuximabandbevacizumabBleedingpossible,wound-healingcomplicationsNocomplicationsPerioperativeHypertension,thromboemboliceventsAcne-likeskinrash

Specificsideeffect+?++RRwithFOLFOX+++RRwithFOLFIRIFirstlineSecond/thirdlineRegistered?YesSingle-agentactivityVEGFproteinEGFreceptorAntibodyBevacizumabCetuximabCharacteristicComparisonofcetuximabandbePhaseIIICRYSTALstudy:StudydesignStratificationfactors:RegionECOGperformancestatusPopulations:Randomizedpatients(n=1217)Safetypopulation(n=1202)ITTpopulation(n=1198)FOLFIRIIrinotecan(180mg/m2)+5-FU(400mg/m2bolus+2400mg/m2

as46-hcontinuousinfusion)+LV(every2weeks)ERBITUX+FOLFIRIERBITUX(IV400mg/m2onday1,then250mg/m2weekly)

+irinotecan(180mg/m2)+5-FU(400mg/m2bolus+2400mg/m2

as46-hcontinuousinfusion)+LV(every2weeks)

REGFR-expressingmCRCVanCutsemE,etal.ASCO2007(AbstractNo.4000)PhaseIIICRYSTALstudy:StudyStudyendpointsPrimaryendpointPFStime(asassessedbyblindedindependentreview)SecondaryendpointsORR(independentlyreviewed)DCR(CR+PR+SD)OSQualityoflife(EORTCQLQ-C30)SafetyVanCutsemE,etal.ECCO2007(AbstractNo.3001)StudyendpointsPrimaryendpoin1.00.80.90.00.10.20.30.40.50.60.702468101214161820Primaryendpoint:PFS(ITTpopulation)PFSestimateVanCutsemE,etal.ASCO2007(AbstractNo.4000)PFStime(months)1-yearPFSrate:

23%vs34%FOLFIRI(n=599)ERBITUX+FOLFIRI(n=599)PFSITT:HR=0.85;p=0.048mPFSERBITUX+FOLFIRI:8.9monthsmPFSFOLFIRI:8.0months1.00.80.90.00.10.20.30.40.50.6IndependentassessmentofresponseVanCutsemE,etal.ECCO2007(AbstractNo.3001)39%47%Responserate(%)p=0.0038aaCochran–Mantel–HaenszeltestIndependentassessmentofrespKRASanalysis:ObjectiveandmethodologyToretrospectivelyinvestigatetheimpactoftheKRASmutationstatusoftumorsonPFSandRRinthefirst-linetreatmentofmCRCwithFOLFIRI±ERBITUXEfficacyanalysesrepeatedonKRASevaluablepopulationGenomicDNAisolatedfromarchivedtumormaterialParaffin-embedded,formalin-fixedtissueKRASmutationstatusofcodons12/13determinedusingquantitativePCR-basedassayVanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2)KRASanalysis:ObjectiveandmKRASevaluablepopulation587subjectsanalysedforKRASmutationstatus540(45%)subjects:KRASevaluablepopulation348(64.4%)KRASwild-type192(35.6%)KRASmutant171subjectswithevents(49.1%)GroupA:105(54.7%)GroupB:87(45.3%)101subjectswithevents(52.6%)1198subjects(ITT)GroupA:172(49.4%)GroupB:176(50.6%)FOLFIRIERBITUX+FOLFIRIVanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2)KRASevaluablepopulation587sPatientdemographicsatbaselineaccordingtoKRASstatusVanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2)PatientdemographicsatbaseliITTandKRASevaluablepopulation:ComparabilityITTpopulation(n=1198)HR=0.85

MedianPFS:ERBITUX+FOLFIRI8.9monthsvsFOLFIRI8.0monthsKRASpopulation(n=540)HR=0.82MedianPFS:ERBITUX+FOLFIRI9.2monthsvsFOLFIRI8.7months1.0PFSestimateTime(Months)0.50.40.30.20.10.60.70.80.90.0802461012141618200.51.00.40.30.20.10.60.70.90.0802461012141618200.8Time(Months)PFSestimateERBITUX+FOLFIRIFOLFIRIVanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2)ITTandKRASevaluablepopulatFirst-lineERBITUX+FOLFIRI:

CorrelationofKRASstatuswithefficacyFirst-linetreatment:ERBITUX(6weeksmonotherapy),followedbyERBITUX+FOLFIRI(n=52)TaberneroJetal,ASCOGI2008First-lineERBITUX+FOLFIRI:RelatingKRASstatustoefficacy

Primaryendpoint:PFS–KRASwild-type0.00.10.20.30.40.50.60.70.80.91.0024681012141618MonthsProgression-freesurvivalestimateERBITUX+FOLFIRIFOLFIRIKRASwild-type(n=348)HR=0.68;p=0.017

mPFSERBITUX+FOLFIRI:9.9months

mPFSFOLFIRI:8.7months1-yearPFSrate25%vs43%VanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2)RelatingKRASstatustoefficaRelatingKRASstatustoefficacy

Primaryendpoint:PFS–KRASmutantKRASmutant(n=192)HR=1.07;p=0.75

mPFSERBITUX+FOLFIRI:7.6months

mPFSFOLFIRI:8.1months0246810121416MonthsERBITUX+FOLFIRIFOLFIRI0.00.10.20.30.40.50.60.70.80.91.0Progression-freesurvivalestimateVanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2)RelatingKRASstatustoefficaRelatingKRASstatustoefficacy:PFSERBITUX+FOLFIRI

HR=0.63(p=0.007)

MedianPFS:Wild-type(n=172)9.9months

vsmutant(n=105)7.6monthsFOLFIRI

HR=0.97(p=0.87)

MedianPFS:Wild-type(n=176)8.7months

vsmutant(n=87)8.1months0.51.00.40.30.20.10.00.60.70.80.9802461016PFSestimateTime(months)ERBITUX+

FOLFIRIwild-typeERBITUX+

FOLFIRImutant12140.51.00.40.30.20.10.00.60.70.80.9Time(months)FOLFIRIwild-typeFOLFIRImutant8024610161214PFSestimateVanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2)RelatingKRASstatustoefficaRelatingKRASstatustoefficacy

Secondaryendpoint:Responsep=0.0025aFOLFIRIERBITUX

+FOLFIRIaCochran-Mantel-Haenszel(CMH)testKRASwild-type(n=348)KRASmutant(n=192)p=0.46aFOLFIRIERBITUX

+FOLFIRIVanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2)RelatingKRASstatustoefficaRelatingKRASstatustooutcome:

Mostcommongrade3/4adverseeventsaTherewasnograde4acne-likerashVanCutsemE,etal.JClinOncol2008;26(Suppl.abstract2)RelatingKRASstatustooutcomConclusions:CRYSTALstudyAddingERBITUXtoFOLFIRIinmCRCleadstoasignificantincreaseinPFS(HR=0.85;p=0.048)ThebenefitofERBITUX+FOLFIRIisgreaterinpatientswithKRASwild-typetumors:PFS(HR=0.68;p=0.017)Responserate59%vs43%(p=0.0025)Thegrade3/4adverse-eventprofilewassimilarintheKRASwild-typeandmutantpopulationsConclusions:CRYSTALstudyAddiOPUS:StudydesignPrimaryendpointOverallconfirmedresponserate

(asassessedbyindependentreview)SecondaryendpointsPFStimeOStimeRateofcurativesurgeryformetastasesSafetyERBITUX+FOLFOX4a400mg/m2initialIVinfusion(day1)then250mg/m2weekly+oxaliplatin85mg/m2+5-FU/LVevery2weeksFOLFOX4aOxaliplatin85mg/m2+5-FU/LVevery2weeksEGFR-detectablemCRCRStratificationby:

ECOGPS0/1,2BokemeyerC,etal.JClinOncol2008;26(Suppl.abstract4000)aTreatmentuntilprogression,symptomaticdeteriorationorunacceptabletoxicityOPUS:StudydesignPrimaryendPhaseIIOPUStrial:KRASanalysisObjectiveToretrospectivelyinvestigatetheimpactoftheKRASmutationstatusoftumorsontheresponserateandPFSinthefirst-linetreatmentofmCRCwithFOLFOX±ERBITUXBokemeyerC,etal.JClinOncol2008;26(Suppl.abstract4000)PhaseIIOPUStrial:KRASanalKRASevaluablepopulation233(69%)subjects:KRASevaluablepopulation134(58%)KRASwild-type99(42%)KRASmutantGroupA:52(53%)GroupB:47(47%)337subjects(ITT)GroupA:61(46%)GroupB:73(54%)FOLFOXERBITUX+FOLFOXBokemeyerC,etal.JClinOncol2008;26(Suppl.abstract4000)KRASevaluablepopulation233(PatientdemographicsatbaselineBokemeyerC,etal.JClinOncol2008;26(Suppl.abstract4000)PatientdemographicsatbaseliKRASwild-type:n=134(58%)KRASmutant:n=99(42%)p=0.011p=0.16RoleofKRASstatusinresponserateBokemeyerC,etal.JClinOncol2008;26(Suppl.abstract4000)37614933KRASwild-type:n=134(58%)KRARelatingKRASstatustoefficacy

Secondaryendpoint:PFS–KRASwild-type0.51.00.40.30.20.10.00.60.70.80.9802461012MonthsKRASwild-type:HR=0.57;p=0.016

mPFSERBITUX+FOLFOX:7.7months

mPFSFOLFOX:7.2monthsProgression-freesurvivalestimateFOLFOXERBITUX+FOLFOXBokemeyerC,etal.JClinOncol2008;26(Suppl.abstract4000)RelatingKRASstatustoefficaRelatingKRASstatustoefficacy

Secondaryendpoint:PFS–KRASmutantKRASmutantHR=1.83;p=0.0192

mPFSERBITUX+FOLFOX:5.5months

mPFSFOLFOX:8.6monthsFOLFOXERBITUX+FOLFOX0.51.0