晚期肠癌靶向治疗进展-徐瑞华教授

晚期肠癌靶向治疗进展徐瑞华MD&PhD中山大学肿瘤医院内科主要内容以分子指标为指导的靶向治疗时代的来临多个靶向药物联合的重新定位靶向药物治疗的广泛研究ERBITUXinfirst-linetreatmentofmCRCPhaseIIICRYSTALstudy: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)1.00.80.90.00.10.20.30.40.50.60.702468101214161820Primaryendpoint: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:8.0monthsIndependentassessmentofresponse

OutcomeFOLFIRI

(n=599)

(%)ERBITUX

+FOLFIRI

(n=599)

(%)CRPRSDPD0.338.446.79.00.546.437.48.8ORR

[95%CI]38.7

[34.8–42.8]46.9

[42.9–51.0]DCR85.484.3VanCutsemE,etal.ECCO2007(AbstractNo.3001)39%47%Responserate(%)p=0.0038aaCochran–Mantel–HaenszeltestKRASanalysis:ObjectiveandmethodologyToretrospectivelyinvestigatetheimpactoftheKRASmutationstatusoftumorsonPFSandRRinthefirst-linetreatmentofmCRCwithFOLFIRI±ERBITUXEfficacyanalysesrepeatedonKRASevaluablepopulationGenomicDNAisolatedfromarchivedtumormaterialParaffin-embedded,formalin-fixedtissueKRASmutationstatusofcodons12/13determinedusingquantitativePCR-basedassayVanCutsemE,etal.JClinOncol2021;26(Suppl.abstract2)KRASevaluablepopulation587subjectsanalysedforKRASmutationstatus540(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.JClinOncol2021;26(Suppl.abstract2)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.JClinOncol2021;26(Suppl.abstract2)RelatingKRASstatustoefficacy

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.JClinOncol2021;26(Suppl.abstract2)RelatingKRASstatustoefficacy: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.JClinOncol2021;26(Suppl.abstract2)RelatingKRASstatustoefficacy

Secondaryendpoint:Responsep=0.0025aFOLFIRIERBITUX

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

+FOLFIRIVanCutsemE,etal.JClinOncol2021;26(Suppl.abstract2)RelatingKRASstatustooutcome:

Mostcommongrade3/4adverseeventsKRASwild-typeKRASmutantAdverseevents,%FOLFIRI

(n=176)

ERBITUX+FOLFIRI(n=173)

FOLFIRI

(n=87)

ERBITUX+FOLFIRI(n=105)

AnyNeutropenia50.616.578.025.455.223.072.421.9

–FebrileneutropeniaDiarrhea0.69.10.617.3012.63.813.3Vomiting2.84.66.92.9Fatigue4.52.32.39.5Acne-likerasha016.2017.1Infusion-relatedreactions01.703.8aTherewasnograde4acne-likerashVanCutsemE,etal.JClinOncol2021;26(Suppl.abstract2)Conclusions: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-typeandmutantpopulationsOPUS:StudydesignPrimaryendpointOverallconfirmedresponserate

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

ECOGPS0/1,2BokemeyerC,etal.JClinOncol2021;26(Suppl.abstract4000)aTreatmentuntilprogression,symptomaticdeteriorationorunacceptabletoxicityKRASevaluablepopulation233(69%)subjects:KRASevaluablepopulation134(58%)KRASwild-type99(42%)KRASmutantGroupA:52(53%)GroupB:47(47%)337subjects(ITT)GroupA:61(46%)GroupB:73(54%)FOLFOXERBITUX+FOLFOXBokemeyerC,etal.JClinOncol2021;26(Suppl.abstract4000)KRASwild-type:n=134(58%)KRASmutant:n=99(42%)p=0.011p=0.16RoleofKRASstatusinresponserateBokemeyerC,etal.JClinOncol2021;26(Suppl.abstract4000)37614933RelatingKRASstatustoefficacy

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.JClinOncol2021;26(Suppl.abstract4000)RelatingKRASstatustoefficacy

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.JClinOncol2021;26(Suppl.abstract4000)RelatingKRASstatustoefficacy:

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.JClinOncol2021;26(Suppl.abstract4000)Mostcommongrade3/4AEsKRASwild-typeKRASmutantAdverseevent,%FOLFOX

(n=73)ERBITUX

+FOLFOX

(n=61)FOLFOX

(n=47)ERBITUX

+FOLFOX

(n=52)Any

Neutropenia–Febrileneutropenia63.0

32.91.483.6

41.0078.7

44.74.367.3

25.00Diarrhea5.511.512.85.8Peripheralsensoryneuropathy8.2

4.9

2.1

3.8

Acne-likerasha014.8011.5Infusion-relatedreactions0

1.4

0

7.7

aTherewasnograde4acne-likerashBokemeyerC,etal.JClinOncol2021;26(Suppl.abstract4000)Conclusions:OPUSstudyTheadditionofERBITUXtoFOLFOXincreasedtheresponserateby10%(46%vs36%)InpatientswithKRASwild-typetumors,additionofERBITUXtoFOLFOXresultedinasignificantandrelevantimprovementin:Responserate(61%vs37%;p=0.011)PFS(HR=0.57;p=0.016)1.VanCutsemE,etal.JClinOncol2021;26(AbstractNo.2);2.BokemeyerC,etal.JClinOncol2021;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)PFSestimateERBITUXinpretreatedmCRCEvidenceofcorrelationbetweenKRASwild-typeandEGFRinhibitorefficacyinchemorefractoryCRC:ResponseReferenceTreatment

No.ofpatients(wild-type:mutant)Objectiveresponse,

n(%)Wild-typeMutantLièvreA,etal.

(JClinOncol2008)ERBITUX±CT114(78:36)34(44)0(0)BenvenutiS,etal.

(CancerRes2007)

PanitumumaborERBITUXorERBITUX+CT48(32:16)10(31)1(6)DeRoockW,VanCutsemE,TejparSetal.(AnnOnc2008)ERBITUXor

ERBITUX+irinotecan113(67:46)27(41)0(0)FinocchiaroGetal.

(ASCOProceedings2007)ERBITUX±CT81(49:32)13(26)2(6)DiFioreFetal.

(BrJCancer2007)ERBITUX+CT59(43:16)12(28)0(0)Khambata-FordSetal.

(JClinOncol2007)ERBITUX80(50:30)5(10)0(0)AmadoR,VanCutsemEetal.(JClinOncol2008)Panitumumab208(124:84)21(17)0(0)NCICCTGCO.17KarapetisC,etal.WCGIC2021June2810:45SessionXVIIRoleofKRASmutationsinpredictingresponse,progression-freesurvivalandoverallsurvivalinirinotecan-refractorypatientstreatedwithcetuximabplusirinotecanforametastaticcolorectalcancer:Analysisof281individualdata

frompublishedseries

AbstractO-018–WorldCongressGICancer–Barcelona2021

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

ResponsenKRASmutation(n)KRASWT(n)Completeresponse(CR)30(0)3(1.6)Partialresponse(PR)740(0)74(40.6)Stabledisease(SD)10741(41.4)66(36.3)Progressivedisease(PD)9758(58.6)39(21.5)Responsetocetuximab-IrinotecanaccordingtoKRASstatus(n=281)DiFioreF,VanCutsemEetal,WCGICBarcelona,AnnOncol,2021abstractO-018Meta-analysisinchemorefractoryCRC6Meta-analysisinchemorefractoryCRCPFSaccordingtoKRASstatusDiFioreF,VanCutsemEetal,WCGICBarcelona,AnnOncol,2021abstractO-018Meta-analysisinchemorefractoryCRCOSaccordingtoKRASstatusDiFioreF,VanCutsemEetal,WCGICBarcelona,AnnOncol,2021abstractO-018OverallsurvivalaccordingtoKRASmutationandskintoxicityTime(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.JClinOncol2021NCICCO.17:randomizedphaseIIItrialEGFRtestingbyIHC

DiseaseprogressionorUnacceptabletoxicityStratification:CenterECOGPS(0or1vs2)REGISTERRANDOMIZE1:1ERBITUX+BSCBSCaloneFailedorintoleranttoallrecommendedtherapiesJonkerD,etal.NEnglJMed2021ERBITUX+BSCCENSOREDBSCCENSOREDSubjectsatriskERBITUX+BSC2872171367837144000BSC285197854426128210Proportionalive00.10.20.30.40.50.60.70.80.91.0Months0369121518212427

HR0.77(95%CI:0.64,0.92)Stratifiedlog-rankp=0.0046StudyarmMS95%CIERBITUX+BSC6.1months5.4,6.7BSCalone4.6months4.2,4.9JonkerD,etal.NEnglJMed2021NCICCTGCO.17:OverallSurvivalERBITUX+BSCCENSOREDBSCCENSOREDProportionprogression-free00.10.20.30.40.50.60.70.80.91.0Months03691215

HR0.68(95%CI:0.57–0.80)Stratifiedlog-rankp<0.0001StudyarmMedPFS95%CIERBITUX+BSC1.9months1.8,2.1BSCalone1.8months1.8,1.9JonkerD,etal.NEnglJMed2021NCICCTGCO.17:ProgressionFreeSurvivalNCICCTGCO.17

K-RasAnalysisGenomicDNAextractedfromFFPETslidesorsectionsAssessedbybidirectionalsequencingforcodon12/13mutationsNodifferencebetweenK-rasmutatedandWTpatientsre:demographics,previoustreatmentorothervariablesN=572randomized:ITTsubsetN=394:K-rasassessedsubset(69%)N=164(42%)mutantN=230(58%)wild-typeKarapetisCetal,WCGICBarcelona,2021NCICCTGC0.17:PFSintheMutantK-rasSubgroupHR0.9995%CI(0.73,1.35)Logrankp-value:0.96StudyarmMedPFS(months)95%CICetuximab+BSC1.81.7–1.8BSCalone1.81.7–1.8KarapetisCetal,WCGICBarcelona,2021NCICCTGC0.17:PFSintheK-rasWild-TypePatientsHR0.4095%CI(0.30,0.54)Logrankp-value:<0.0001StudyarmMedPFS(months)95%CICetuximab+BSC3.83.1–5.1BSCalone1.91.8–2.0KarapetisCetal,WCGICBarcelona,2021NCICCTGC0.17:OverallsurvivalinK-rasMutantpatientsHR0.9895%CI(0.70,1.37)Logrankp-value:0.89StudyarmMS(months)95%CICetuximab+BSC4.53.8–5.6BSCalone4.63.6–5.5KarapetisCetal,WCGICBarcelona,2021NCICCTGC0.17:OverallsurvivalinK-rasWild-TypepatientsHR0.55

95%CI(0.41,0.74)Logrankp-value:<0.0001StudyarmMS(months)95%CICetuximab+BSC9.57.7–10.3BSCalone4.84.2–5.5KarapetisCetal,WCGICBarcelona,2021

NCICCTGC0.17:OverallSurvivalbyK-rasStatusinBSCARMHR1.0195%CI(0.74,1.37)Logrankp-value:0.97KRASstatusMS(months)95%CIMutated4.63.6–5.5Wild-Type4.84.2–5.5KarapetisCetal,WCGICBarcelona,2021

NCICCTGC0.17:OverallSurvivalbyK-rasStatusinBSCARMHR1.0195%CI(0.74,1.37)Logrankp-value:0.97KRASstatusMS(months)95%CIMutated4.63.6–5.5Wild-Type4.84.2–5.5NOPROGNOSTICIMPACTOFK-rasSTATUSKarapetisCetal,WCGICBarcelona,2021Conclusions:pretreatedmCRCInpretreatedpatientswithmCRC,ERBITUXshowssignificantlyincreasedsurvivalbenefitaswellasaPFSbenefitinpatientswithKRASwildtypetumorsErbituxincombinationwithirinotecanismoreactivethanErbituxmonotherapyinirinotecanrefractorypatients.Thebenefitisstatisticallysignificant,butalsoclinicalrelevantCrosstrialcomparison00.20.40.60.81024681012141618TimefromRandomisation(Months)ProportionAliveBSCinNCICCO17ErbituxinNCICCO17ERBITUXwithwildtypeinNCICCO17Erbitux+IriinBondERBITUX+Iriwithwildtypeinpretreatedpatients4.5m6.1m8.6m9.5m>10mConclusionsKRASisthefirstmolecularmarkerusedtoselectatargetedtherapyincombinationwithastandardchemotherapyregimenERBITUXbringsaneweraoftailoredtherapytotreatmentofmCRCERBITUXincombinationwithastandardfirst-linetreatmentforpatientswithmCRCisanimportantnewoptioninpatientswithKRASwild-typetumors主要内容以分子指标为指导的靶向治疗时代的来临多个靶向药物联合的重新定位靶向药物治疗的广泛研究InterimresultsfromPACCE–irinotecan+bevacizumab±panitumumabforfirst-linetreatmentofmCRC–studydesignHechtJ,etal.Abstract279S

C

R

E

EN

I

N

GR

A

N

D

O

M

I

Z

EOx-basedCT

(e.g.FOLFOX)

N=800

invchoiceIn-basedCT

(e.g.FOLFIRI)

N=200

invchoicePanitumumab

6mg/kgQ2W

Ox-CT

BevacizumabPanitumumab

6mg/kgQ2W

Iri-CT

BevacizumabOx-CT

BevacizumabIri-CT

Bevacizumab1:11:1InterimresultsfromPACCE–irinotecan+bevacizumab+/-panitumumabforfirst-linetreatmentofmCRC–medianPFS(centralreview)HechtJ,etal.Abstract279100806040200PFS(%) 0 5 10 15 20 25Time(days)Panitumumab+Bevacizumab/Iri-CTBevacizumab/Iri-CT*PFSevents(%)Median(95%CI

months54(47)10.1(8.2–13.1)43(37)11.1(9.0–13.2)HR=1.2(95%CI:0.80–1.82)**DescriptiveonlyBACKInterimresultsfromPACCE–irinotecan+bevacizumab±panitumumabforfirst-linetreatmentofmCRC–responsebyKRASstatusHechtJ,etal.Abstract279NPmab+Bev/iri-CT

n/N(%)Bev/iri-CT

n/N(%)Oddsratio(95%CI)Wild-typeKRAS11531/57(54)27/58(47)1.42(0.63–3.21)MutantKRAS8514/46(30)15/39(38)0.59(0.23–1.55)BACK 0 5 10 15 20 25InterimresultsfromPACCE–oxaliplatin+bevacizumab+/-panitumumabforfirst-linetreatmentofmCRC–PFS(centralreview)HechtJR,etal.Abstract273100806040200PFS

events(%)Median

(95%CI)monthspmab+bev/Ox-CT599.6(8.8–10.9)bev/Ox-CT5211.1(10.3–11.9)HR=1.27(95%CI:1.05–1.53)*

*DescriptiveonlyTime(months)PFS(%)BACKSurviving(%)InterimresultsfromPACCE–oxaliplatin+bevacizumab+/-panitumumabforfirst-linetreatmentofmCRC–OS(centralreview)HechtJR,etal.Abstract273 0 6 12 18 24100806040200Time(months)Death

eventsn(%)Median

(95%CI),monthspmab+bev/Ox-CT143(35)19.4(18.4–20.8bev/Ox-CT108(26)NEHR=1.43(95%CI:1.11–1.83)*

*Descriptiveonly.Statisticalsignificanceislimitedbythelack

ofaprespecifiedsignificanceboundaryInteri