ASCO2011结直肠癌更新.pptx

ASCO2011-UpdatesinColorectalCancer-AxelGrotheyProfessorofOncologyMayoClinicRochesterNoteworthyatASCOforCRC?Nopractice-changinginformation,butconfirmationofstandardsofcareEarlyrectalcancer:CapecitabinecanbeusedasradiosensitizerinneoadjuvanttherapyAdditionofoxaliplatinmoretoxic,noincreaseinpCRrateIstherearoleforTNT(TotalNeoadjuvantTherapy)?NoteworthyatASCOforCRC?Earlycoloncancer:ValueofoxaliplatinasadjuvanttherapyinstageIIcancersdebatablePalliativetherapyofCRC:IGF-R1inhibitorsconclusivelyineffectiveNotallKRASmutationsarecreatedequalAflibercept(VEGF-TRAP)isactiveandimprovesOSin2ndlineaddedtoFOLFIRI(tobepresentedinBarcelona)TheImpactofCapecitabineandOxaliplatininthePreoperativeMultimodalityTreatmentofPatientswithCarcinomaoftheRectum:NSABPR-04MSRoh,GAYothers,MJOConnell,RWBeart,HCPitot,AFShields,DSParda,SSharif,CJAllegra,NJPetrelli,JCLandry,DPRyan,AArora,TLEvans,GSSoori,LChu,RVLandes,MMohiuddin,SLopa,NWolmark1400PatientsGroup 4Capecitabine 825 mg/m2 PO BID+Oxaliplatin 50 mg/m2/week X 5+4600cGy+540-1080cGyAdenocarcinoma of rectum amenable to surgical resection located 12 cm from anal vergeSTRATIFICATIONGenderClinical Tumor Stage II or IIIIntent for Type of Surgery(sphincter saving;non-sphincter saving)RANDOMIZATIONGroup 3Capecitabine 825 mg/m2 PO BID+4600cGy+540-1080cGyGroup 25FU(CVI 225mg/m2 5d/week)+Oxaliplatin 50 mg/m2/week X 5+4600cGy+540-1080cGyGroup 15FU(CVI 225mg/m2 5d/week)+4600cGy+540-1080cGySURGERYSURGERYRohetal.ASCO2011GastrointestinalToxicity5-FuorCAPEvsadditionofOxaliplatinGIToxicity*NoOxaliOxaliTotalGrade3diarrhea5815341115Grade3/4diarrhea4197138TotalPatients6226311253Incidence(%)6.615.4P-value0.0001OxaliNoOxali0.040.080.120.160.2*CTCAEVersion3.0Rohetal.ASCO2011SurgicalDownstaging(SD)byTreatment5-FUvsCapecitabineSDStatus5-FUCapeTotalwithoutSD149144293withSD394382TotalPatients*188187375SDRate(%)95%CI20.715.2-27.223.017.2-29.7P-value.62*Restrictedtopatientswithoutpre-trialintentforSSS5-FUCape0.150.20.250.3Rohetal.ASCO2011SurgicalDownstaging(SD)byTreatmentOxaliplatinvsNoneSDStatusNoOxaliOxaliTotalwithoutSD117122239withSD352964TotalPatients*152151303SDRate(%)95%CI23.016.6-30.519.213.3-26.4P-value.48*Restrictedtopatientswithoutpre-trialintentforSSSNoOxaliOxali0.10.150.20.250.30.35Rohetal.ASCO2011PathologicCompleteResponsebyTreatment5-FUvsCapecitabinepCRStatus5-FUCapeTotalwithoutpCR5845501134withpCR135157292TotalPatients7197071426pCRRate(%)95%CI18.816.0-21.822.219.2-25.5P-value.125-FUCape0.140.160.180.20.220.240.26Rohetal.ASCO2011PathologicCompleteResponsebyTreatmentOxaliplatinvsNonepCRStatusNoOxaliOxaliTotalwithoutpCR469457926withpCR111121232TotalPatients5805781158pCRRate(%)95%CI19.116.0-22.620.917.7-24.5P-value0.46NoOxaliOxali0.160.180.20.220.240.26Rohetal.ASCO2011NSABPR-04ConclusionsAdministration of capecitabine with preoperative RT achieved rates similar to continuous infusion 5-FU forSurgical downstagingSphincter saving surgeryPathologic complete responseAddition of oxaliplatin did not improve outcomes and added significant toxicityLonger follow up will be needed to assess local-regional tumor relapse,DFS and OSRohetal.ASCO2011Capecitabineversus5-fluorouracil-based(neo-)adjuvantchemo-radiotherapyforlocallyadvancedrectalcancer:LongtermresultsofarandomizedphaseIIItrialR.Hofheinz,F.Wenz,S.Post,A.Matzdorff,S.Laechelt,J.Hartmann,L.Mller,H.Link,M.H.Moehler,E.Kettner,E.Fritz,U.Hieber,H.W.Lindemann,M.Grunewald,S.Kremers,C.Constantin,M.Hipp,D.Gencer,I.Burkholder,A.Hochhaus,on behalf of the German MARGIT study groupTreatmentregimenArmAChemoradiotherapy50.4 Gy+Cape 1,650 mg/m days 1 38 N=197plus 5 cycles of Cape 2,500 mg/m d 1 14,rep.d 22 S I:2 x Cape CRT 3 x Cape S II:CRT TME surgery(4 6 weeks after CRT)Cape x 5 ArmBChemoradiotherapy50.4 Gy+5-FU 225 mg/m c.i.daily S I or N=1955-FU 1,000 mg/m c.i.d 1 5 and 29 33 S II plus 4 cycles of bolus 5-FU 500mg/m d 1 5,rep.d 29 S I:2 x 5-FU CRT 2 x 5-FU S II:CRT TME surgery(4 6 weeks after CRT)5-FU x 4 Cape:capecitabine;CRT:chemoradiotherapy;TME:total mesorectal excision;5-FU:5-fluorouracilHofheinzetal.ASCO2011TreatmentregimenAdjuvantstratumSIArmAArmB159131721Radiotherapy50.4GyCapecitabine 2,500mg/m/day(during radiotherapy 1,650mg/m/day)Week5-FU 500mg/m day 1 5 (during radiotherapy 225 mg/m/day)Radiotherapy50.4GyHofheinzetal.ASCO2011TreatmentregimenNeodjuvantstratumSIArmAArmB15162428Week1020SurgerySurgeryCapecitabine 2,500mg/m/day(during radiotherapy 1,650mg/m/day)5-FU 500mg/m day 1 5(during radiotherapy 1000 mg/m d 1 5,d 29 33)Radiotherapy50.4GyRadiotherapy50.4GyHofheinzetal.ASCO2011NeoadjuvantstratumComparisonArmA&ArmBCapecitabine5-FUp-value(test)Typeofresection,%Deep anterior Abdominoperineal Local excisionn=7372.626.0 1.4n=7478.421.60p=0.56Resectionstatus,%R0 R1/R2 Unknownn=7295.8 4.20n=7491.9 2.7 5.4p=1.00ypT-status,%ypT 0 ypN 0(pCR)ypT 0 2 ypT 3 4 n=7313.555.444.6n=74 5.439.260.8p=0.16p=0.07pCR:pathological complete remissionHofheinzetal.ASCO2011NeoadjuvantstratumTrendofimproveddownstagingwithCapecitabinePatients receiving capecitabine exhibited less ypN-positive tumors(p=0.09)improved T-downstaging (i.e.ypT0 2)(p=0.07)more pCR(ypT0 ypN0):13.2%vs.5.4%(p=0.16)Comparison(test)ClinicalstagingPathohistologyTstatusp=0.5p=0.07Nstatusp=0.7p=0.09Hofheinzetal.ASCO2011Diseasefreesurvival(DFS)Secondaryendpoint(MedianFollow-up52mon.)Hofheinzetal.ASCO2011Overallsurvival(OS)Primaryendpoint(MedianFollow-up52mon.)Hofheinzetal.ASCO2011ConclusionsBoth treatment regimens were well tolerated.Cape patients had more all grade HFS,proctitis,diarrhea and fatigue,while alopecia and leukopenia were more frequently observed with 5-FU.In the neo-adjuvant stratum Cape led by trend to improved downstaging and a numerical higher rate of pCR.Cape was non-inferior to 5-FU regarding 5-year survival.Exploratory test for superiority was borderline significant.3-year DFS was significantly better with Cape.HFS indicated superior 3-year DFS and 5-year OS.Capecitabine may replace 5-FU in the perioperative treatment of locally advanced rectal cancer.Hofheinzetal.ASCO2011Preoperativechemoradiotherapyandpostoperativechemotherapywith5-FUandoxaliplatinversus5-FUaloneinlocallyadvancedrectalcancer:FirstresultsofCAO/ARO/AIO-04C.Rdel,H.Becker,R.Fietkau,U.Graeven,W.Hohenberger,C.Hess,T.Hothorn,M.Lang-Welzenbach,T.Liersch,L.Staib,C.Wittekind,R.Sauer German Rectal Cancer Study Group RT50.4Gy+5-FU1000 mg/m days 1-5+29-33 RT50.4Gy+5-FU/OXOx:50 mg/m d 1,8,22,295-FU:250 mg/m d 1-14+22-35 Note:Chemogap3rdweekofRT!TMEmFOLFOX6Oxaliplatin:100 mg/m d1,q15Folinic Acid:400 mg/m d15-FU:2400 mg/m d1-28cycles(4months)5-FU500 mg/m d 1-5,q294cycles(4months)PhaseIII:CAO/ARO/AIO-04Best arm of CAO/ARO/AIO-94:Based on phase I/II trials:Rdeletal.ASCO2011MainInclusionCriteria Carcinoma of rectum Within 12 cm above anal verge ECOG PS 0-2 cT3/4 and/or cN+,cM0 Staging:EUS+CT and/or MRI Rdeletal.ASCO2011Toxicity(NCI/CTCAE3.0)ComplianceofCRTPreop.CRT-5FUn=624Preop.CRT-5FU/OXn=613Overallgrade3/4(%)2223Grade3/4(%)AllgastrointestinalDiarrheaAllHematologicAllgenitourinaryNeuropathy(grade2/3)12831=5mm=N14ormore10mmnodes=N2StudySchemaNoProgressionProgressionFOLFOXx6Restage5FUCMTTMEFOLFOXx2TMEFOLFOXx6TMEFOLFOXx8RANDOMIZE:1:1“selectivearm”“standardarm”5FUCMTValueofOxaliplatinasPartofAdjuvantTherapyinStageIIColonCancer?-PooledAnalysisofNSABPTrials-Yothersetal.ASCO2011Adjusted*KM-EstimateofDFSStageIIYothersetal.ASCO2011OxaliplatinHRbyRiskGroupStageIIYothersetal.ASCO20115-YearAdjustedEstimatesYothersetal.ASCO2011DecisionAlgorithminAdjuvantTherapyResectedColonCaStageIIStageIIIFOLFOXXELOXHigh-RiskdMMRNotherapy!5-FU/LVorCapecitabine*ptsnotconsideredcandidatesforoxaliplatinT4and/or12LNsLow-RiskIntermed.Riskyesyesnono?MolecularSignatureGrothey,Oncology2010mAbsTargetTumorCell-BoundEGFRExtracellularIntracellularLigandEGF-RPI3KAktRafMEKMAPKCellMotilityMetastasisAngiogenesisProliferationCellsurvivalDNAPTENRasmAbsTargetTumorCell-BoundEGFRExtracellularIntracellularLigandEGF-RPI3KAktRafMEKMAPKCellMotilityMetastasisAngiogenesisProliferationCellsurvivalDNARasPTENKRASasBiomarkerforPanitumumabResponseinMetastaticCRCPFSlogHRsignificantlydifferentdependingonK-rasstatus(P.0001)Percentagedecreaseintargetlesiongreaterinpatientswithwild-typeKRASreceivingpanitumumabPatientsWithMutantKRASMeanin WksStratified log rank test:P .0001115/124(93)PatientsWithWild-TypeKRAS1.00.9ProportionWithPFS0.80.70.60.50.40.30.20.1002 4 6 8 10Events/N(%)Medianin WksPmab+BSCBSC alone114/119(96)12.37.319.09.3HR:0.45(95%CI:0.34-0.59)12 141618 202224262830 32 3436 38 4042444648 50 52WeeksProportionWithPFS1.00.90.80.70.60.50.40.30.20.1002 4 6 8 10 12 141618 202224262830 32 3436 38 4042444648 50WeeksPmab+BSCBSC aloneMeanin Wks76/84(90)Events/N(%)Medianin Wks95/100(95)7.47.39.910.2HR:0.99(95%CI:0.73-1.36)52Amado et al.JCO 2008Amado et al.JCO 2008NCICCTGCO.17:RandomizedPhaseIIITrialinmCRCCetuximabvsBSC(nocross-over)KRASmutKRASwild-typeAllpatientsBSCn=83Cetuxn=81BSCn=113Cetuxn=117BSCn=285Cetuxn=287RR0%1.2%0%12.8%0%6.6%PFS(mos)1.81.81.93.81.81.9OS(mos)4.64.54.89.54.66.1Karapetis et al.NEJM 2008Karapetis et al.NEJM 20080.00010.00010.00010.0046CRYSTALStudy(1stLine)FOLFIRI+CetuximabFOLFIRIEGFR-expressingmetastaticCRCPFSStratifiedby:Stratifiedby:RegionsRegions ECOGPSECOGPS PrimaryEndpoint:PFS(independentreview)PrimaryEndpoint:PFS(independentreview)SecondaryEndpoints:RR,DCR,OS,Safety,QoLSecondaryEndpoints:RR,DCR,OS,Safety,QoL SampleSize:1217patientsrandomized,ITT:1198ptsSampleSize:1217patientsrandomized,ITT:1198ptsN=599N=599N=599N=599VanCutsemetal.NEJM2009R5-FU/LV/IRI(FOLFIRI)+/-Cetuximab:PFSNon-KRASadjustedMonthsPFSestimate1.00.80.90.00.10.20.30.40.50.60.702468101214161820FOLFIRIFOLFIRI+CetuximabVanCutsemetal.NEJM2009HR=0.851P=0.04798.0vs8.9mosSubgroupeffectNobenefitCRYSTAL-KRAS wild-typemCRC(N=348):PFS0.00.10.20.30.40.50.60.70.80.91.0024681012141618MonthsProgression-freesurvivalestimateCetuximab+FOLFIRIFOLFIRIFOLFIRI+Cetuximab:9.9mosFOLFIRI:8.7mosHR=0.68,p=0.017 1-yr PFS rate25%vs 43%VanCutsemetal.NEJM2009WTKRASMTKRASMTKRASMTKRASMTKRASEGFREGFREGFREGFRANTI-EGFRANTIBODYBekaii-Saab,T.Adaptedfrommultiplesources:1-WheelerDL,etalNatRevClinOncol20107(9):493-507;2-DeRoocketal.LancetOncology,201011:753-762;3-FrattiniM,BJC200797;1139-1145;4-DiNicolantonioFetal.JournalofClinOncol200826(35);5705-5712;5-LoupakisFetal.BJC2009101;715-721;Anti-EGFRAntibodiesandKRASmutations79%18%3%?MTBRAF5-10%Others40%InVitroandInVivoEffectsoftheG13DMutationEffectofCetuximabonCellularProliferationinIsogenicCellLinesProliferationAssayonIsogenicCelllinesEffectofCetuximabonGrowthofTumorDeRoock,W.etal.JAMA2010;304:e-suppl.AreAllKRASMutationsCreatedEqual?G13DDeRoocketal.,JAMA2010RetrospectiveanalysisPatientstreatedwithinandoutsideofclinicaltrialsSometrialsrandomized,somenotVariouslinesoftherapyCetuximabsingleagent(n=10)andwithchemo(n=22)Andstillonly45patientstotal!AreAllKRASMutationsCreatedEqual?G13DTejparetal.,ASCO2011PooledanalysisofOPUSandCRYSTALBRAFMutationsinCRCBRAFisprimaryeffectorofKRASsignalingBRAFmutations:Occurmostfrequentlyinexon15(V600E)Foundin4%-14%ofpatientswithCRCMutuallyexclusivewithKRASmutationsRafMEKErkPP PPTumorcellproliferationandsurvivalEGFTumorCellRasYarden.Nat Rev Mol Cell Biol.2001;2:127;DiNicolantonio.J Clin Oncol.2008;26:5705;Artale.J Clin Oncol.2008;26:4217.Wild-typeBRAFisrequiredforresponsetoEGFRinhibitorsinmCRCDiNicolantonioetal.,JClinOncol2008BRAFwild-typeBRAFmutantp=0.0010PatientswithKRASwild-typestatus100806040200OS(%)0200400600800 1,000 1,2001,400BRAFwild-typeBRAFmutantp0.0001Timesincestartoftreatment(days)Timesincestartoftreatment(days)100806040200PFS(%)0100 200 300 400 500 600 700 800 900CRYSTALtrialupdate:outcomeinKRAS wild-type/BRAFmutatedmCRCKRASwt/BRAFwt(n=566)KRASwt/BRAF mt(n=59)FOLFIRI(n=289)FOLFIRI+Cetuximab(n=277)FOLFIRI(n=33)FOLFIRI+Cetuximab(n=26)mOS(mo)21.625.110.314.1HR 95%CIp-valuea0.83 0.6871.0040.05490.91 0.5071.6240.7440 mPFS(mo)8.810.95.68.0HR 95%CIp-valuea0.68 0.5330.8640.00160.93 0.4252.0560.8656RR(%)95%CI42.636.848.561.055.066.815.25.131.919.26.639.4p-valueb80%forallcomponentsMedianf/u:22.3mos(863deaths)VanCutsem,etal.WCGC2011VELOUR:SideeffectsGrade3/4AdverseEventswith2%higherincidenceinAFLvsPLarm:Diarrhea,asthenia/fatigue,stomatitis/ulceration,infection,hypertension,GI/abdominalpain,neutropenia/neutropeniccomplications,proteinuriaAEsleadingtotreatmentdiscontinuation:AFL:26.6%PL:12.1%VanCutsem,etal.WCGC2011VELOUR:ResultsFOLFIRI+PLFOLFIRI+AFLN patients612614mOS(mos)12.0613.5HR0.81795%CI 0.713-0.937 p=0.0032mPFS(mos)4.676.9HR0.758p=0.00007RR(%)11.119.8P=0.0001VanCutsem,etal.WCGC2011ComparisonVELOURvsE3200VELOURE3200Prior TxOxaliplatin-based Irinotecan-based(IFL)Prior BEV30%noneArmsFOLFIRI+PLFOLFIRI+AFLHRp-valueFOLFOX+PLFOLFOX+BEVHRp-valuemOS(mos)12.0613.50.8170.003210.812.90.750.0011mPFS(mos)4.676.90.7580.000074.77.30.610.0001RR(%)11.119.80.00018.622.70.0001VanCutsem,etal.WCGC2011;Giantonio,etal.JCO2007I4T-MC-JVBBPhaseIIITrial2ndLineFOLFIRI+/-RamucirumabStratificationfactors:RegionKRASstatusFirst-lineTTP(6mos)1:1mCRCafterfailureFP/oxaliplatin+BEVregimenR525ptsRamucirumabIV+FOLFIRIq2weeks525ptsPlacebo+FOLFIRIq2weeks65PrimaryEP:OSPIs:Tabernero,GrotheyCytokineincreaseonBEVtherapyKopetzetal.,JCO2010RegorafenibAMulti-KinaseInhibitorCellular Phosphorylation AssaysIC50 nMVEGFR-2Phosphorylation,293Cells8TIE2-ReceptorPhosphorylation,CHOCells31PDGFR-Phosphorylation,AorticSMCells90mVEGFR3Phosphorylation,293Cells150MutantRETPhosphorylation,ThyroidTTCells10Mutantc-KITPhosphorylation,GIST882Cells20FGF-10FGFRMCF-7Cells150-300MAPKERK-PHCC,HepG2Cells500Cell Proliferation AssaysIC50 nMVEGF/HuVEC(2%FCS)BrdU4bFGF/HuVEC(2%FCS)BrdU120PDGFBB/AorticSM(0.1%BSA)BrdU121ThyroidTTRETC643W(10%FCS)33GIST882KITK642E(10%FCS)45Breast,MDAMB231(10%FCS)570Melanoma,A375(10%FCS)900HCCHepG2(10%FCS)560RegorafenibSalvageTherapyRegistrationTrialPrimaryendpointOS:increaseOSfrom4.5to6.0months;HR=0.75Significancelevel/power:0.025(one-sided)/90%Accrualperiod(months):26(accrualrate30pat./month)Studyduration(months):31.5Totalnumberofevents:582Totalnumberofpatients:690Primaryendpoint:OSCRC3rd/4thlineRegorafenib160mgod3wkson/1wkoff+BSCPlacebo+BSC2:1randomizationAccrualcompletedFeb2011,within10mosHowACancerCellWorks