抗血管生成的在NSCLC的应用ppt课件.ppt

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1、文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。DisclosuresAdvisoryboardsforGenentechandAstraZenecaResearchsupportfromAstraZeneca文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Case#156yowomanwith15pack-yearhistorypresentswithamalignantpleuraleffusion,mediatinaladenopathy,anda3-4smallCNSmetastases.Shehasbeenhavingmil

2、dheadachesrecently.Cytologyrevealsadenocarcinoma,TTF1+EGFRmutatationtestingcouldnotbeperformedfromcellblockandadditionalbiopsyrefused.文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。SheisinitiallytreatedwithstereotacticXRTforherCNSlesionsandcomesforsystemictherapy.Whichchemotherapyregimenisnotsupportedbyrand

3、omizedphaseIIIdata?A.Carbo/pacB.Carbo/pac/BVC.Pem/cisD.Pem/carbo/BVQuestion1文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Question#1SheisinitiallytreatedwithstereotacticXRTforherCNSlesionsandcomesforsystemictherapy.WhichchemotherapyregimenisnotsupportedbyrandomizedphaseIIIdata?A.Carbo/pacB.Carbo/pac/BVC.Pe

4、m/cisD.Pem/carbo/BV文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Case#1Sheisstartedontreatmentwithcarboplatin,paclitaxel,andBVx6cycles.Shehasapartialresponse,toleratestreatmentwell,andwantstobetreatedaggressively.文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Whichmaintenancetherapyispartofaregimenthathasbeenshown

5、toprolongOSinarandomizedphaseIIIstudy?A.BVmonotherapyB.PemetrexedC.BV+PemD.BV+erlotinibE.AandBF.A,B,andDG.NomaintenancetherapyQuestion2文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Question#2WhichmaintenancetherapyispartofaregimenthathasbeenshowntoprolongOSinarandomizedphaseIIIstudy?A.BVmonotherapyB.Pemetr

6、exedC.BV+PemD.BV+erlotinibE.AandBF.A,B,andDG.Nomaintenancetherapy文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。12mo.24mo.43.7%16.9%51.9%22.1%0.00.20.40.60.81.0ProbabilityPCPCBP=0.007061218243036MonthsMedians:10.2,12.5HR:0.77(0.65,0.93)PhaseIIITrialofBevacizumabinNon-SquamousNSCLC(ECOG4599)Sandleretal,NEJM2

7、006Overall survival文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。DoesBVmaintenanceprovidebenefitinfirst-lineNSCLC?InECOG4599,60.1%completed6cyclesofCPBand48%receivedBVmaintenance.44%completed6cyclesofCPwithoutPD.Sandleretal,ProcWorldLungmeeting2011,posterP3.216BVmaintNomaintOS(m)4.42.8PFS(m)12.411.2OS(from

8、startoftx)17.316.1文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。JMEN:Outcomeinnon-squamoushistologypemetrexedvsBSCforNSCLCCiuleanuetal,Lancet,2009PFS 4.5vs2.6monthsHR0.44P.0001OS 15.5vs10.3monthsHR0.70P.002文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。ATLASstudydesignMillerVA,et al.J Clin Oncol 2009;27(Suppl1):Ab

9、stractLBA8002Post-progressiontherapyUnblind at PD1:1Bevacizumab(15 mg/kg)+erlotinib(150 mg)to PDBevacizumab+Placebo to PDPrimary endpointPFSinallrandomizedpatientsSecondary endpointsOverallsurvivalSafetyExploratory endpointsBiomarkeranalyses(IHC,FISH,EGFR&K-Rasmutation)Eligibility StageIIIB*/IVNSCLC

10、ECOGperformancestatus01Stratification factors GenderSmokinghistory(nevervsformer/current)ECOGperformancestatus(0vs1)Chemotherapyregimen*Carbo/paclitaxel;cis/vinorelbine;carboorcis/gemcitabine;carboorcis/docetaxel*IIIBwithpleuraleffusionNon-PDn=768(66%)4 cycles of 1st-line chemotherapy*+bevacizumabCh

11、emo-naveadvanced NSCLCN=1160文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。ATLASprogression-freesurvivalMillerVA,et al.J Clin Oncol 2009;27(Suppl1):AbstractLBA8002373142582715630370178814320631No.of patients at risk:Bev+placeboBev+erlotinibProgression-freesurvival(months)0369121518210.00.20.40.60.81.0Propor

12、tionwithouteventHR=0.722(0.5920.881)Log-rank p=0.0012 Bevacizumab+placebo(n=373)Bevacizumab+erlotinib(n=370)文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。ATLASupdateonoverallsurvivalA40%crossoverrate(placebopatientstoreceiveEoncediseaseprogressed)andunderpowereddesignpreventedtrialfromreachingsignificancef

13、orOSanalysis2-monthOSbenefitwasobservedintheBvandEmaintenancearmafteroccurrenceof57%eventsBiomarkeranalysisdataofATLASstudyareexpectedsoonKabbinavarFF,et al.J Clin Oncol 2010;28:15s(suppl;abstr7526)Data cut-offPatients with events,n/N(%)Median OS(months)Bv+E vs BvHR(95%CI)18July2008(pre-specified)22

14、8/743(31)14.4vs13.30.92(0.701.21)19June2009439/768*(57)15.9vs13.90.90(0.741.09)*25patientswererandomizedaftercut-offformainanalysisofPFS文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。ECOG5508:PhaseIIItrialofBV,Pem,orBV+PemasmaintenancetherapyinadvancedNSCLCCarbo/pac/BVQ3wx4cyclesEligibility-BVeligible-non-s

15、quam-chemonaive-noCNSmetsPI:S.Ramilingam;clinictrials.gov;trialNCT01107626RNon-PDBVInductionMaintenancePemBV+PemPrimaryendpoint:OSSecondary:PFS文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。S130trial:PhaseIIItrialofCP+BvBvvsPemCarbo+BvPeminfirstlineNSCLCEligibility-BVeligible-non-squam-chemonaive-treatedbra

16、inmetsSponsor:Lilly;fromclinictrials.gov;trialNCT00948675RCarboplatinpaclitaxel+BV(15mg/kg)q3wBVPemCarboplatinpemetrexedInductionMaintenancePrimaryendpoint:PFSwithoutgrade4toxicitySecondary:PFS,ORR,DCR,toxicity文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。PointBreak:phaseIIItrialofCP+BvBvvsPemCarbo+BvPem+B

17、V(SandlervsPatel)infirstlineNSCLCEligibility-BVeligible-non-squam-chemonaive-treatedbrainmetsPIJ.Patel;Pateletal,ClinLungCancer,2009RCarboplatinpaclitaxel+BV(15mg/kg)q3wBVBV+PemCarboplatinpemetrexed+BV(15mg/kg)q3wInductionMaintenanceN900Primaryendpoint:OS(superiority)Secondary:PFS,ORR,toxicity文档仅供参考

18、，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。AVAPERL1:PhaseIIIBV+Pemasmaintenanceaftercis/pem/BVinductionas1stlinetherapyCisplatinPemetrexedBV(7.5mg/kg)Q3wx4cyclesEligibility-BVeligible-non-squam-chemonaive-noCNSmetsSponsor:Hoffman-LaRoche;clinictrials.gov;trialNCT00961415RNon-PDBV(7.5mg/kg)InductionMaintenance

19、BV(7.5mg/kg)+PemetrexedPrimaryendpoint:PFSSecondary:RR,DCR,durationofresponse,OS文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Case#1continuedSheeventuallydevelopedshortnessofbreathfromarecurrentpleuraleffusion,andisfoundtohavemediastinaladenopathy.Abiopsyconfirmedthepresenceofadenocarcinoma.Mutationtesting

20、demonstratedanexon19deletioninEGFR.文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Sheisgivenaprescriptionforerlotinib,butaskswhetherBVshouldberestartedaswell.Whichofthefollowingistrue?A.InphaseIIItesting,theadditionofBVtoerlotinibprolongedPFSandimprovedresponseratesbutdidnotimproveOS.B.PatientswithmutantEGF

21、RappeartoderivegreaterrelativebenefitfromBV+erlotinib(comparedtoerlotinibalone)thanthosewithwtEGFR.C.BothAandB.D.Noneoftheabove.Question3:Second-linetreatment文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Question#3:second-linetreatmentSheisgivenaprescriptionforerlotinib,butaskswhetherBVshouldberestartedasw

22、ell.Whichofthefollowingistrue?A.InphaseIIItesting,theadditionofBVtoerlotinibprolongedPFSandimprovedresponseratesbutdidnotimproveOS.B.PatientswithmutantEGFRappeartoderivegreaterrelativebenefitfromBV+erlotinib(comparedtoerlotinibalone)thanthosewithwtEGFR.C.BothAandB.D.Noneoftheabove.文档仅供参考，不能作为科学依据，请勿

23、模仿；如有不当之处，请联系网站或本人删除。RandomizedphaseIIIstudycomparingBV+erlotinibvserlotinib(BeTa)Herbstetal,Lancet377:1846-54,2011EB+EHRpOS(m)9.29.3.97(0.80-1.18)NSPFS(m)1.73.4.62(.52-.75)ORR(%)613.006N=636;peripheralsquamous,treatedCNSmetsallowedDidnotprolongOS(primaryendpoint)文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人

24、删除。RandomizedphaseIIIstudycomparingBV+erlotinibvserlotinib(BeTa)Herbstetal,Lancet377:1846-54,2011PFSHR=0.62OSHR=0.97P=0.76文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。RandomizedphaseIIIstudycomparingBV+erlotinibvserlotinib(BeTa):greaterbenefitforBVinEGFRmutants?Herbstetal,Lancet377:1846-54,2011HR EGFRmuta

25、nt:0.44HRwtEGFR:1.11文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。ElevatedMETandHIF-1alevelsincelllineswithmutatedEGFRXuetal,Oncogene,2010文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。RegulationofHIFandMETbyEGFRXuetal,Oncogene,2010文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。05001000150020002500VEGF(pg/3x105cells)-+-+-

26、+-+-+-+-+-+-+-EGFErlotinib(1mM)A549HCC827H1975H3255DifferentialRegulationofVEGFSecretioninHumanNSCLCCellsbyEGFRInhibitionMFFFXuetal,Oncogene,2010文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。PhaseIIIstudyofBV+erlotinibvserlotinibinEGFRmut+patients(CALGB31002/CHUGAIA+T)First-line chemo-nave NSCLCStage IIIB/

27、IVPresence of EGFR mutation(L858R/exon 19)Treated brain mets okBV+ErlotinibErlotinibPrimary endpoint:PFS(IRF)Secondary endpoints:PFS(Inv),ORRQoLRandomization SchemapresentedbyR.Lilenbaum,AstroChicagoLungSymposium2010文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Case#1:thirdlinetreatmentSheeventuallydevelop

28、sPDaftertreatmentwitherlotinib.Sheistreatedwithpemetrexedbutdevelopsrenalinsufficiency.Docetaxelisrecommended.ShewantstoknowifthereisanyroleofaddingaVEGFinhibitortodocetaxel.文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。WhichofthefollowinghasbeenfoundtobetrueinphaseIIItestingin2nd/3rdlineNSCLC?A.BVprolongs

29、PFS,ORR,andOSincombinationwithdocetaxel.B.NoVEGFinhibitorhasbeenshowntoprolongoverallsurvivalincombinationwithdocetaxel.C.NoVEGFinhibitorhasbeenshowntoprovideclinicalbenefitincombinationwithdocetaxelinphaseIIItesting.D.BothBandCQuestion4:third-linetreatment文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Ques

30、tion#4:thirdlinetreatmentWhichofthefollowinghasbeenfoundtobetrueinphaseIIItestingin2nd/3rdlineNSCLC?A.BVprolongsPFS,ORR,andOSincombinationwithdocetaxel.B.NoVEGFinhibitorhasbeenshowntoprolongoverallsurvivalincombinationwithdocetaxel.C.NoVEGFinhibitorhasbeenshowntoprovideclinicalbenefitincombinationwi

31、thdocetaxelinphaseIIItesting.D.BothBandC文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Recurrent(stageIIIB/IV)NSCLCafterfailureoffirst-linechemotherapyTotalrecruitment=1391patientsVandetanib100mg/d+docetaxel75mg/m2(maxsix21-daycycles)n=694Placebo+docetaxel75mg/m2(maxsix21-daycycles)n=697ZODIACVandetanib100m

32、g/d+pemetrexed500mg/m2(every21days)n=256Placebo+pemetrexed500mg/m2(every21days)n=278LocallyadvancedormetastaticNSCLC(stageIIIB/IV)afterfailureoffirst-linetreatmentn=534ZEALZESTVandetanib300mg/dn=623Erlotinib150mg/dn=617Recurrent(stageIIIB/IV)NSCLCafterfailureofatleastonepreviouschemotherapyPriortrea

33、tmentwithcetuximaborbevacizumabwaspermittedn=1240DeBoerR,et al.J Clin Oncol 2009;27(Suppl15):Abstract8010;NataleRB,et al.J Clin Oncol 2009;27(Suppl15):Abstract8009;HerbstR,et al.J Clin Oncol 2009;27(Suppl15):AbstractCRA80031:1RANDOMIZE1:1RANDOMIZE1:1RANDOMIZEPhase III randomized vandetanib trials in

34、 NSCLC文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。PFSinZODIACtrial69438017381402063069733813649175100At risk(n)VandetanibPlaceboHerbstR,et al,Lancet Oncol 2010;11:604Time(months)0Progression-free survival00.10.20.30.40.50.60.70.80.91.03691215182124HR=0.79(0.700.90);P0.001Median PFS(m):Van 4.0;Placebo 3.2

35、ORR:Van 17%;Placebo 10%,P0.001Vandetanib 100 mg+docetaxelPlacebo+docetaxel文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。VandetanibinNSCLCZODIACZEALZESTVandetanib+docetaxel(n=694)Placebo+docetaxel(n=697)Vandetanib+pemetrexed(n=256)Placebo+pemetrexed(n=278)Vandetanib(n=623)Erlotinib(n=617)MedianPFS4.0mths3.2

36、mths17.6wks11.9wks11.3wks8.9wksHR(p-value)0.79(0.001)0.86(0.108)0.98(0.721)MedianOS10.6mths10.0mths10.6mths9.2mths6.9mths7.8mthsHR(p-value)0.91(0.196)0.86(0.219)1.01(0.830)DeBoerR,et al.J Clin Oncol 2009;27(Suppl15):Abstract8010;NataleRB,et al.J Clin Oncol 2009;27(Suppl15):Abstract8009;HerbstR,et al

37、.Lancet Oncol 2010;11:604;HerbstR,et al.J Clin Oncol 2009;27(Suppl15):AbstractCRA8003文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。SummaryBVmaintenanceisindicatedformaintenancetherapyafterCP+BValthoughbenefitsofmaintenanceBVhavenotbeenestablishedinrandomizedphaseIIItrialsBV+PembeingtestedasmaintenanceMulti

38、pletrialscomparingBV,pem,orcombinationinmaintenancesettingareongoingNoOSbenefitestablishedtodateforcombinationsofVEGFinhibitorswithchemoorerlotinibinplatinum-refractoryNSCLCalthoughadditionaltrialsongoingPFSbenefitobservedinZODIACandBeTaBVmayprovidegreaterrelativebenefitinEGFRmut+;randomizedphaseIIItestingisinprogress