肺癌摘要讨论.ppt

BestofASCOinChinaLungCancerSession3 ProfessorTonyMokDept ofClinicalOncologyTheChineseUniversityofHongKongHongKong China Chemotherapy BettercytotoxicdrugNewercombinationwithtargetedtherapyLongerdurationoftreatment Chemotherapy BettercytotoxicdrugPhaseIIIstudyonnab paclitaxel Abaxane NewercombinationwithtargetedtherapyPhaseIIIstudyoncombinationoffigitumumab IGFR1inhibitor andchemotherapyLongerdurationoftreatmentMaintenancegemcitabineaftergem carbo ResultsofaRandomized PhaseIIITrialofnab PaclitaxelandCarboplatinComparedWithCremophor basedPaclitaxelandCarboplatinasFirst lineTherapyinAdvancedNon smallCellLungCancer Abstract LBA7511 MASocinski 1IBondarenko 2NAKaraseva 3AMMakhson 4IOVynnychenko 5IOkamoto 6JHon 7VHirsh 8PBhar 9JIglesias9 1LinebergerComprehensiveCancerCenter UniversityofNorthCarolinaatChapelHill NC USA 2CityHosp 4 Dnepropetrovsk Ukraine 3CityOncologyCenter St Petersburg Russia 4CityOncologyHospital 62 Moscow Russia 5RegionalOncologyCenter Sumy Ukraine 6KinkiUniversitySchoolofMedicine Osaka Sayama Japan 7ClearviewCancerInstOncSpecialties P C Huntsville AL USA 8McGillUniversity Montreal Quebec Canada 9AbraxisBioScience LosAngeles CA nab PaclitaxelWithCarboplatin nab P C inAdvancedNSCLC ADose findingNonrandomizedPhaseII A7armtrialinvestigatedthesafetyandefficacyofnab P Catbothweeklyandq3wdosingschedules Socinski JTO5 852 61 2010 Weeklynab paclitaxel 100mg m2d1 8 15 pluscarboAUC6q3wdemonstratedoptimaltherapeuticindexRR 48 medianPFS 6 2months medianOS 11 3monthsGrade3 4toxicity neutropenia64 neuropathy8 thrombocytopenia20 anemia16 BasedonthephaseIIresults aphaseIIItrialwasdesignedtoinvestigatetheefficacy safetyofnab P CvsP Casfirst linetherapyinadvancedNSCLC PhaseIIInab P CvsP CStudyDesign Chemo naivePS0 1StageIIIb IVNSCLCN 1 050 Stratificationfactors Stage IIIbvsIV Age 70 SexHistology squamousvsnonsquamous Geographicregion nab Paclitaxel100mg m2d1 8 15CarboplatinAUC6d1NoPremedicationn 525 1 1 Paclitaxel200mg m2d1CarboplatinAUC6d1WithPremedicationofDexamethasone Antihistaminesn 525 StudyEndpoints Primaryendpoint ObjectiveresponseratebyindependentradiologicreviewbasedonRECISTcomplete partialresponse CR PR Secondaryendpoints Progression freeandoverallsurvivalDiseasecontrolrate CR PR stabledisease SD 16weeksSafety NCICTCAEv3 FDAdoesnotconsidernab palcitaxelasanewdrug butamodificationofanexistingdrug PatientEligibility MajorInclusionHistologically cytologicallyconfirmedadultpatientswithstageIIIb IVNSCLCECOGperformancestatusof0or1MeasurablediseasebyRECISTAdequatehematologic hepatic andrenalfunctionNopriortreatmentformetastaticdisease adjuvanttherapyallowedifitwas 1yearpriortostudyentry MajorExclusionActivebrainmetastases treated controlledmetsallowed Baselineperipheralneuropathy grade2 StatisticalConsiderationsPrimaryEndpoint ObjectiveresponserateofP CinECOG1594 17 Basedontheactivityofnab PinMBC arelativeimprovementof 40 fornab P CoverP Cwasassumed correspondingtoanORR 24 Basedonthisassumption 525patientsoneacharmprovides80 powerwithatwo sidedTypeIerrorof0 049torejectthenullhypothesis US12 25sites Russia45 29sites Australia1 5sites Japan14 21sites PatientAccrual Canada4 6sites Ukraine24 16sites Plannedenrollment fromDec142007toAug1 2009Actualenrollment fromDec142007toJuly14 2009Plannedfollow up 18months ofpatientsenrolled 1052 ofpatientsevaluableforefficacy 1052 ofpatientsevaluablefortoxicity 1038 Results BaselineDemographics Datawasmissingfor1ptatthetimeofthisanalysis PrimaryEndpointResultsObjectiveResponses AllHistologies ResponseRatio 1 31 1 082 1 593 P 0 005 PercentResponses ResponseRatio 1 31 1 082 1 593 P 0 005 ResponseRatio 1 26 1 060 1 496 P 0 008 PercentResponses PrimaryEndpointResultsObjectiveResponses AllHistologies n 521 n 531 PercentResponses Notapre specifiedendpoint ObjectiveResponsesbyHistology Squamous P 0 001 P 0 060 n 228 n 221 PercentResponses ObjectiveResponsesbyHistology Squamous Nonsquamous P 0 001 P 0 060 P 0 808 P 0 069 n 228 n 221 n 292 n 310 Notapre specifiedendpoint Safety Nohypersensitivityreactionoccurredinthenab P Carmwithoutprophylacticpremedication while3occurredintheP Carm grade1 2 and3 respectively Favorsnab P C FavorsP C Conclusions bySocinski InthisphaseIIIrandomizedtrial nab P CdemonstratedastatisticallysignificanthigherresponseratethanP C 33 vs25 P 0 001 Theresponserateinthesquamouscellsubsetwas41 inthenab P Carmvs24 intheP Carm P 0 001 nab P Cwaswelltoleratedandassociatedwithlesssensoryneuropathy myalgia andneutropeniathanP C nab P CwasassociatedwithmoreanemiaandthrombocytopeniathanP C Progression freesurvivalanalysisisplannedforlaterthisyear KeyMessage byme Nab paclitaxel CarboachieveahigherresponseratePredominantlyinsquamouscellNegativeinnon squamouscellbyindependentreviewersNab paclitaxelmaybelesstoxicLessgrade4neutropeniabutsimilarinneutropenicfeverSlightlymoregradeIII IVthromobocytopeniaLessgradeIIIsensoryneuropathy 3vs10pts Keyquestions byme WhyisthePFSnotavailablenow LastpatientenrolledinJuly2009 Cantheimprovementinresponserateandlowertoxicitybearesultofweeklyadministrationofpaclitaxelratherthanthenab paclitaxel Newercombinationwithmoleculartargeteddrug Randomized OpenLabel PhaseIIITrialofFigitumumabinCombinationwithPaclitaxelandCarboplatinversusPaclitaxelandCarboplatininPatientswithNon SmallCellLungCancer NSCLC JJassem CLLanger DDKarp TMok SNovello KPark JStrausz RJBenner SGreenandAGualberto Abstract7500 MedicalUniversity Gdansk Poland AbramsonCancerCenter Philadelphia PA MDAndersonCancerCenter Houston TX ChineseUniversity HongKong NewTerritories UniversityofTurin Italy SungkyunkwanUniversity Seoul Korea KoranyiNatl Inst forPulmonology Budapest Hungary PfizerOncology NewLondon CT InsulinLikeGrowthFactor1Receptor CentralcomponentofasignaltransductionpathwaythatincludestheIGF 1andIGF 2ligandsandtheirbindingproteins IGFBPs1to7 1IGFBPsregulateIGFsbioavailabilityandbiologicalactivityIGFsaresurvivalfactorsfornormalandcancercellsHighcirculatingIGF 1levelsareassociatedwithincreasedriskofcancerrelateddeath2LowcirculatingIGF 1levelsareassociatedwithincreasedriskofheartfailureandmyocardialevents3 PollakM NatRevCancer2008 8 915 928MajorJMetal JClinEndocrinolMetab 2010 95 1054 9 LaughlinGAetal JClinEndocrinolMetab 2004 89 114 20 Figitumumab CP 751 871 FullyhumanIgG2subtypemonoclonalantibodyagainsttheIGF 1RwithaT1 2ofapproximately28days1Welltoleratedasasingleagentandincombinationwithchemotherapy targetedagentsinearlystudies2PhaseIsingle agentactivityinEwing ssarcoma3PhaseIIactivityinfirst lineNSCLCincombinationwithpaclitaxel carboplatin4 Cohenetal ClinCancerRes2005 11 2063 73GualbertoA ExpertOpinBiolTher2010 10 575 85Olmosetal LancetOncol2010 11 129 35Karpetal JClinOncol 200927 2516 22 PhaseIIstudy ObjectiveResponseRatebyDoseandHistology PCPCF10mg kgPCF20mg kg StudyA1016 PhaseIIIStudyofCarboplatin Paclitaxel Figitumumabin1stLineNSCLCofnon adenocarcinomahistology KeyEntryCriteriaHistologyotherthanAdenocarcinomaBrainmetsallowedAdjuvant 12monthprior RANDOMIZE N 820 Figitumumab 20mg kg PaclitaxelCarboplatin PaclitaxelCarboplatin N 410 N 410 BaselinePatientCharacteristics BaselinePatientCharacteristics cont MostFrequentGrade3 5AdverseEvents 5 forPCF Glucoselevelsingrade3hyperglycemia 251 500mg dL grade4 500mg dL AEswiththeLargestDifferencebetweenStudyArms OverallSurvival PCmOS 10 3mo PCFmOS 8 5mo Months ProbabilityofSurvival HR 95 CI 1 23 1 0 1 5 p 0 051 OverallSurvivalbySubsets HR95 CIClinicalParametersdidnotProvidePositiveSubsets FavorsPCF FavorsPC Overall StageIIIB CurrentSmoker NeverorExSmoker StageIV Non squamous Squamous Female Male ECOGPS0 ECOGPS1 0 61 01 62 7 HR 121086420 FreeIGF 1quartiles Study1002 PFS months 1st 2nd 3rd 4th 0 9ng mL PC PC F10mg kg PC F20mg kg P 0 0533 P 0 0009 Phase2BiomarkerAnalysisSuggestedaFreePlasma unboundtoIGFBPs IGF 1 TreatmentInteraction 4months Hixonetal JClinOncol 27 15s 2009 abstr3539 OSofPCFimprovedathighFreeIGF 1levelsinthePhase3Study 1016 FreeIGF 1Criterion ng mL 0 60 70 80 91 01 1 1 2 0 8 1 0 1 2 1 4 FreeIGF 1Criterion ng mL 0 40 60 81 0 1 2 12 10 8 6 PCF PC MedianOSaboveFreeIGF 1Criterion HazardRatioaboveFreeIGF 1Criterion HazardRatioPCF PC MedianOS months pre treatment pre treatment PCmOS 10 3mo PCFmOS 7 0mo 1 00 80 60 40 20 0 Survivalprobability 05101520 MedianOSatFreeIGF 1 1 0ng mlFavoredPC N 324 Provisionofsamplesforpharmacodynamicswasoptional Time months HR 95 CI 1 40 1 0 1 9 PCFmOS 10 2mo PCmOS 7 0mo 1 00 80 60 40 20 0 Survivalprobability 05101520 Time months MedianOSatFreeIGF 1 1 0ng mlFavoredPCF N 125 Provisionofsamplesforpharmacodynamicswasoptional HR 95 CI 0 97 0 6 1 7 Additionalfollowupisnecessary Grade5AEsbyFreeIGF 1HigherPCFGrade5ToxicityatLowFreeIGF 1 Conclusions ByJassem Additionoffigitumumabtostandardchemotherapydidnotincreaseoverallsurvivalinadvancednon adenocarcinomaNSCLCPotentialbenefitoffigitumumabmaybecompromisedbyitssideeffectsRisk benefitoffigitumumabinadditiontostandardchemotherapyappearstoberelatedtothelevelsofcirculatingfreeIGF 1AdditionalresearchisnecessarytoverifythepotentialofbenefitinpatientswithhighfreeIGF 1 KeyMessage byme Combinationoffigitumumabandtaxol carbofailedtoimprovesurvivalinpatientswithSCCFooledbyapromisingphaseIIstudyagainIsIGFR 1atruetarget MoresideeffectthanexpectedWeignoredtheimportanceofhyperglycemia KeyQuestions byme IstheplasmafreeIGF 1areliablesurrogatebiomarker Cutofflevel 1ng mlisnotabsolute Howtovalidatethiscut offlevel HRof0 97inthesubgroupwithpatients 1ng ml IsitworthwhiletoinvestigatefurtherwithanotherphaseIII CanweexpectbetteroutcomesfromotherIGF Rinhibitors Longerdurationoftherapy C P Belani1 D M Waterhouse2 H H Ghazal3 S Ramalingam4 J M Waples5 R E Bordoni6 G A Reznikoff7 C P Curran8 R H Greenberg91PennStateHersheyCancerInstitute Hershey PA USA 2OncologyHematologyCare Cincinnati OH 3KentuckyCancerClinic Hazard KY 4EmoryUniversityWinshipCancerInstitute Atlanta GA 5ClearviewCancerInstitute Huntsville AL 6GeorgiaCancerSpecialists Atlanta GA 7MedicalSpecialistsofFairfield Fairfield CT 8PalmettoHematologyOncology Spartanburg SC 9TheCenterforCancerandHematologicDisease CherryHill NJ RandomizedTrialofGemcitabine Carboplatin G Cb TherapyFollowedbyGemcitabine G MaintenanceorBestSupportiveCare BSC inAdvancedNSCLC Abstract 7507 MaintenancetherapyrepresentsausefulstrategytoimprovepatientoutcomesinadvancedstageNSCLCRecentstudiesofmaintenancetherapy sequential consolidation switch toanewagent immediatelyfollowingfirst linetherapy havedemonstratedastatisticallysignificantsurvivalbenefit MaintenanceTherapyinAdvancedNSCLC ArmB Gemcitabine1000mg m2d1 8q21days Bestsupportivecare BSC ArmA Gemcitabine1000mg m2d1 8CarboplatinAUC5d1q21daysX4cycles PD Offstudy CRPRSD StudyDesign 1 1Randomization PrimaryEndpoint OS Chemona veStageIIIB IVNSCLCRandomizationfactors PSstagebesttumorresponse Bestsupportivecare BSC HistologicorcytologicdiagnosisofstageIIIBwithpleuraleffusionand orpositivesupraclavicularnodesorstageIVNSCLCAge 18yearsECOGperformancestatusof0 2Adequaterenal hepaticandbonemarrowfunctionPatientswithasymptomatic treated controlledbrainmetastaseswereallowedPresenceofmeasurablediseaseNopriorchemotherapyforNSCLCSignedinformedconsent EligibilityCriteria PrimaryObjectiveOverallsurvivalcomparingGemcitabinemaintenance BSCvs BSCfollowingrandomizationSecondaryObjectivesObjectiveresponserateProgression freesurvivalfollowingrandomizationSafetyandtolerability Objectives Samplesizeof600patientsforinitialtherapywithG Cbwasplannedtoallow332patientstoberandomizedtomaintenanceGemcitabine BSCvs BSC assuming45 progressiontoinitialtherapy basedon80 powerusingtwo sidedalphalevelof0 05Overallsurvival OS analysisplannedafter238eventstoachievefullpowerAssumedhazardratioof0 69comparingGemcitabine BSCvs BSConOSPlannedpatientaccrualtimewas18months StatisticalDesign Samplesizeof600patientsforinitialtherapywithG Cbwasplannedtoallow332patientstoberandomizedtomaintenanceGemcitabine BSCvs BSC assuming45 progressiontoinitialtherapy basedon80 powerusingtwo sidedalphalevelof0 05Overallsurvival OS analysisplannedafter238eventstoachievefullpowerAssumedhazardratioof0 69comparingGemcitabine BSCvs BSConOS WhatisthebaselineOSforthecontrolarm Plannedpatientaccrualtimewas18months StatisticalDesign StudyAccrual PatientenrollmentwasfromJanuary2002toAugust2007519patientswereenrolledtoG Cbphaseoftrial 87 ofplan 255patientswererandomizedtomaintenanceGemcitabine BSCvs BSCfollowinginitialtreatmentStudywasclosedinSeptember2008duetoslowaccrualFinalAnalysisat179eventsamongst255randomizedpatients 67months BaselineCharacteristicsInitialPhase BestTumorResponsetoTherapyInitialPhase BaselineCharacteristicsMaintenancePhase BestTumorResponsetoTherapyMaintenancePhase StudyTreatmentMaintenancePhase P 0 05forgrade3 4ratesofneutropenia anemia Treatment relatedToxicities SystemicPost studyTherapy ThisstudyfailedtoshowasurvivalbenefitformaintenanceGemcitabineinnon progressorsfollowingstandardtreatmentofG CbforpatientswithadvancedNSCLCNearlytwothirdsofpatientswereECOGPS2atstudyentryGemcitabineinthemaintenancesettingwaswelltoleratedFewpatientsreceivedpost studytherapylikelyduetopoorPS Conclusions ByBelani KeyMessage byme Anegativestudyoncontinuationofgemcitabineaftergem carboRelativelypoorlyconductedstudywithlongandslowaccrualWhysuchslowaccrualinaUSAstudy 16 withpoststudytreatmentisunusuallylowforUnitedStates KeyQuestion byme ShouldweincludepatientswithPS2ormoreinmaintenancetrial ShouldPS2patientsreceivemaintenancetherapyoutsidetrial TheRoleofChemotherapyforAdvancedStageNSCLC AfterASCO2010 ProfessorTonyMokDept ofClinicalOncologyTheChineseUniversityofHongKongHongKong China EGFRMutation EGFRMutation EGFRTKI Chemotherapy MolecularTargetedDrugs BetterChemotherapy Chemotherapy Targeteddrug Longerduration OurGoodOldFriend Ourpreviouseffortstoimprovetreatmentoutcomesoffirstlinechemotherapy Personalizechemotherapy Cis PemvsCis GeminFirst lineNSCLC StudyDesign Cisplatin75mg m2day1plusGemcitabine1250mg m2days1 8 RandomizationFactorsStagePerformancestatusGenderHistologicvscytologicdiagnosisHistoryofbrainmetastases Cisplatin75mg m2day1plusPemetrexed500mg m2day1 VitaminB12 folate anddexamethasonegiveninbotharms Eachcyclerepeatedq3weeksupto6cycles ScagliottiGVetal Presentedat12thWorldConferenceonLungCancer Sept5 2007 Seoul Korea Cis PemvsCis GeminFirst lineNSCLC OverallSurvival ScagliottiGVetal Presentedat12thWorldConferenceonLungCancer Sept5 2007 Seoul Korea Cis PemvsCis GeminFirst lineNSCLC OverallSurvival AdenocarcinomaorLargeCell ScagliottiGVetal Presentedat12thWorldConferenceonLungCancer Sept5 2007 Seoul Korea ThymidylateSynthaseasBiomarker ThymidylateSynthasemRNALevel Ceppietal Cancer2006 107 7 1589 1596 Scagliottietal JClinOncol2008 26 21 3543 3551 SWOGDataBank BiomarkerSCCAversusAC 1Analysisofoneormorebiomarkers GandaraetalASCO2010abst SWOGDataBank BiomarkerMaleversusFemale 1Analysisofoneormorebiomarkers PercentResponses ASCO2010PhaseIIIstudyonnab Paclitaxel Squamous Nonsquamous P 0 001 P 0 060 P 0 808 P 0 069 n 228 n 221 n 292 n 310 Notapre specifiedendpoint SocinskiASCO2010 Possibleexplanationforthisobservation A NabpalcitaxelisabetterdrugB WeeklypalcitaxelisabetterscheduleC LowBeta 3tubulinlevelinSCCD Allofabove Graveyardforthechemotherapy targeteddrugstudies RIPFigitumumab E4599 bevacizumab basedtherapysignificantlyextendedoverallsurvival 1 00 80 60 40 20 06121824303642 Time months Probabilityofsurvival 10 3 12 3 Sandler etal NEJM2006 HR hazardratio Bevacizumab CPCP HR 0 79 0 67 0 92 p 0 003 20 increaseinmedianoverallsurvival Medianoverallsurvival months 151050 Bevacizumab CP CP AVAiL highuseofefficacioussubsequentlinesoftherapyconfoundedOS 1 00 90 80 70 60 50 40 30 20 10 ProbabilityofOS Time months 061218243036 Reck etal IASLC ASTRO ASCO2008 Overallsurvivalexceeded13months FLEXStudydesign Chemotherapy CetuximabuntilPDorintolerabletoxicity Chemotherapy Cetuximab NSCLCwetIIIB IVEGFR expressing Maintenance PirkerRetal JClinOncol2008 18S abstract3 PirkerRetal Lancet2009 373 1525 PirkerRetal Lancet2009 373 1525 FLEX OverallSurvival Howtoselectpatient K RasMutations Notapredictivemarker HarbisonC etal ASCO2010 Abstract7548 CT chemotherapy HR hazardratio CI confidenceinterval EGFRMutation Notapredictivemarker HarbisonC etal ASCO2010 Abstract7548 OSbenefitobservedinbotharmsofstudymaybeduetochemotherapyuseorpost studyTKItreatment EGFRGeneCopyNumber PredictorinPhaseIISWOG0342butnotPhaseIIIFLEXorBMS099 HarbisonC etal ASCO2010 Abstract7548 Keymessage Wedon thaveabiomarkerforpatientselectionforeitherthechemo bevacizumaborthechemo cetuximabcombinations ASCO2010Chemothrapy Figitumumab InferiorOverallSurvival PCmOS 10 3mo PCFmOS 8 5mo Months ProbabilityofSurvival HR 95 CI 1 23 1 0 1 5 p 0 051 JessemetalASCO2010 PCFmOS 10 2mo PCmOS 7 0mo 1 00 80 60 40 20 0 Survivalprobability 05101520 Time months Biomarkerselection FreeIGF 1 1 0ng mlFavoredPCF N 125 Provisionofsamplesforpharmacodynamicswasoptional HR 95 CI 0 97 0 6 1 7 Additionalfollowupisnecessary Jessemetal ASCO2010 Targetedtherapyisforpatientwiththetarget Thisalsoapplytothecombinationtherapywithchemotherapy MaintenanceTherapy Chemox4 6 observe 2nd 3rdlinetherapy Death MaintenanceTherapy Chemox4 6 observe 2nd 3rdlinetherapy Chemox4 6 Maintenance 2nd 3rdlinetherapy Death Death Chemox4 6 Maintenance 2nd 3rdlinetherapy Death Vinorelbine Westeeletal JNatlCancerInst 2005 Gemcitabine Brodowiczetal LungCancer2006 IIIb IVNSCLCN 562 GCPhaseN 552 388received4cycles OffStudyN 245 Randomized SD PR CRN 307 ImmediateN 153 DelayedN 154 ImmediateTreatedN 142 DelayedTreatedN 91 Treated ORR29 Docetaxel Fidiasetal JClinOncol2008 PatientsatRisk ImmediateVersusDelayedDocetaxelAfterInductionProgression FreeSurvival Fidiasetal JClinOncol 2008 StageIIIB IVNSCLCPS0 14priorcyclesofgem doc ortax cisorcarb withCR PR orSDRandomizationfactors genderPSstagebesttumorresponsetoinductionnon platinuminductiondrugbrainmets Pemetrexed500mg m2 d1 q21d BSC N 441 PrimaryEndpoint PFS Placebo d1 q21d BSC N 222 B12 folate anddexamethasonegiveninbotharms 2 1Randomization JMEN Double blind Placebo controlled Multicenter PhaseIIITrialofMaintenancePemetrexedvs Placebo CiuleanuetalLancet2009 Progression freeSurvival Progre