2014非小細(xì)胞肺癌進(jìn)展課件

Non Small CellLungCancerforCliniciansWorkingWithintheVeteransHealthAdministration Thisprogramissupportedbyeducationalgrantsfrom AboutTheseSlides Usersareencouragedtousetheseslidesintheirownnoncommercialpresentations butweaskthatcontentandattributionnotbechanged UsersareaskedtohonorthisintentTheseslidesmaynotbepublishedorpostedonlinewithoutpermissionfromClinicalCareOptions emailpermissions DisclaimerThematerialspublishedontheClinicalCareOptionsWebsitereflecttheviewsoftheauthorsoftheCCOmaterial notthoseofClinicalCareOptions LLC theCMEproviders orthecompaniesprovidingeducationalgrants ThematerialsmaydiscussusesanddosagesfortherapeuticproductsthathavenotbeenapprovedbytheUnitedStatesFoodandDrugAdministration Aqualifiedhealthcareprofessionalshouldbeconsultedbeforeusinganytherapeuticproductdiscussed Readersshouldverifyallinformationanddatabeforetreatingpatientsorusinganytherapiesdescribedinthesematerials Faculty MillieDas MDClinicalAssistantProfessorDivisionofOncologyDepartmentofMedicineStanfordUniversityStanford CaliforniaStaffPhysicianDivisionofOncologyDepartmentofMedicineVAPaloAltoHealthCareSystemPaloAlto California HeatherWakelee MDAssociateProfessorofMedicine OncologyDepartmentofMedicine OncologyStanfordUniversityStanford California FacultyDisclosures MillieDas MD hasnosignificantfinancialrelationshipstodisclose HeatherWakelee MD hasdisclosedthatshehasreceivedconsultingfeesfromGileadSciencesandfundsforresearchsupportpaidtoStanfordUniversityfromAgennix Celgene Clovis Exelixis Genentech EliLillyandCompany Novartis Pfizer Regeneron andRoche Introduction AdvancedNSCLC LungCancerIncidenceandMortality Newcasesin2013 228 19040 withstageIVdiseaseatpresentation 90 000 160 000deathsin2013 comparabletoprostate pancreas breast andcoloncancercombined5 yearrelativesurvivalrate 13 overall 2 forpatientswithdistant stage disease NCI Non small celllungcancertreatment PDQ ACS Cancerfacts figures 2013 EstimatedCancerDeathsbySite 2013 OtherCancers LungCancer 180 000 160 000 140 000 120 000 100 000 80 000 60 000 40 000 20 000 0 Lungcancer Prostate Pancreas Breast Colon RiskFactorsforLungCancer Smoking91 men 80 womenEnvironmentalfactorsSecond handsmoke3 to5 Radon3 to5 Industrialpollution0 to5 Radiationexposurerare GuidelinesforLungCancerScreening 1 USPSTF ScreeningforLungCancer RecommendationStatement May2004 2 WenderR etal CACancerJClin 2013 63 107 117 3 BachPB etal JAMA 2012 307 2418 2429 4 NCCN LungCancerScreeningGuidelines V1 2014 5 JaklitschMT etal JThoracCardiovascSurg 2012 144 33 38 6 USPSTF ScreeningforLungCancer RecommendationStatement August2013 Draft NationalLungScreeningTrial TrialOverview 53 345patientsscreenedandthenfollowedfor2years95 ofabnormalCTscanswere falsepositives 20 relativemortalityreduction P 004 356vs443lungcancer relateddeathsinLDCTvsCXRNumberneededtoscreentoprevent1lungcancerdeath 320 Asymptomaticpatientswith 30 pack yearsmokinghistoryAge55 74years N 53 439 LDCTAnnualscreeningx3yrs CXRAnnualscreeningx3yrs NationalLungScreeningTrialResearchTeam etal NEnglJMed 2011 365 395 409 NationalLungScreeningTrial SurvivalCurves Relativereductioninall causemortalityof6 7 P 02 1877deathsinLDCTgroup 2000inCXRgroup LungCancerMortality AllMortality NationalLungScreeningTrialResearchTeam etal NEnglJMed 2011 365 395 409 012345678 1 000 990 980 970 960 950 940 930 920 910 90 CTarmlungcancerCXRarmlungcancerCTarmall causeCXRarmall cause ProbabilityofSurvival AllParticipants YrsFromRandomization NationalLungScreeningTrial Questions LungcancerscreeningnowrecommendedbyUSPSTF draftstatementissuedsummer2013 1 WillthisbeimplementedbytheVA Apilotprogramisunderwayat8VAcentersWhattodowith95 of benign nodules Adjustsizecriterionforintervention Followvsbiopsyvsmorespecifictest 1 USPSTF ScreeningforLungCancer RecommendationStatement August2013 Draft ComplexitiesofLungCancerPathogenesisResultinDiverseHistologicSubtypes SCLC 15 NSCLCAdenocarcinoma 45 SCC 25 Largecell 5 10 LPA formerlyBPA 5 10 NOS 10 30 SunS etal NatRevCancer 2007 7 778 790 TravisWD etal JClinOncol 2013 31 992 1001 NSCLC AJCCStaging EdgeSB etal AJCCCancerStagingManual 7thed NewYork NY Springer 2010 P 253 270 Changesinstagingareshowninitalics AdvancedNSCLC PrognosticFactors FactorscorrelatedwithadverseprognosisPoorperformancestatusWeightlossof 10 MalegenderSquamouscellhistologyAdvancedagealonehasnotbeenshowntoinfluenceresponseorsurvivalwiththerapy NCI Non small celllungcancertreatment PDQ ConsiderationsforFirst lineTherapy PerformancestatusAgeOrganfunction nutritionalstatusHemoptysisHistologyMolecularvariablesOtherCNSmetastasesPreviouschemotherapyinadjuvantorlocallyadvancedsetting PathologicAssessmentofHistologyIsCriticaltoOptimizeTreatment ClassifypatientsassquamousornonsquamousAllpatientsthatdonothavebonafidesquamousNSCLCshouldbeconsiderednonsquamousSquamouscellsaretypicallyp63positiveandTTF1negativeAdenocarcinomasareTTF1positive 70 to90 andgenerallyp63negative DiLoretoC etal JClinPathol 1997 50 30 32 FabbroD etal EurJCancer 1996 32A 512 517 RekhtmanN etal ModPathol 2011 24 1348 1359 First lineTreatmentConsiderationsintheAbsenceofEFGRorALKBiomarkers Howwellestablishedisthehistologicdiagnosis NonsquamousSquamousMixedOptimalchemotherapyregimenRoleoftargetedtherapiesAntiangiogenicAnti EGFR Advanced stage previouslyuntreatedNSCLCpatients N 1725 Cisplatin75mg m2onDay1 Gemcitabine1250mg m2onDays1and8Six3 wkcycles Cisplatin75mg m2onDay1 Pemetrexed500mg m2onDay1Six3 wkcycles ScagliottiGV etal JClinOncol 2008 26 3543 3551 PhaseIIIStudy Cisplatin GemcitabinevsCisplatin PemetrexedasFirst lineTherapy Stratifiedby ECOGperformancestatus 0vs1 Diseasestage IIIBvsIV Brainmetastases yesvsno Sex malevsfemale Pathologicdiagnosis histologicvscytologic Treatmentcenter Cisplatin PemetrexedvsCisplatin GemcitabineinAdvancedNSCLC OS ScagliottiGV etal JClinOncol 2008 26 3543 3551 SurvivalTime Mos inAllPatients SurvivalProbability HR 0 94 95 CI 0 84 1 05 C PC G MedianSurvival 10 3mos 10 3mos 1 0 0 9 0 8 0 7 0 6 0 5 0 4 0 3 0 2 0 1 0 0 6 12 18 24 30 C PvsC GinAdvancedNSCLC OSbyHistology SurvivalTime Mos inAllPatientsWithSquamousHistology SurvivalProbability Squamous Nonsquamous SurvivalTime Mos inPatientsWithNonsquamousHistology SurvivalProbability ScagliottiGV etal JClinOncol 2008 26 3543 3551 C PC GC PvsC G MedianSurvival 9 4mos 10 8mos AdjustedHR 1 23 95 CI 1 00 1 51 1 0 0 9 0 8 0 7 0 6 0 5 0 4 0 3 0 2 0 1 0 30 0 6 12 18 24 1 0 0 9 0 8 0 7 0 6 0 5 0 4 0 3 0 2 0 1 0 30 0 6 12 18 24 MaintenanceTherapyforNon ProgressiveDiseaseAfterInitialPlatinum BasedCT Patientswithatleaststablediseaseafter4 6cyclesofCT ECOGPS0 1 bevacizumab cetuximab pemetrexed docetaxel pemetrexed erlotinib gefitinib NCCN ClinicalPracticeGuidelinesinOncology non small celllungcancer V2 2014 Options SwitchMaintenanceTrials 1 FidiasPM etal JClinOncol 2009 27 591 598 2 CiuleanuT etal Lancet 2009 374 1432 1440 3 CappuzzoF etal LancetOncol 2010 11 521 529 4 JohnsonBE etal JClinOncol 2013 31 3926 3934 5 ZhangL etal LancetOncol 2012 13 466 475 ContinuationMaintenanceTrials 1 BelaniCP etal ASCO2010 Abstract7506 2 P rolM etal JClinOncol 2012 30 3516 3524 3 Paz AresLG etal JClinOncol 2013 31 2895 2902 BevacizumabinNonsquamousNSCLC KeyResults 1 SandlerA etal NEnglJMed 2006 355 2542 2550 2 ReckM etal JClinOncol 2009 27 1227 1234 3 ReckM etal AnnOncol 2010 21 1804 1809 4 NihoS etal LungCancer 2012 76 362 367 PointBreakPhaseIIIStudy Pem BevvsBevasMaint inNonsquamousNSCLC Primaryendpoint OSOtherendpoints PFS ORR safety QOL PK Pemetrexed Carboplatin Bevacizumabfor4cycles Paclitaxel Carboplatin Bevacizumabfor4cycles Chemotherapy naivepatientswithstageIIIB IVnonsquamousNSCLC N 904 Pemetrexed Bevacizumab Bevacizumab Patientswithoutdiseaseprogression PatelJD etal 2012MultidisciplinarySymposiuminThoracicOncology AbstractLBPL1 ClinicalTrials gov NCT00762034 Stratifiedbystage IIIbvsIV PS 0vs1 sex measurablevsnonmeasurabledisease PatelJ etal 2012ChicagoMultidisciplinarySymposiuminThoracicOncology AbstractLBPL1 PointBreak OSFromRandomization ITT CensoringrateforPem Cb Bev 27 8 Pac Cb Bev 27 2 0 3 6 9 12 15 18 21 24 27 30 33 36 39 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 1 0 MosFromInduction SurvivalProbability Pem Cb BevPac Cb Bev PatelJ etal 2012ChicagoMultidisciplinarySymposiuminThoracicOncology AbstractLBPL1 PointBreak PFSFromRandomization ITT PFSwithoutgrade4toxicity 0 3 6 9 12 15 18 21 24 27 30 33 36 0 10 20 30 40 50 60 70 80 90 100 MosFromInduction PFS Pem Cb BevPac Cb Bev AVAPERL UpdatesonBevacizumab PemetrexedMaintenanceTherapy PhaseIIItrialofCis Pem Bev 7 5mg kg every3weeksfor4cycles N 376 NonprogressorsrandomizedtoreceivemaintenanceBev Pem n 128 orBev n 125 PFSfrominduction primaryendpoint 10 2vs6 6months HR 0 58 95 CI0 45 0 76 P 001At58 ofevents OS Bev PemvsBev Frominduction 19 8vs15 9months HR 0 88 95 CI 0 64 1 22 P 32Fromrandomization 17 1v13 2months HR 0 87 95 CI 0 63 1 21 P 29 RittmeyerA etal ASCO2013 Abstract8014 ECOG5508 OngoingNSCLCPhaseIIIStudyExploringMaintenanceTherapy RandomizedphaseIIItrialinpatientswithstageIIIB IVNS NSCLCandPS0 1whoareeligibleforbevacizumabtherapy PaclitaxelCarboplatinBevacizumab N 1236 Nonprogressors n 864 Bevacizumab Pemetrexed BevacizumabPemetrexed Primaryendpoint OSSecondaryendpoints PFS RR safety PK ClinicalTrials gov NCT01107626 Bevacizumab PatientSelection TreatmentDuration Maintenance andContinuation BevacizumabincreasesRRandPFSwhenaddedtofirst linechemotherapyforNSCLC improvedOSin1phaseIIItrialCanusewithanticoagulants brainmetastases cautioninelderlyEncouragingdatasupportstandardpracticeofcontinuedmaintenancebevacizumabuntilPDOngoingE5508willaddressthesequestionsDatatosupportcarboplatin paclitaxel bevacizumabORcarboplatin pemetrexed bevacizumabORcarboplatin pemetrexedasreasonablefirst lineoptionsfornonsquamousNSCLCPredictiveandprognosticmarkersareindevelopmenttohelpguidepatientselection butnonevalidatedtodateICAM VEGFlevels VEGFpolymorphisms C Afs LiT etal JClinOncol 2013 31 1039 1049 NSCLCasonedisease EvolutionofNSCLCSubtypingtoaMultitudeofMolecular definedSubsets Histology basedSubtyping MolecularTestingGuideline EGFRandALK Recommendedforadenocarcinomas mixedlungcancers notforsquamous small cell orlarge cellcarcinomasPrimarytumorsandmetastaticlesionsequallysuitableDiscordancebetweenmutationstatusofprimarytumorandmetastasesappearsrare inpreviouslyuntreatedpatients MoleculartestingresultsforEGFRandALKshouldbeavailablewithin2weeksofspecimenreceiptPathologicsamplepreparationsusingheavymetalfixativesoracidicsolutionscompromisemoleculartestingeg bonedecalcifyingsolutions LindemanNI etal JThoracOncol 2013 8 823 859 First lineTreatmentWithEGFRTKIsvsChemotherapyinEGFR MutatedPatients 1 MaemondoM etal NEnglJMed 2010 362 2380 2388 2 MitsudomiT etal LancetOncol 2010 11 121 128 3 MitsudomiT etal ASCO2012 Abstract7521 4 ZhouC etal LancetOncol 2011 12 735 742 5 ZhangC etal ASCO2012 Abstract7520 6 RosellR etal LancetOncol 2012 13 239 246 7 SequistLV etal JClinOncol 2013 31 3327 3334 TargetingALKGeneTranslocations TypicalphenotypeYoung maleorfemale never scantsmokers butnotalways Adenocarcinoma signetringmorphologyPoorresponsetoEGFRTKI conventionalresponsetostandardchemotherapyNooverlapwithEGFRmutationgenotype CamidgeDR etal LancetOncol 2012 13 1011 1019 CrizotinibinALK PositiveNSCLC N 133 100 80 60 40 20 0 20 40 60 80 100 ChangeFromBaseline PDSDPRCR Excludedpatientswithearlydeathbeforereimaging nonmeasurablenontargetdisease orindeterminateresponses SquamousCellLungCancer AnUnmetNeed Clinicallychallengingpopulation older comorbiditiesPlatinumdoubletsremainthestandardofcareGemcitabine ortaxane basedregimenscommonlyusedRoleofnab paclitaxelnotyetclearAntiangiogenicstrategiesconsideredtootoxicPemetrexednolongerapprovedforuseinthissubsetNewstrategiesareneededforthislargegroupofpatients 35 PhaseIIIStudy Carboplatin Nab PaclitaxelvsCarboplatin PaclitaxelinAdvancedNSCLC Primaryendpoint ORRSecondaryendpoints PFS OS safety PatientswithstageIIIb IVNSCLC ECOGPS0 1 nopreviouschemotherapyformetastaticdisease N 1050 Nab Paclitaxel100mg m2onDays1 8 15 CarboplatinAUC6onDay1Nopremedication Paclitaxel200mg m2onDay1 CarboplatinAUC6onDay1Premedication dexamethasone antihistamines Stratifiedbystage IIIbvsIV age 70yrs sex histology squamousvsnonsquamous geographicregion 21 daycycles SocinskiMA etal JClinOncol 2012 30 2055 2062 P 005RRR 1 31 33 25 IndependentRadiologicReview ITT SocinskiMA etal JClinOncol 2012 30 2055 2062 Carboplatin Nab PaclitaxelvsCarboplatin PaclitaxelinAdvancedNSCLC RR Carboplatin nab paclitaxelCarboplatin paclitaxel ResponseRate P 001RRR 1 680 P 808RRR 1 034 41 26 24 25 0 10 20 30 40 50 Squamous Nonsquamous n 229 n 221 n 292 n 310 InteractionPvalueforhistology 036 n 521 n 531 Carboplatin Nab PaclitaxelvsCarboplatin PaclitaxelinNSCLC Safety Nohypersensitivityreactionsoccurredinthenab P Carmwithoutprophylacticpremedication whereas3occurredintheP Carm grade1 2 and3 respectively Favorsnab P C FavorsP C SocinskiMA etal JClinOncol 2012 30 2055 2062 Conclusions StandardofCareinPatientsWithoutIdentifiableDriverMutations NonsquamousNSCLCPemetrexedortaxane baseddoubletsBevacizumabinselectedpatients4 6cyclesConsiderationofmaintenancetherapyafter4 6cyclesSquamousNSCLCTaxane orgemcitabine baseddoublets4 6cyclesConsiderationofmaintenancetherapyafter4 6cycles 2013 First lineTreatmentofAdvanced MetastaticNSCLC 75 25 Non SCCa SCCa Platinum paclitaxel docetaxel gemcitabine orvinorelbine nab paclitaxel Nohemoptysis Anyhemoptysis 90 10 Carboplatin paclitaxel bevacizumaborplatinum pemetrexed Platinum pemetrexed paclitaxel docetaxel orgemcitabine EGFRmutation 15 KRASornoother actionable mutation 80 EGFR TKI EML4 ALKROS1 CrizotinibOrchemotherapy Mutationalanalysis Othermutations5 to10 ModifiedfromGandaraD etal ClinLungCancer 2009 10 392 394 IFCT 0501 DoubletvsSingle AgentChemotherapyinElderlyAdvancedNSCLC Doubletchemotherapy carboplatin paclitaxel superiortosingle agentchemotherapy gemcitabineorvinorelbine inelderlywithadvancedNSCLC QuoixE etal Lancet 2011 378 1079 1088 HR 0 64 95 CI 0 52 0 78 P 0001 Doubletchemotherapy 177deaths Monotherapy 199deaths 1 0 0 8 0 6 0 4 0 2 0 0 OS 6 12 18 24 30 36 42 Duration Mos PatientsatRisk nDoubletMonotherapySurvivalProbabilityDoubletMonotherapy 225226 160117 9254 44 525 4 5225 3215 22 411 7 198 72 9 04 0 22 Patientsaged70 89yrs stageIII IVNSCLC andPS0 2 N 451 SalvageTherapyandEmergingTherapeuticApproaches Second line orThird line Therapy ECOGperformancestatus0 2 ifnotalreadygiven DocetaxelPemetrexedErlotinib EGFRWT afatinib EGFRmutant GemcitabinePlatinumdoublet bevacizumab erlotinib iferlotiniborcrizotinibfirst linetherapyANDnonsquamoussubtype ECOGperformancestatus3Erlotiniborbestsupportivecare NCCN ClinicalPracticeGuidelinesinOncology non small celllungcancer v 2 2014 OverviewofCurrentSecond lineTreatment NocombinationtherapyhasprovenbenefitoversingleagentsNumerousfactorsinvolvedinchoiceoftreatmentPrevioustherapyHistologyPerformancestatusOrganfunction EGFRTKIsmaybeanoptioncomparabletochemotherapy EGFRWT Lesstoxic betterQoLSurvivalsimilaracrossallsubgroupsConsiderablecrossoveronallstudiesInmanycases thequestionisnotwhetherapatientwillreceiveadrug butwhenandinwhatsequence BlockadeofPD 1BindingtoPD L1 B7 H1 andPD L2 B7 DC RevivesTCells PD L1expressionontumorcellsisinducedby interferonInotherwords activatedTcellsthatcouldkilltumorsarespecificallydisabledbythosetumors SznolM etal ClinCancerRes 2013 19 1021 1034 Nivolumab MDX 1106 ONO 4538 Anti PD 1TargetedTherapyinNSCLC FullyhumanIgG4antihumanPD 1 blockingantibody 1 PD 1expressionontumor infiltratinglymphocytesinNSCLCiscorrelatedwithdecreasedcytokineproductionanddecreasedeffectorfunction 2 PD L1expressionnotedaspotentialbiomarkerinNSCLC 3 4 InNSCLCpatients n 129 5 All gradeAEs 71 inNSCLCvs75 intotalpopulation N 306 Mostcommonincludedfatigue diarrheaGrade3 4AEsoccurredin14 ofpatientswithNSCLCAll gradepneumonitiswasnotedin8 6 patientswithNSCLCDrug relateddeaths 2 occurredinNSCLCpatientswithpneumonitis 1 BrahmerJR etal JClinOncol 2010 28 3167 3175 2 ZhangY etal CellMolImmunol 2010 7 389 395 3 TopalianSL etal ASCO2012 AbstractCRA2509 4 TykodiSS etal ASCO2012 Abstract2510 5 BrahmerJR etal ASCO2013 Abstract8030 1patientofunknownhistologywhoreceived1mg kghadanOR ClinicalActivityofNivolumabbyHistology EfficacyPopulation BrahmerJR etal ASCO2013 Abstract8030 OverallSurvivalforPatientsWithNSCLCTreatedWithNivolumabMonotherapy MedianOS 95 CI 9 6months 7 8 12 4 1 yearOS 42 2 yearOS 14 BrahmerJR etal ASCO2013 Abstract8030 MPDL3280AAnti PD L1AntibodyPhaseIa EfficacySummary InvestigatorAssessed Allresponderscontinuedtorespondatlastassessment 1patienthadanundeterminedhistologystatus Spigel etal ASCO2013 Abstract8008 DocorGem FGFRi DocorGem DocorGem FGFRAmplification Mutation Fusion CDK4 6i DocorGem CyclinD1AmplificationorCDKN2loss RBWT PI3Ki DocorGem PI3KCAMutation BiomarkerProfiling NGS CLIA HGFi Erlotinib Erlotinib METExpression IHCscore PD L1i BiomarkerNon Match MultiplePhaseII IIIArmswith Rolling Opening Closure MASTERLUNG 1 S1400 Biomarkersand2ndLineTherapyforSquamousCellNSCLC ManagementofDiseaseSymptomsandAdverseEvents ManagementofBrainMetastases Brainmetastasesoccurin 30 ofpatientswithlungcancerManagementofpatientswithbrainmetastasesincludessurgicalresection radiationtherapy orsystemictherapyBrainmetastasesinpatientswhoharborEGFR activatingmutationsarefrequentlyresponsivetotherapywitherlotinibandmaybeafavorablesubsetofpatientscomparedwiththosewhodonotharborsuchamutationStereotacticradiosurgerydeliversasingleorverylimitednumberoffractionsofhighdoseofradiationtoawell definedtumorvolume FanY etal OncoTargetsTher 2013 6 1789 1803 ManagementofBrainMetastases Limited 1 3 brainmetastasesForpatientswithasinglemetastasisinasurgicallyaccessiblelocation resectionmayofferbestchanceforlocalcontrol postoperativeSRStothetumorbedisusedtodecreasethechanceoflocalrecurrenceSRSisaneffectivealternativetosurgeryifametastasisisinasurgicallyinaccessiblearea 3cmindiameter orifthepatientisnotasurgicalcandidateWBRTcanbeusefulinconjunctionwithsurgeryorSRStopreventlocalrecurrence butWBRTmayincreaselikelihoodofcognitiveadverseeffectswithoutincreasing