【文档说明】非小细胞肺癌的标靶治疗培训课件.ppt，共(74)页，4.102 MB，由小橙橙上传

转载请保留链接：https://www.ichengzhen.cn/view-247790.html

以下为本文档部分文字说明：

非小细胞肺癌的标靶治疗主要癌症每十萬人口死亡數非小细胞肺癌的标靶治疗2FryWA,etal.Cancer.1996;77:1953.020406080100120I1007954644842II1006542322822III1003415975IV100249643012345

YearsNSCLC-SurvivalbyStage非小细胞肺癌的标靶治疗3NSCLCTreatmentEarlystageLocallyadvancedMetastasticSurgeryCT+surgeryCT+RTCCRTSurg

ery+CTCTTargetIa,IbIIa,IIbIIIaIIIbnocy+effusionIIIbcy+effusionIVcurativeintentpalliativeintentmetastasectomy非小细胞肺癌的标靶治疗4The“FirstG

eneration”Agents◼Methotrexate,cyclophosphamide,vincristine,anddoxorubicin—wereessentiallyinactiveinNSCLC,despitebeingwidelyusedi

nthe1970sand1980s.Thorax.58(4):352-6,2003Apr.非小细胞肺癌的标靶治疗5The“2ndGeneration”Agents◼Cisplatin,ifosfamide,mitomycin,vindesine,vinblastine,andetoposi

deinlate1980.Thorax.58(4):352-6,2003Apr.非小细胞肺癌的标靶治疗6The“3rdGeneration”Agents◼Paclitaxel,docetaxel,gemcitabineandvinorelbineemerged

inthechemotherapyofNSCLCInthemiddle1990s.◼Cisplatin-baseddoubletsarethemainstayofchemotherapyforadvancedNSCLC.Thorax.5

8(4):352-6,2003Apr.ASCO.NSCLCtreatmentguideline,2003非小细胞肺癌的标靶治疗7The“4thGeneration”Agents◼Targetedtherapyinearly2000s.Thorax.58(4):352-6,2003Apr.非小细胞肺

癌的标靶治疗8TargetValidation◼Thetargetshouldbepresentandfunctionallyabnormalrelativetonormaltissue.◼Thetargetshou

ldinfluencetumorbiologymanifestedthroughdifferencesinptoutcome.◼Interferingwithtargetfunctioninmodelsystemsshouldaltertumorbiology.

◼Interferingwiththetargetintheclinicsshouldalterptsurvivalorreverseclinicalsymptomsassociatedwiththecancer

undertreatment.非小细胞肺癌的标靶治疗9非小细胞肺癌的标靶治疗10EpidermalGrowthFactorReceptorInhibition(EGFRI)非小细胞肺癌的标靶治疗11EGFRexpressioninhumantum

oursNSCLC40-80%Prostate40-80%Gastric33-74%Headandneck90-100%Breast14-91%Colorectal25-77%Pancreatic30-50%Ovarian35-70%InvasionMet

astasisLate-stagediseaseChemotherapyresistanceHormonaltherapyresistancePooroutcomeTumoursshowinghighEGFRexpressionHighexpressiongenerallyassociated

with非小细胞肺癌的标靶治疗12InhibitionoftheEGFRsignalingpathwayMetastasisProliferation/maturationSurvival/apoptosisAngiogenesisMAPKMEKG

enetranscriptionCell-cycleprogressionPI3-KRASRAFSOSGRB2PTENAKTSTATKpYMG1SpYpYKEGFRG2HER1Baselga2002非小细胞肺癌的标靶治疗1

3Tyrosinekinaseinhibitors(TKIs)Gefitinib(Iressa,艾瑞莎)Erlotinib(Tarceva，得舒緩)非小细胞肺癌的标靶治疗14非小细胞肺癌的标靶治疗15IDEAL1&2:designschemaRandomisationIRESSA®

250mgoncedailyIRESSA®500mgoncedailyReceived1or2(IDEAL1)or2(IDEAL2)previouschemotherapyregimensContinueIRESSA®untildiseaseprogressionor

unacceptabletoxicityPrimaryendpointsPatients⚫Responserate(bothtrials)⚫Safetyprofile(IDEAL1)⚫Symptomrelief(IDEAL2)JCli

nOncol2003;21:2237–46.JAMA2003;290:2149–58.非小细胞肺癌的标靶治疗16IDEAL1:tumourresponserate0102030405060IRESSA®250mg/dayIRESSA®500mg/day18.419.0Patie

ntswithCRorPR(%)CR,completeresponse;PR,partialresponse非小细胞肺癌的标靶治疗170102030405060IDEAL1:diseasecontrolratePatientswithCR,PRorSD(%)54.4

51.4CR,completeresponse;PR,partialresponse;SD,stablediseaseIRESSA®250mg/dayIRESSA®500mg/day非小细胞肺癌的标靶治疗18IDEAL1:tumourrespons

erate0102030405060PatientswithCRorPR(%)Japanese(n=102)Non-Japanese(n=106)IRESSA®250mg/dayIRESSA®500mg/day

27.59.611.127.5非小细胞肺癌的标靶治疗19IDEAL2:tumourresponserate0102030405060IRESSA®250mg/dayIRESSA®500mg/day11.88.8Patients

withCRorPR(%)CR,completeresponse;PR,partialresponse非小细胞肺癌的标靶治疗200102030405060IDEAL2:diseasecontrolratePatientswithC

R,PRorSD(%)42.236.0IRESSA®250mg/dayIRESSA®500mg/dayCR,completeresponse;PR,partialresponse;SD,stabledisease非小细胞肺癌的标靶治疗2101020304050607081

216202428Timetoimprovement(days)%patientsIDEAL1:TimetoSymptomimprovement(n=54)6915467BaselgaJetal2001Median=8days非小细胞肺癌的标靶治疗22IDEAL2:Ti

metoSymptomImprovement010203040123456789101112131415161718Median=2weeksPercentTimetoImprovement(Weeks)非小细胞肺癌的标

靶治疗23PrognosticFactorsAssociatedwithanObjectiveResponse◼Adenocarcinoma>non-Adeno◼Female>male◼Japanese>non-Japa

nese◼BAC◼Non-smokerJClinOncol21:2237-2246,2003JClinOncol22:1103-1109,2004非小细胞肺癌的标靶治疗24IDEAL1:drug-relatedtoxicitiesbydoseRashDiarrhoeaPrurit

usDryskinAcneNauseaALTincreasedASTincreasedGrade1263225241011109IRESSA®250mg/dayIRESSA®500mg/dayGrade3/410000120Grade1303432225161314G

rade3/477102163Valuesare%patientsALT,alanineaminotransferase;AST,aspartateaminotransferaseGrade2198533112Grade23317388756非小

细胞肺癌的标靶治疗25IDEAL2:drug-relatedtoxicitiesbydoseRashDiarrhoeaDryskinAcneVomitingNauseaGrade13941121997IRESSA®250mg/dayIRESSA®500mg/dayGrade3

/4010011Grade136452418511Grade3/4350431Valuesare%patientsGrade2461625Grade2151731116非小细胞肺癌的标靶治疗26Pre-treatmentPo

st-treatment,10days非小细胞肺癌的标靶治疗27Acceleratedapprovalregulations◼FDAallowpharmaceuticalmanufacturerstoof

ferptstreatmentforlife-threateningdiseases.◼Thismayoccurwhenearlyevidencesuggeststhattheagentislikelytoimprovesurvivalorreducesymptoms,beforeco

nfirmatorystudiesaresafeandefficacious.◼IressawasmarketedinMay,2003inU.S.A.◼AZneedanotherphaseIIItrial.非小细胞肺癌的标靶治疗

28AcuteInterstitialPneumonitis◼IressawasapprovedinJapaninJuly,2002.◼FromAugusttoDecember,19000ptsreceivediressa(1)358(1.9%)

ptsdevelopedinterstitiallungdisease(ILD).(2)114(0.6%)haddied.◼EpidemiologicalsurveyinJapan(1)4.6%patientshaddeveloped

ILD.(2)1.5%haddiedduetoILDbyiressa.WJTOGreport非小细胞肺癌的标靶治疗29JChinMedAssoc•April2005•Vol68•No4非小细胞肺癌的标靶治疗30Iressa-relatedAIPinTaiwan◼Responseratefo

rgefitinibinchemotherapytreatedptswithadvancedNSCLCwas22.7%.◼12of428pts(2.8%)hadAIPwithgefitinibtreatment.◼4of12pts(0

.9%)died.JournalofThoracicOncology•Volume1,Number6,July2006非小细胞肺癌的标靶治疗31Iressacombinedwithchemotherapy◼IressaNSCLCTrialAssessingComb

inationTreatment1and2(INTACT1,2),chemonaivepts◼INTACT1:Gemcitabine+Cisplatin+Iressa◼INTACT2:Taxol+Carboplatin+Ir

essa◼Failuretoprolongsurvivalandresponserate.JClinOncol2004;22:777-84.JClinOncol2004;22:785-94非小细胞肺癌的

标靶治疗32EndpointsPrimary:⚫SurvivalSecondary:⚫TTF⚫ORR⚫QoL,symptoms⚫SafetyExploratory:⚫Tumourbiomarkeranalysis(egEGFR)IressaSurvival

EvaluationinLungCancer,ISEL◼1692patientsin210centresacross28countriesGefitinib(250mg/day)+BSCPlacebo+BSC

Randomisation(2:1ratio)CT,chemotherapy;BSC,bestsupportivecare;TTF,timetotreatmentfailure;ORR,objectiverespon

serate;QoL,qualityoflifePatientswith:⚫Histologically/cytologicallyconfirmedNSCLC⚫Locallyadvancedormetastaticdisease⚫

1or2priorCTregimens⚫IntoleranttomostrecentCTregimenorprogression90daysoflastCTcycleLancet.2005;366(9496):152

7-37.非小细胞肺癌的标靶治疗33非小细胞肺癌的标靶治疗34SurvivalHRand95%CI0.40.60.81.01.5AdenocarcinomaAllpatientsFemalePS0,11priorlineRefractor

yNeversmokedNon-adenocarcinomaEversmokedIntolerant2priorlinesPS2,3Male11.9%8.0%14.7%8.8%7.6%7.9%18.1%4.8%5.3%9.4%8.4%6.6%5.

1%GefitinibORRSubgroupanalysisFavoursgefitinibFavoursplaceboLancet.2005;366(9496):1527-37.非小细胞肺癌的标靶治疗35Surv

ivalSubgroupanalysis11.1%8.0%12.4%7.4%6.9%9.0%6.8%7.5%10.1%7.7%6.4%7.2%10.2%PriordocetaxelAllpatientsAsianethnicity<65yearsNopriordocetaxel

65yearsNon-AsianethnicityPriorCTresponse:PD/NEPriorCTresponse:CR/PRPriorCTresponse:SDTimesinceDx:<6mon

thsTimesinceDx:6–12monthsTimesinceDx:>12monthsGefitinibORRFavoursgefitinibFavoursplacebo0.40.60.81.01.5HRan

d95%CILancet.2005;366(9496):1527-37.非小细胞肺癌的标靶治疗36非小细胞肺癌的标靶治疗37MarketingAuthorizationApplicationWithdrawninEuropeAZ收回歐洲市場的上市申

請非小细胞肺癌的标靶治疗38ErlotinibinPreviouslyTreatedNon-small-cellLungCancer,BR21NEnglJMed2005;353:123–32.非小细胞肺癌的标靶治疗39非小细胞肺癌的标靶治疗40非小细胞肺癌的标靶治疗41Tarcevacomb

inedwithChemotherapy◼ChemonaiveNSCLC(1)Tarceva+taxol+carboplatin(2)Tarceva+cisplatin+gemcitabine◼Failu

retoprolongsurvival.◼EGFR-TKIfailtobecombinedwithconventionalchemotherapy.JClinOncol2005;23:5892–99.JCli

nOncol2007;25(12):1545-52.非小细胞肺癌的标靶治疗42WhocorrelatedwithEGFR-TKIresponse◼EGFRisoverexpressedin40%-80%NSCLC.◼EGFRexpressiondoesn’tcor

relatedwithEGFR-TKIresponse.◼Adenocarcinoma>squamouscellcarcinoma.非小细胞肺癌的标靶治疗43EGFRMutation◼ConformationalEGFRchang

e,sensitivetoEGF-TKI.◼Asian,never-smoker,female,adenocarcinomahavehighEGFRmutationrate.Science2004;304:1

497-500NEnglJMed2004;350:2129-39非小细胞肺癌的标靶治疗44非小细胞肺癌的标靶治疗45非小细胞肺癌的标靶治疗46EGFRMutation◼Exon19deletion:46%◼Exon21missensemutation:41%.◼Exon20dup

lication/insertion:5%◼Asian(34%)>non-Asian(8%)◼Female(46%)>male(18%)◼Never-smoker(56%)>smoker(13%)◼Adenocarcinoma(39%)>otherNSCLC(2

%)Signal2005;6:4-8.非小细胞肺癌的标靶治疗47健保局適應症◼Gefitinib:(96/8/1)限單獨使用於先前已使用過platinum類及docetaxel或paclitaxel化學治療後，但仍局部惡化或轉移之腺性非小細胞肺癌之第三線用藥。◼Erlotinib（96/8/1）

限單獨使用於先前已使用過platinum類及docetaxel或paclitaxel化學治療後，但仍局部惡化或轉移之非小細胞肺癌之第三線用藥。非小细胞肺癌的标靶治疗48EGFRMonoclonalAntibodyCetuximab,Erbitux非小细

胞肺癌的标靶治疗49非小细胞肺癌的标靶治疗50Cetuximab◼Human-murinechimericmonoclonalantibody.◼Inexperimentalstudies,cetuximabcombinedwithC/TorR/Thas

additiveorsynergisticeffect.◼Proveneffectincolorectal,headandneckcancer.ExpertOpinPharmacother2004;5:1621–33非小细胞肺癌的标靶治疗5

1Cetuximab◼400mg/m2atfirstweek,250mg/m2weekly,4weeksas1cycle.◼Sideeffectsincludeskintoxicity(21%),fever(13.5%),asthenia(13.5%)

,transaminaseelevation(11.5%)andnausea(11.5%)JClinOncol2000;18:904–14.非小细胞肺癌的标靶治疗52MulticenterphaseI/IIstudyofcetuximabwithpaclitaxeland

carboplatininuntreatedptswithstageIVNSCLC.◼Thecombinationofcetuximab,paclitaxel,andcarboplatinwassafeandwelltolerat

edstageIVpts.◼Theresponserate,timetoprogression,andmediansurvivalwereslightlysuperiortohistoricalcontrolstreatedwithpa

clitaxelandcarboplatinalone.JClinOncol.2005;23(34):8786-93.非小细胞肺癌的标靶治疗53PhaseIITrialofCetuximabinPatientsWithPreviouslyTreatedNon–Small-C

ellLungCancer◼Theresponseratewithsingle-agentcetuximabinadvancedNSCLCptsreceivingatleastoneC/Twas4.5%.◼Thediseasecontrolratesand

overallsurvivalseemcomparabletothatofpemetrexed,docetaxel,anderlotinibinsimilargroupsofpts.JClinOncol.2006;24(33):5253-58.非小细胞肺癌的标靶治疗54Va

scularEndothelialGrowthFactor(VEGF)MonoclonalAntibodyBevacizumab,Avastin非小细胞肺癌的标靶治疗55◼FolkmanJ.Tumorangiogenesis:therapeuticimplica

tions.NEnglJMed1971;285:1182-1186.非小细胞肺癌的标靶治疗56◼Tumorsabsorbnutrientsandoxygenbysimplediffusionuptoasizeof1-2mm.◼Theirf

urthergrowthrequirestheelaborationofavascularsupply.Carcinogenesis2000;21:505-515.非小细胞肺癌的标靶治疗57PhaseIITrialComparingBevacizumabPlusCarboplatin

andPaclitaxelWithCarboplatinandPaclitaxelAloneinPreviouslyUntreatedLocallyAdvancedorMetastaticNon–Small-CellLungCancerJ

ClinOncol2004;22(11):2184-91.非小细胞肺癌的标靶治疗58非小细胞肺癌的标靶治疗60Bleedingsideeffect◼Minormucosalbleeding(eg,epistaxis),pulmonaryhemorrhage

.◼6/66(9.1%)life-threateningpulmonaryhemorrhagesinptsreceivingbevacizumab.◼4(6%)ptsdied.◼Nevernotedinpreviouscolorectal,breast,andren

alcellcarcinoma.JClinOncol2004;22(11):2184-91.非小细胞肺癌的标靶治疗61PulmonaryHemorrhage◼Highriskgroupsinclude:(1)centrallylocat

edtumors,(2)tumorscloselyadjacenttomajorbloodvessels,(3)thepresenceoftumorcavitation,(4)squamouscellcarcinoma.JClinOncol2004;22(11):2

184-91.非小细胞肺癌的标靶治疗62Paclitaxel–CarboplatinAloneorwithBevacizumabforNon–Small-CellLungCancerNEnglJMed2006;355:2542-50.非小细胞肺

癌的标靶治疗63◼ECOGconductedarandomizedstudyinwhich878ptswithrecurrentoradvancedchemonaiveNSCLC(stageIIIBorIV)(1)paclitaxelandcarboplatinalone

(444)(2)paclitaxelandcarboplatinplusbevacizumab(15mg/kg)(434).◼Chemotherapywasadministeredevery3weeksforsixcycles.NEnglJMed2006;355:2542-50.非小细胞肺

癌的标靶治疗64ExclusionCriteria◼Squamous-celltumors,◼Brainmetastases,◼Clinicallysignificanthemoptysis,◼Inadequateor

ganfunction,◼ECOGperformancestatus>1,◼Coagulopathy,◼Medicallyuncontrolledhypertension.NEnglJMed2006;355:2542-50

.非小细胞肺癌的标靶治疗65Result◼Themediansurvivalwas12.3monthsvs.10.3months(BPCvs.PC)(P=0.003).◼Themedianprogre

ssion-freesurvivalwas6.2v.s.4.5months(BPCvs.PC)(P<0.001).◼Responseratesof35%v.s.15%(P<0.001).◼Ratesofclinicallys

ignificantbleedingwere4.4%and0.7%,(P<0.001).NEnglJMed2006;355:2542-50.非小细胞肺癌的标靶治疗66非小细胞肺癌的标靶治疗67非小细胞肺癌的标靶治疗68非小细胞肺癌的标靶治疗69非小细胞肺癌的标靶治疗70

Treatment-relatedDeath◼Twodeaths(gastrointestinalhemorrhageandfebrileneutropenia)occurredinPCgroup.◼15occurredinBPCgroup(1)5wereattrib

utedtopulmonaryhemorrhage,(2)5tocomplicationsoffebrileneutropenia,(3)2eachtoacerebrovasculareventorGIhemorrhage,(4)1toprobablepulmonaryemb

olus.◼Mostofthedeathsoccurredduringthefirsttwocyclesoftherapy.NEnglJMed2006;355:2542-50.非小细胞肺癌的标靶治疗71適應症◼美國食品藥物管理局目前核准它使用在

晚期已轉移的大腸直腸癌病人的第一線療法、非鱗狀細胞的非小細胞癌與化療合併使用。◼台灣目前只核准使用在晚期已轉移的大腸直腸癌病人，健保仍未給付。晚期非小細胞肺癌的病人未納入使用範圍。非小细胞肺癌的标靶治疗72FutureDirection◼Newtargetsforintervention.◼Be

tterpatientselection,lesssideeffect.◼CombinedC/TorR/T.◼Multi-targetedagents.非小细胞肺癌的标靶治疗73TheEnd非小细胞肺癌的标靶治疗74