肺癌驅(qū)動基因與精準(zhǔn)治療的研究近況Jin-JiYangMD.楊衿記GuangdongLungCancerInstituteGuangdongGeneralHospitalGuangdongAcademyofMedicalSciencesP.R.ChinaAugust22,2015TheoutlineEGFR:

第1、2、3代TKIALK：第1、2代TKIOthers:ROS1,RET,BRAFandc-METEGFRispartofafamilyofreceptortyrosinekinases(RTKs)PharmacogenomicsandPersonalizedMedicine2014:7WJOG5108L：全組PFS(主要終點(diǎn))

Erlotinibvs.GefitinibN.Katakami,etal.2014ASCOAbstract8041.CTONG0901:Evs.Ginexon19or21LUX-Lung3andLUX-Lung6PublishedonlineJanuary12,2015/10.1016/S1470-2045(14)71173-8Del19L858REGFRdel19-positivediseasemightbedistinctfromL858R.UncommonEGFRmutationsLancetOncol2015PublishedOnlineJune5,2015.Correspondenceto:YLWu.syylwu@Afatinib

wasactiveinG719X,L861QandS768I.LowerbenefitindenovoT790Mandexon20Ins.EGFRTKIsVs.ChemoinEGFR-MutantLung

Cancer:AMeta-AnalysisJClinOncol33.?2015byAmericanSocietyofClinicalOncologyGreaterbenefitswereobservedinthosewithexon19deletions,never-smokers,andwomen.AZD9291inEGFRInhibitor–ResistantNSCLCNEnglJMed2015;372:1689-99.T790M-positivedisease(yellow),mPFSwas9.6mvs2.8mwithT790M-negativedisease(blue).RociletinibinEGFR-MutatedNSCLCBestResponsetoRociletinib(AllDoses)in243CentrallyConfirmedTissueT790M+Patients<br/>PresentedByLeciaSequistat2015ASCOAnnualMeetingRociletinib:治療相關(guān)的一般不良事件500mgBID劑量組未觀察到ILD總體發(fā)生率1.5%(7/456)給予激素后患者可持續(xù)接受Rociletinib沒有出現(xiàn)致死性ILD沒有觀察到甲溝炎或口腔炎；輕微皮疹500mgBID組3級QTc延長發(fā)生率2.5%500mgBID組因治療相關(guān)不良事件導(dǎo)致的藥物中止發(fā)生率2.5%通過口服藥物輕松管理高血糖對于既往已經(jīng)存在的糖尿病患者沒有禁忌證SequistVI,etal.2015ASCOAbstract8001.超過10%的患者中出現(xiàn)各級治療相關(guān)的不良反應(yīng)N(%)AERociletinib劑量500mgBID(N-119)625mgBID(N=236)750mgBID(N=95)1000mgBID(N=6)高血糖35455967腹瀉33403067惡心19343750乏力29302725QT延長13232650食欲降低15162533肌肉痙攣14132117嘔吐816140體重減輕1091717超過10%的患者中出現(xiàn)3/4級治療相關(guān)的不良反應(yīng)，N(%)AERociletinib劑量500mgBID(N-119)625mgBID(N=236)750mgBID(N=95)1000mgBID(N=6)高血糖17243633PresentedByLeciaSequistat2015ASCOAnnualMeetingResponseRateinFirst-lineCohortsbyDosePresentedBySureshRamalingamat2015ASCOAnnualMeetingAZD9291FLAURAStudyDesignPresentedBySureshRamalingamat2015ASCOAnnualMeetingOngoingDevelopmentofRociletinibPresentedByLeciaSequistat2015ASCOAnnualMeeting3rd-VS.1stor2nd-generationEGFRTKI?Rationale

--targetingbothsensitizingandT790Mmut

--20~30%RRforT790Mneg.patients

--preliminarydataofphase1trialsin1st-lineIfsuccessful

--howtodealwith1stor2nd-generationTKI

--AZD9291+gefitinibVS.gefitinib+AZD9291?ClinicalCancerResearchFeb.27th,2015Crizotinib+ceritinib

leadingtoalongsurvivalASCEND-1N=71CompassionateuseN=2retrospectivelyN=7310-1st-linecrizotinib；53withoutintervalbetweencrizotinibandceritinib；2

withdrawnfromthetreatmentduetohightransaminaseanddeterioratingrenalcysts，buttheothersstoppedthedrugafterPD.CrizotinibCeritinibCrizotinibmPFSCeritinibmPFSCombinedmPFSOSGainor,J.F.etal.ClinCancerRes2015;EpubOS32ptswith2nd-linecrizotinib，similartoPROFILE1007Gainor,J.F.etal.ClinCancerRes2015;EpubOS:fromthedateofmetastaticNSCLCdiagnosiscOS:fromthedateofcrizotinibtreatmentMyviewpointson3rd-generationTargetingintrinsicT790Min1st-settings.Focusingonexon21-positivetreatment-na?vepatients.(Exon19issuperiortoexon21intermsofOS).IncombinationwithMETinhibitorforEGFRmu+ptswithbothacquiredT790MandMET.Markedactivityofalectinibinpatientswithcrizotinib-resistantALK+NSCLCPresentedBySai-HongOuat2015ASCOAnnualMeeting2nd-generationALKTKIsHighresponseanddiseasecontrolrateofalectinibinCNSmetastasesinALK+NSCLCPresentedBySai-HongOuat2015ASCOAnnualMeetingMarkedactivityofalectinibinALK+NSCLCpatientswithmeasurableCNSmetastasesPresentedBySai-HongOuat2015ASCOAnnualMeetingHighresponseanddiseasecontrolrateinCNSmetastasesinALK+NSCLCpatientsregardlessofpriorradiationPresentedBySai-HongOuat2015ASCOAnnualMeetingALEXphaseIIIstudydesignPresentedBySai-HongOuat2015ASCOAnnualMeetingHowtochoosewisely？CrizotinibCeritinib1L2LCeritinib3LAlectinibCNSCrizotinibCeritinib1L2LAlectinibI1171T2LWhichALKinhibitor??CNSefficacy?Tolerability?Resistancemechanism3LIstherearolefora3rdlineALKinhibitor??CNSdisease?ResistancemechanismMedianPFSwas9.1months,andthePFSrateat12monthswas44%.ResponsetoCabozantinibinPatientswith<br/>RET-RearrangedLungAdenocarcinomasPresentedByAlexanderDrilonat2015ASCOAnnualMeetingmPFS=7m;mOS=10m.D+TinBRAFV600EmutatedNSCLCORR=63%;DCR=88%PPHGF

HGF

HGF

HGF

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CYSCYSTKTKPPPPPPPHGFOverexpressionIPTJMCatalyticregionPPPAmplificationOverexpressionMutationHGF

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HGF

SEMAGrowthAngiogenesisCellularmotilityInvasionIncidence41.2%33.6%9.8-20.0%0.8-4.0%Abnormalitiesinc-MetsignalinginNSCLC1.IchimuraE,etal.JpnJCancerRes.1996;87(10):1063-9.2.MaPC,etal.CancerRes.2005;65(4):1479-88.3.BenedittiniE,etal.AmJPathol.2010;177(1):415-23.4.CappuzzoF,etal.AnnOncol.2009;20:298-304.5.BeanJ,etal.ProcNatlAcadSciUSA.2007;104:20932–20937.6.EngelmanJA,etal.Science.2007;316:1039–1043.7.SequistLV,etal.SciTranslMed.2011;3:75ra26-75ra26.8.UjiieH,etal.AnticancerRes.2012;32:3251-3258.9.HosodaH,etal.AnnThoracCardiovascSurg.2012;18:1-7.10.OnitsukaT,etal.JThoracOncol.2010;5:591-596.Li

A,Gao

HF,

WuYL.

201512891711104613191411618325715Thenumberonthetopofthebarmeansthepatients’numberintable1CrizotinibinNSCLCswithc-MetIHC/FISHstatusLiAnna,etal.ASCO2015.Abs#8090

ORR=58%METMutationAssociatedwithResponsivenesstoCrizotinibJournalofThoracicOncology??Volume10,Number5,May2015aMETmutationoccurringatasplicesitewithinthejuxtamembranedomain.MET/CEP7=0.96OncogenicmutationsintheMETexon14splicesitesthatcauseexon14skippingoccurin4%oflungadenocarcinomas.PaulK.Paik,AlexanderDrilon,HelenaYu,etal.CancerDiscoveryPublishedOnlineFirstMay13,2015..CabozantinibCrizotinib組織Met擴(kuò)增IHC腺癌6300腺癌無300腺癌3.8NA腺癌無300組織Met擴(kuò)增IHC腺癌6300腺癌無300腺癌3.8NA腺癌無300METexon14mutation:3%inlungadeno.2.3%inotherlungneoplasm0.4%inbrainglioma0.4%intumorsofunknownprimaryoriginHistiocyticsarcomatreatedwithcrizotinib.NSCLCtreatedwithINC280(capmatinib).Largecelllungca.METex14mu.METgcn6METIHC+++;270METFISHNALungSCCMETex14mu.METgcn4METIHC+++;300METFISH13.8MET/CEP7=2.3METmutationsleadingtoexon14skippingwereidentifiedineight(22%)of36patientcaseswithpulmonarysarcomatoidcarcinoma;0