肺癌耐药的驱动基因

AssociateProfessorofMedicine,OncologyrsityStanfordCancerInstituteUSAvs的临床研究结果显示:lTKI靶向治疗的疾病控制率更好；lTKI靶向治疗的PFS更⻓:但中位生存时间仅有9-13个月；其他药物合用的报道较少–阿法替尼/西妥昔单抗,3rd代EGFRTKIskaTheCancerJournalCamidgeNatRevClinOncoloLungCAWangJHemOncHashidaCancerSciChengOncotarget2015;LantermannCancerRes2015;SudaLungCancer2015;SudaScientificRep2015PLoSMedYingScientificReportsMaJCAResTherAResWuetalLancetOncol2013–PFS16.8月vs6.9月(HR0.25,p<0.0001)–OS31.4月vs20.6月(HR0.48,p=0.009)EB联合RT90MT90MSQoLgranksttwogranksttwoBmgkgqwEBEBEMedian(months)0.54(95%CI:0.36–0alueE0246810121416182022242628E73929854241ufumiKatoASCOabsLancetOncologyJOstudygroupEGFRmutNSCLC(n=462)EGFRmutNSCLC(n=462)Arm1Arm2ompareOngoingriaActivatingActivatingEGFRTKITKImoPrimaryendpoint:progression-freesurviOIZEDrexedrexedtinibRANDOMIRANDOMIZEDAdvancedNSCLCActivatingEGFRTKIResponsetoEGFRTKI>4moNopriorchemotherapyPS0/1N=120ressionfreesurvivalCisCis/Carbo+Pemetrexed+ongoingerlotinibtrexedClinicaltrialsgovshowNCTAccessedMay14,2014.2.C/ct2/show/record/NCT01928160.AccessedMay14,2014.MedOS14.8mo(G)vs17.2mo(P)SoriaLancetOncol2015&MokWCLC2015HRSoriaLancetOncol2015&MokWCLC2015Moketal,WCLC2015,oral17stJuly“3rd”genN~8.0--ASP8273*TMsubgroupsareverysmallMultipleotheragentsearlierindevelopment102030OsimertinibOsimertinib:BestPercentageChangeinTargetLesionSizeCRNoUnconfirmConfirmedCRORedPRPR1020304016080mg4020mgmgmg24016080mg4020mgmgmgmg102030CR,completeresponse;OR,overallresponse;PR,partialresponse.JännePA,etal.NEnglJMed.2015;372:1689-1699.18l2-PhII2ndlineafterPDl3-PhIIIvschemolCombinationstudies:Osimertinib和RociletiniblOsimertinib-AURAl2-PhII2ndline(T790M+)l3-PhIIIvchemoT790M+lCombinationstudies:MEK,MET,PD-1/PD*PD-L1expression/EGFRmutationsassociated(earlystage)MutantEGFRupregulatesPD-L1viaPI3K–AKT/MEK–ERKsignalingpathwaysAzumaAnnalsOnc2014;OtaClinCanResearch2015AZD9291lltllformationformationlnThressNatureMedicine5;PiotrowskaCancerDiscovery2015T790M-wildtypeclonesemergeinT790M-positivecancerstreatedwiththeT790M-specificEGFRinhibitorrociletinib.etalCancerDiscoveryTumorheterogeneitycreatesvariablepatternsoftwithEGFRinhibitorsllcherayCancerRestalJTOrepeatbiopsyseriesptsrepeatsamesiteTMstatuschangedovertimewith/withouttherapyCZD目前Rociletinib和Osimertinib耐药的报道(n=34)TwtT790MMaintained(Noadditionalresistancemechanismidentified)Her2Amp/T790-wtTMLostThressKS,PaweletzCP,FelipE,etal,NatMed.2015;21(6):560-562.PiotrowskaZ,NiederstMJ,KarlovichCA,etal,CancerDiscov.2015;5(7):713-722.YuHA,TianSK,DrilonAE,etal,JAMAOncol.2015;1(7):982-984.PlanchardD,LoriotY,AndréF,etal,AnnOncol.2015;26(10):2073-2078.KimTM,SongA,KimDW,etal,JThoracOncol.2015.otrowskaayionossKPTENMEKNF-kB,formation(TGFb,MED12,AXL,Notch1)l一线EGFRTKI治疗仍是EGFR突变型肺癌的标准