非小细胞肺癌治疗展望

非小细胞肺癌治疗展望晚期NSCLC一线化疗疗效StudyDrugs#Pts%,St.IV%,ORRMST%,1-YSKelly,2001SWOG9509Vnr/CisTax225/Cb20220888892825883336Schiller,2002ECOG1594Tax135/CisGem/CisTxt/CisTax225/Cb2922882932908986868621.32117.315.38.18.17.48.331363135Scagliotti,2002ILCPVnr/CisGem/CisTax225/Cb2012052018181823030329.59.89.9373743Belani,2002TAX326Vnr/CisTxt/CisTxT/Cb40440840267676725322410.111.39.4414638Tax:泰素；Gem:健择；Txt:泰索帝；Vnr:诺维本；Cis:顺铂；Cb:卡铂8-10月30-40%~35%非小细胞肺癌治疗的瓶颈Cisplatin/paclitaxelCisplatin/gemcitabineCisplatin/docetaxelCarboplatin/paclitaxel1.00.80.60.40.20ProportionofpatientsMos051015202530SurvivalbyTreatmentGroupAllRandomizedCasesSchillerJH,etal.NEnglJMed.2002;346:92-98.ECOG1594:OS无论使用何种第三代化疗药物的组合，患者的总生存都没有差异。非小细胞肺癌治疗的瓶颈为什么疗效没有得到提高？是新药物并没有什么大的突破？还是……1.SchillerJH,etal.NEnglJMed2002;346:92-98.2.ScagliottiGV,etal.JClinOncol2008;26:3543-3551.3.YangCH,etal.Presentedat2010ESMO.4.InoueA,etal.2011ASCOAbstract7519.5.MitsudomiT,etal.LancetOncol2009;DOI:10.1016/s1470-2045(09)70364-X.ECOG1594含铂两药化疗未经选择患者(N=1207)1JMDB顺铂/培美曲塞非鳞癌患者(N=618)2IPASS卡铂/紫杉醇腺癌、不/少吸烟患者(N=608)3NEJ002易瑞沙EGFR基因敏感突变患者(N=114)4WJTOG3405易瑞沙EGFR基因敏感突变患者(N=86)5中位生存期(月)8.011.817.427.730.905101520253035未经选择人群临床特征选择人群基因靶点选择人群个体化治疗才能解除魔咒NCCN指南变迁根据PS评分选择治疗手段初治的病人进行EGFR突变检测初治病人要进行EGFR突变和ALK融合基因的检查Whatisthenextgene?非小细胞肺癌驱动基因的发现之旅Pao,WGirard,NLancetOncol.2011Feb;12(2):175-80.肿瘤驱动基因/突变驱动突变（drivermutation）能提供所在细胞的生长优势，是肿瘤发生的病因因素，能被正选择，驱动正常细胞向增殖癌细胞的转化。'Driver'mutationsconfergrowthadvantageonthecellinwhichtheyoccur,arecausallyimplicatedincancerdevelopmentandhavethereforebeenpositivelyselected.Greenman,CNature446,153-158针对这些驱动基因的治疗药物及手段靶点药物靶点药物EGFRGefitinibMAP2K1CI-1040ErlontinibAZD6244ALKCrizotinibTAK-733HER2Afatinib/BIBW2992AS703026LapatinibGSK1120212HKI-272PD-325901PertuzumabGDC-0973/XL518TrastuzumabRO4987655PI3KBEZ2235RO5126766GDC-0941METCrizotinibXL147GSK1363089/XL880AKTMK2206XL184BRAFSorafenibAMG102PLX4032MetMAbGSK2118436ARQ197XL281SCH900105Pao,WGirard,NLancetOncol.2011Feb;12(2):175-80.MassachusettsGeneralHospitals,dataonfileATShaw,personalcommunicationMitsudomietal.NSCLC驱动基因在人种上的差别欧美人群肺腺癌的驱动基因突变情况KrisMG,etal.ASCO2011腺癌不吸烟的人群驱动基因突变情况KRASUnknownEGFRHER2ALKfusionPhamDetal.JClinOncol2006;24(11):1700.StephensPetal.Nature2004;431(7008):525.ShawATetal.JClinOncol2009;27(26):4247.RielyGJetal.ClinCancerRes2008;14(18):5731.美国人群亚洲人群ChenguangLietal.PloSONE2011;6(11)97%的基因突变互相排斥单个突变数ALKAKTBRAFEGFRHER2KRASMEK1METNRASPIK3CAALK(38)X1211AKT(1)XBRAF(9)X1EGFR(89)X13HER2(3)XKRAS(114)X11MEK1(2)X11METAMP(3)XNRAS(2)XPIK3CA(6)XKrisMG.etal.ASCO2011,Abstract#7506.驱动基因小结目前非小细胞肺癌几乎半数的驱动基因已经被发现。绝大多数情况下，这些驱动基因的突变不会同时出现。对于已知的靶点，已经有很多上市或在研的药物。他们将会改变现有非小细胞肺癌的治疗策略。不同的人种，病理类型，吸烟状况，驱动基因的突变状态各异。其中非吸烟的肺腺癌的驱动基因突变状态已知最全面，且目前可以获得的治疗效果最好。Doesdreamcometrue?EGFRTKI被证实在EGFR敏感突变的患者中疗效显著0时间(天)无进展生存率(%)020406080100100200300400500600700800NEJGSG002研究时间(月)0102030401.00.80.60.40.20.0无进展生存概率WJTOG3405研究13.14.6PFS概率1.00.80.60.40.20时间(月)OPTIMAL研究时间(月)PFS概率1.00.80.60.40.20036912151821242730339.75.2EURTAC研究ProgressivediseaseStablediseaseConfirmedpartialresponseConfirmedcompleteresponseMaximumchangeintumorsize(%)–30%*Partialresponsepatientswith100%changehavenon-targetdiseasepresent*TumorResponsestoCrizotinibforPatientswithALK-positiveNSCLCKwakELetal.NEnglJMed2010;363:1693-703.PFSprobabilityat6months:72%(95%CI:61,83%)Progression-freesurvival(months)Progression-freesurvivalprobability02.55.07.510.012.515.017.5Medianfollow-upforPFS:6.4months(25–75%percentile:3.5–10months)95%Hall-WellnerconfidencebandsPFSMedianPFSHasNotBeenReached70%ofPatientsinFollow-upforPFSKwakELetal.NEnglJMed2010;363:1693-703.CurrentCrizotinibClinicalTrialsPROFILE1007:NCT00932893;PROFILE1005:NCT00932451Keyentrycriteria•PositiveforALKbycentrallaboratory•1priorchemotherapy(platinum-based)N=318PROFILE1007Crizotinib250mgBID(N=250)administeredonacontinuousdosingscheduleKeyentrycriteria•PositiveforALKbycentrallaboratory•ProgressivediseaseinArmBofstudyA8081007•1priorchemotherapyPROFILE1005RANDOMIZEN=250Crizotinib250mgBID(n=159)administeredonacontinuousdosingschedulePemetrexed500mg/m2ordocetaxel75mg/m2(n=159)infusedonday1ofa21-daycyclec-METastherapeutictargetinNSCLC•HGF/METaxisisassociatedwithinvasivenessandisregulatedinpartbytheHIFandEGFRpathways•METamplificationsareassociatedwithEGFRinhibitorresistance•HGF/METmaypromoteresistancetoVEGFinhibitorsXuetal,Oncogene,2010;Engelmanetal,Science,2006;Casconeetal,ASCO2010c-METreceptortyrosinekinaseinhibitors—PromisingtherapeutictargetinNSCLCWithpermissionfromSchillerJHetal.ProcASCO2010;AbstractLBA7502.ARQ-197,anovelandselectivenon-ATPcompetitiveinhibitorofc-METEndpoints•Primary:PFS•Secondary:ORR,OS•Subsetanalyses•Crossover:ORRRANDOMIZEPD•ARQ209enrolled167advancedNSCLCpatients•Studyaccrualover11months(10/08–9/09)•Randomizationstratifiedbysex,age,smoking,histology,performancestatus,priortherapyandbestresponse,andgeographyNSCLC•Inoperablelocallyadv/metastaticdz•≥1priorchemo(nopriorEGFRTKI)Erlotinib150mgPOQD+ARQ-197360mgPOBID28-daycycleErlotinib150mgPOQD+placebo28-daycycle*Coxregressionmodel.WithpermissionfromSchillerJHetal.ProcASCO2010