吉非替尼的循证之路

吉非替尼的循证之路贾筠东莞市人民医院1980sMendelsohnproposesEGFRasanticancertarget1983Firstanti-EGFRagents(mAbs)1990sFirstclinicaltrialofanti-EGFRagent(mAb)confirmsMOA1994DiscoveryofnewclassofEGFR-TKIsbyAstraZeneca1997FirstclinicaltrialsconfirmMOAofIRESSA.1998FavourabletolerabilityandunprecedentedresponsesinPhaseItrials,reportedatNCI-EORTC-AACR,HKellyetal2000EAPstartsinparallelwithPhaseII/IIItrials(IDEAL/INTACT)2002July:JapaneseapprovalAugust:INTACTstudiesshownoaddedbenefitofaddingIRESSAtostandard1stlinedoubletchemotherapyforNSCLC2003May:USapproval2004April:EGFR-TKmutationsclarifythemechanismforsomeofthedramaticresponsesproducedDecember:ISELdatademonstratenosurvivaladvantageoverBSCinoverallpopulation,thoughsubgroupsshowbenefit2005Approvalsin36countriestodateSIGNdata–firstdirectcomparisonofEGFR-TKIvschemotherapyISELbiomarkeranalysissuggestsFISH+patientsmorelikelytobenefitfromIRESSA2006INVITE(1stlineNSCLC)IMEX(H&Ncancer)September:CCSdatapublishedinformingaboutILDinJapan2007V-15-32(2ndlineNSCLCvsdocetaxel—Japan)INTEREST(2ndlineNSCLCvsdocetaxel)INSTEP1977IdentificationofEGFreceptorbyCohen1975IsolationofhumanEGF/urogastronefromhumanurinebyCohen(VanderbiltUniv.)andGregory(ICI)1984HumanEGFRclonedandsequencedLate1980sAccumulatingevidencethatEGFRisassociatedwithtumourprogressionandthatEGFRkinaseactivitycanbeinhibitedinvitrobysmallmolecules1960sCohen’sdiscoveryofepidermalgrowthfactor(EGF)inmicein1962pioneersmajorprogressincellgrowth/differentiationresearch.2008IPASSResults易瑞沙的历史正是肺癌靶向治疗的历史的缩影易瑞沙在中国全球和中国第一个上市的EGFR-TKI启动了中国NSCLC的靶向研究将中国医生带上了国际靶向研究的历史舞台，由此开始中国肺癌靶向新纪元。伴随着研发的不断深入，共识在争论中显现吉非替尼从二线到一线的跨越吉非替尼在中国争议与共识吉非替尼从二线到一线的跨越吉非替尼在中国争议与共识FerryD,theUniversityofBirminghaminEnglandPR：4/16（25%）KusabaH,theNationalCancerCenterinJapanPR：5/23（21%）GossG,theNationalCancerInstituteofCanada药代动力学:抑制EGFR-TKI的自主磷酸化NSCLCMovingBeyondtheSnail'sPace2000，ASCO由此启动了临床试验：二线单药（phase2)一线联合化疗（phase3)总体n=209日本亚组n=102Patients(%)ORRDCR54.451.418.419.0010203040506070ORRDCR70.470.627.527.5010203040506070250mg500mgIDEAL1and2首次发现易瑞沙疗效与种族相关IDEAL1,Fukuokaetal2003MST(Month):7.61-YearSurvival:35%PFS(Month):2.7MST(Month):13.81-YearSurvival:57%PFS(Month):3.8ISEL：吉非替尼VS安慰剂所有人群总生存期延长但未达显著性差异中位生存期(月)1年生存率(%)Log-rankHR(95%CI),0.89(0.77,1.02);p=0.087;Coxanalysis,p=0.030吉非替尼5.627安慰剂5.1210246810121416(月)0.00.20.40.60.81.0生存率HR,hazardratio;CI,confidenceintervalThatcherNetal,2005美国FDA修改Iressa的适应症：只能用于有效的晚期肺癌患者ISEL亚洲亚组：易瑞沙显著延长亚裔患者生存期5.59.5生存概率(%)0.01.00.80.60.40.20246810121416生存时间(月)N=342HR=0.6695%CI:0.48-0.91p=0.01023%41%易瑞沙安慰剂研究结论：易瑞沙能显著改善亚裔既往接受过治疗的难治性晚期NSCLC的总生存期峰回路转ChangA,etal.JThoracOncol2006;1:847-855.易瑞沙上帝送给东方人的礼物循证实践：易瑞沙的临床应用KParkandKGoto.CurrMedResOpin2006;22(3):561-573.OverallsurvivalTimetoProgressionJapanChinaKoreaTaiwanTime(months)010155化疗MST5.7-8.3月化疗TTP2.1-2.9月MST3-14月TTP2-6月吉非替尼启动晚期NSCLC二线对照标准化疗的临床研究：吉非替尼VS多西他赛吉非替尼VS多西他赛OSSIGNV-1532INTERESTISTANA易瑞沙对照多西他赛治疗复治的晚期NSCLC患者：来自四项临床研究的荟萃分析ComparisonofGefitinibandDocetaxelinpatientswithpretreatedadvancedNSCLC:Meta-AnalysisfromfourclinicaltrialsShepherdFA,etal.2009ASCOAbstract8011.荟萃分析的主要结果：易瑞沙与多西他赛总生存期相似生存概率自随机时间(月)N=2224HR(95%CI)=1.03（0.93-1.13）易瑞沙多西他赛自随机时间(月)生存概率0.040363228242016128400.20.40.60.81.0N=963HR(95%CI)=1.04(0.88-1.22)p=0.6506易瑞沙多西他赛亚裔亚组全组人群P=0.5773易瑞沙无进展生存期显著优于多西他赛(亚裔患者)无进展概率3228242016128400.00.20.40.60.81.0N=839HR(95%CI)0.81(0.69-0.94);p=0.0059自随机时间(月)吉非替尼多西他赛无进展生存期主要采用经过调整的分析；HR1提示吉非替尼的进展风险更低ShepherdFA,etal.2009wclc.易瑞沙治疗缓解的概率显著优于多西他赛(亚裔患者)OR(吉非替尼vs.多西他赛)与95%CI13患者例数研究INTERESTV-15-32ISTANA荟萃分析292EFR387EFR161ITT839OR(95%CI)2.67(1.29-5.53)2.14(1.21-3.78)4.74(1.81-12.41)0123456789101112吉非替尼更有利多西他赛更有利2.64(1.77-3.93)p0.0001ShepherdFA,etal.2009wclc.“Resultswereconsistentwiththoseoftheindividualstudies.Giventhesimilar/superiorefficacydemonstratedbyG,itsfavorabletolerabilityprofile,qualityoflifebenefitsandoraladministration,Ghasafavorablebenefit-riskprofilecomparedwithDinabroadpre-treatedadvancedNSCLCpatientpopulation”——FrancesSherpherdetal.荟萃分析的结论本荟萃分析与每个研究的结果一致吉非替尼证明（在未经选择的患者中）与多西他赛疗效相似，安全性更好，能明显改善患者生活质量，并且口服给药，这些特点使吉非替尼在治疗复治的晚期NSCLC患者时，相比多西他赛具有更好的疗效-风险比荟萃分析亚裔亚组分析结果显示两者总生存期相似无进展生存期：HR=0.81，易瑞沙比多西他赛降低19%的进展风险，P=0.0059客观缓解率：易瑞沙缓解的概率显著高于多西他赛达2.64倍，P0.0001EGFR突变和吉非替尼疗效相关吉非替尼二线治疗一线治疗IPASS、NEJGSG002、WJTOG3405、First-SIGNAL亚洲的崛起IressaPanASiaStudy–IPASS2006/3---2007/109个亚洲国家1217入组患者371例来自中国大陆ESMO2008/9月15日大会报告2009/9/8发表于《NEnglJMed》第一个泛亚地区的肺癌一线治疗研究IPASS:PFS(ITT人群)609453(74.4%)608497(81.7%)NEventsHR(95%CI)=0.741(0.651,0.845)p0.0001吉非替尼吉非替尼组显著优于卡铂/紫杉醇组HR1意味着吉非替尼组复发风险低卡铂/紫杉醇卡铂/紫杉醇吉非替尼中位PFS(月)4个月无进展6个月无进展12个月无进展5.761%48%25%5.874%48%7%6092127624506081182231036341204812162024月0.00.20.40.60.81.0PFS概率患者数:T.Moketal2008ESMOIPASS：EGFR突变阳性和临床特征总体EGFR突变率=59.7%(261/437)MaleFemalePS0/1PS0/2NeversmokedLightex-smokerLocallyadvancedMetastaticAge65yrsAge65yrs%ofsamplesEGFRmutationpositive49.063.060.057.160.746.957.860.256.768.5FukuokaM,etal.2009ASCOAbstract8006.根据生物标志物分析的缓解率(ITT)P-valuesfromlogisticregressionwithcovariates71.21.151.53458.922.247.323.541.826.326.144.801020304050607080ORR(%)GefitinibC/Pp=0.0243p=0.5580p=0.4146