非小细胞肺癌表皮生长因子受体酪氨酸激酶抑制剂（英文）

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1、Epidermalgrowthfactorreceptor-tyrosinekinaseinhibitorinnon-small-celllungcancerYuh-MinChen,MD,PhD.ChestDept.,TaipeiVGH10/6/20211YMCSurvival(anti-apoptosis)PI3-KActivationoftheepidermalgrowthfactorreceptortyrosinekinase(EGFR-TK):apivotaldriverofcarcinogenesisEGFR-TKEGFRLigandRASRAFSOSGRB2PTENAKTSTAT

2、3MEKGenetranscriptionCell-cycleprogressionDNAMycMycCyclinD1JunFosPPMAPKProliferation/maturationChemotherapy/radiotherapyresistanceAngiogenesisMetastasisBalabanetal1996;Akimotoetal1999;Wells1999;Woodburn1999;Hanahan2000;Raymondetal2000CyclinD1pYpYpY10/6/20212YMCRppRExtracellularIntracellularMembra

3、nepKpKpppTGFaSubstrateSubstrateSignallingMoleculesProliferationInhibitApoptosisAngiogenesisMetastasisNucleusMonoclonalAntibodiesEGFRTyrosineKinaseInhibitors10/6/20213YMCIDEAL1and2trialdesignGefitinib250mg/dayGefitinib500mg/dayContinuegefitinibuntildiseaseprogressionorunacceptabletoxicityIDEAL,Ires

4、saTMDoseEvaluationinAdvancedLungcancerRandomisationIDEAL1(n=209)1or2priorregimensIDEAL2(n=216)>2priorregimensPrimaryendpointsObjectivetumourresponseSymptomimprovement(IDEAL2)Safety(IDEAL1)10/6/20214YMCMediantimetoimprovement-symptomsandQOL*Timeof1stassessmentMediantimetoimprovement,daysSymptom/QOLm

5、easureLCSFACT-L8*29*10/6/20215YMCIDEAL1and2:overallsurvivalbysymptomimprovement(250mg/day)Probability1.00.80.60.40.20.0IDEAL1MonthsfromrandomisationImprovementNoimprovement2740183013.33.5Patients(n)Deaths(n)Median(months)024681012141618204458265613.63.7Patients(n)Deaths(n)Median(months)1.00.80.6

6、0.40.20.0ProbabilityIDEAL2Monthsfromrandomisation02468101214161820Douillardetal2002;Lynchetal200310/6/20216YMCISEL(IRESSASurvivalEvaluationinLungCancer):ClinicalTrialDesignRandomisationGefitinib(250mg)+*BSCPlacebo+*BSCSURVIVALSecondary:TTF,ORQoL,safetyPrimaryendpoint:ENDBENEFIT2:1ratioAdoubleblindP

7、haseIIIsurvivalstudycomparingIRESSA(250mg)plusBSCvs.placeboplusBSCinpatientswithadvancedNSCLCwhohavereceived1–2priorchemotherapyregimensandarerefractoryorintoleranttotheirmostrecentregimen1692patients