非小细胞肺癌表皮生长因子受体酪氨酸激酶抑制剂（英文）课件

2020 2 28 YMC 1 Epidermalgrowthfactorreceptor tyrosinekinaseinhibitorinnon small celllungcancer Yuh MinChen MD PhD ChestDept TaipeiVGH 2020 2 28 YMC 2 Survival anti apoptosis PI3 K Activationoftheepidermalgrowthfactorreceptortyrosinekinase EGFR TK apivotaldriverofcarcinogenesis EGFR TK EGFR Ligand RAS RAF SOS GRB2 PTEN AKT STAT3 MEK GenetranscriptionCell cycleprogression DNA Myc Myc CyclinD1 JunFos PP MAPK Proliferation maturation Chemotherapy radiotherapyresistance Angiogenesis Metastasis Balabanetal1996 Akimotoetal1999 Wells1999 Woodburn1999 Hanahan2000 Raymondetal2000 CyclinD1 pY pY pY 2020 2 28 YMC 3 2020 2 28 YMC 4 IDEAL1and2trialdesign Gefitinib250mg day Gefitinib500mg day IDEAL IressaTMDoseEvaluationinAdvancedLungcancer Randomisation IDEAL1 n 209 1or2priorregimensIDEAL2 n 216 2priorregimens Primaryendpoints ObjectivetumourresponseSymptomimprovement IDEAL2 Safety IDEAL1 2020 2 28 YMC 5 Mediantimetoimprovement symptomsandQOL Timeof1stassessment Mediantimetoimprovement days Symptom QOLmeasureLCSFACT L 8 29 2020 2 28 YMC 6 IDEAL1and2 overallsurvivalbysymptomimprovement 250mg day Probability 1 0 0 8 0 6 0 4 0 2 0 0 IDEAL1 Monthsfromrandomisation ImprovementNoimprovement 2740 1830 13 33 5 Patients n Deaths n Median months 0 2 4 6 8 10 12 14 16 18 20 4458 2656 13 63 7 Patients n Deaths n Median months 1 0 0 8 0 6 0 4 0 2 0 0 Probability IDEAL2 Monthsfromrandomisation 0 2 4 6 8 10 12 14 16 18 20 Douillardetal2002 Lynchetal2003 2020 2 28 YMC 7 ISEL IRESSASurvivalEvaluationinLungCancer ClinicalTrialDesign Randomisation Gefitinib 250mg BSC Placebo BSC SURVIVALSecondary TTF ORQoL safety Primaryendpoint ENDBENEFIT 2 1ratio AdoubleblindPhaseIIIsurvivalstudycomparingIRESSA 250mg plusBSCvs placeboplusBSCinpatientswithadvancedNSCLCwhohavereceived1 2priorchemotherapyregimensandarerefractoryorintoleranttotheirmostrecentregimen 1692patientsin210centresacross28countries342patientsoforientaloriginNoJapanese USsites BSC BestSupportiveCare Lancet2005 366 1527 37 2020 2 28 YMC 8 ISEL OverallSurvival Percentsurviving Time months Atrisk Gefitinib112910239017615884553252451751137645199 IRESSA Placebo Placebo563517446382289220160115774428201242 2020 2 28 YMC 9 ISELSurvival Orientals Percentsurviving Time months Atrisk Gefitinib235221199179145119957864514025128 IRESSA Placebo Placebo10797847456433529221387311 5 5M 9 5M 2020 2 28 YMC 10 JChemother2005 17 679 2020 2 28 YMC 11 RESULTS 3CR 9PR withaR R of33 3 SD14 controlrateof72 2 Alltreatment relatedtoxicitieswerefewandmildinseverity exceptonepatientsufferedfromreversiblegrade3interstitialpneumonitis JChemother2005 17 679 2020 2 28 YMC 12 Survival Mediansurvival 9 5monthsOne yearsurvivalrate 45 1 JChemother2005 17 679 2020 2 28 YMC 13 Survival Survivalaccordingtoresponseornot JChemother2005 17 679 2020 2 28 YMC 14 StudyDesignofBR 21 Stratifiedby CentrePS 0 1vs2 3 Responsetopriortreatment CR PR SD PD Priorregimens 1vs2 Priorplatinum yesvsno Tarceva150mgdaily Placebo RANDOMISE PS performancestatus NEnglJMed2005 353 123 32 2020 2 28 YMC 15 BR 21 SignificantclinicalpredictorsofresponsetoTarceva Significancebetweensubgroups Datacollectedretrospectively Inmultiplelogistic regressionanalyses onlyneverhavingsmoked p 0 001 andadenocarcinomahistology p 0 01 wereassociatedwithresponse Shepherdetal NEJM2005 353 123 2020 2 28 YMC 16 ImprovementinSurvivalwithTarceva 42 5 improvementinmediansurvival Survivaldistributionfunction Survivaltime months HR 0 73 p 0 001 1 000 750 500 250 051015202530 NEnglJMed2005 353 123 32 Tarceva n 488 Placebo n 243 Mediansurvival months 6 7 4 7 1 yearsurvival 31 21 2020 2 28 YMC 17 BR 21 Timetosymptomdeterioration months Placebo Tarceva 179 179 153 n 348 353 298 n 1 9 1 8 2 8 2 9 2 4 8 3 7 2 4 9 Median 95 CI 0 02 2 8 2 4 3 Pain 0 01 4 7 3 8 6 2 Dyspnea 0 04 4 9 3 8 7 4 Cough pvalue Median 95 CI Log ranktest unadjustedformultiplesymptoms BezjakA etal JClinOncol2006 24 3831 7ShepherdF etal NEnglJMed2005 353 123 32 2020 2 28 YMC 18 TRUST TarcevaMO18109AnexpandedaccessclinicalprogramofTarceva erlotinib inptswithadvancedstageIIIB IVNSCLCLungCancer2008 2020 2 28 YMC 19 PatientPopulation Response FromMay2005toJuly2006 300patientswereenteredfrom14hospitalsinTaiwan Thisanalysiswasbasedon299patientswhoreceivedatleastonedoseofTarceva 2020 2 28 YMC 20 Responserateandcontrolratebypretreatmentcharacteristicsandskintoxicity Thebestresponserateswerea29 partialresponseand44 stablediseasein273patientswhohadresponsedataavailable Non smoking p 0 033 adenocarcinoma BAC p 0 0027 female p 0 0013 agedlessthan65years p 0 0115 stageIV p 0 0492 patientswithskinrash p 0 0216 andahighergradeofskinrash p 0 003 weresignificantlycorrelatedwithresponsetotreatment 2020 2 28 YMC 21 Timetodiseaseprogressionof299NSCLCptstreatedwitherlotinib Themediantimetodiseaseprogressionwas5 6months 95 C I 4 4 6 5months 45ptscensored 2020 2 28 YMC 22 EGFR TKIvs chemotherapeuticagentsinsalvagechemotherapy 2020 2 28 YMC 23 Inconclusion bothchemotherapeuticagents suchasdocetaxelaloneorgemcitabine vinorelbine andgefitinib areappropriatesalvageregimensforChineseNSCLCptswhohavefailedpreviouschemotherapy However gefitinibhasabettersafetyprofileandprobablybettersurvivalthanthechemotherapeuticagents andwouldbeanappropriatealternativechoiceforsalvagechemotherapy eveninasecond linesettingforChinesepts JThoracOncol2006 1 545 50 2020 2 28 YMC 24 EfficacyofSalvageTherapyinNSCLC 2020 2 28 YMC 25 SalvageChemotherapy n 342 Grade Neutroopenia 2020 2 28 YMC 26 SalvageChemotherapy n 342 Grade Fatigue Docetaxel40andvinorelbinepluscisplatininducedmorefrequentseverefatiguethanotherregimens Patientsthatreceivedsingle agentgemcitabineandgefitinibreportednoseverefatiguesensation 2020 2 28 YMC 27 Interest INTEREST gefitinibvs docetaxelinptswithLAormeta NSCLCpre treatedwithplatinum basedchemotherapy WCLC2007 1466ptsfromMar2004toFeb2006 2020 2 28 YMC 28 Interest QoFandsymptomimprovement WCLC2007 2020 2 28 YMC 29 Interest WCLC2007 2020 2 28 YMC 30 Interest Overallsurvival 2020 2 28 YMC 31 Clinicalcharacteristics responserate ptnumber 1974 IntJClinOncol2006 11 190 8 2020 2 28 YMC 32 EGFRMutation EurJCancer2006 17 23 NEnglJMed2004 350 2129 39 2020 2 28 YMC 33 FailureofDoubletChemotherapyplusEGFR TKI INTACTI IITRIBUTE TALENT 2020 2 28 YMC 34 Giaccone JCO2004 22 777 OverallSurvivalofINTACT 1inEachTreatmentGroup GEM CDDPc sIressa PoorsurvivalforthoseuseIressawithGEM CDDP 2020 2 28 YMC 35 Canwefurtherprolongdisease freesurvivalandoverallsurvival FailureofdoubletchemotherapyplusTKIINTACTI II Gefitinib TRIBUTE TALENT Erlotinib MajorityperformedinCaucasianptsUnknownforAsianptswithhighEGFRmutationrateToassesstheefficacyofaddingchronicintermittentlow dosevinorelbinetogefitinibtreatmentforadenocarcinomaoflungwhofailedtwoormoreregimensofchemotherapy 2020 2 28 YMC 36 2020 2 28 YMC 37 Conclusions Additionoflow dosevinorelbinetogefitinibhasshownhighefficacyinadenocarcinomalungcancerpatientswhohavefailedtwopreviousregimensofchemotherapy GiventhefactthattherearefournegativephaseIIIrandomizedtrialsofEGFRTKI swithchemotherapy INTACTIandII TRIBUTE TALENT onlystudiesinselectedEGFRmutation enrichedpatientpopulationscanbejustifiedatthistimeforfurtherclinicaltrialscombiningchemotherapywithEGFRTKIs 2020 2 28 YMC 38 FreefromProgression 1 yearprogression freesurvivalratewas57 1 intheGVarmand21 2 intheGarm p 0 008 2020 2 28 YMC 39 ErlotinibinducesG1arrestwhichcanblockM phaseactivityofdocetaxel DocetaxelinducesM phasearrestandapoptosisthatisenhancedbyerlotinib Sequence specificInteraction ClinLungCancer2006 7 385 2020 2 28 YMC 40 First lineAsianSequentialTarcevaplusChemotherapyTrial FAST ACT StudyDesign Placebo Erlotinib150mg day PreviouslyuntreatedstageIIIB IVNSCLC n 150 R 1 1 PD Sixcyclesgemcitabine cisplatinorcarboplatin placebo q4wks Sixcyclesgemcitabine d1 8 cisplatin d1 orcarboplatin d1 erlotinib d15 28 q4wks PD Stratifiedbycentre stage histology smokingstatus Studytreatment Post treatment Screening Post study Gemcitabine1250mg m2 d1 8 cisplatin75mg m2ORcarboplatin5 AUC d1 erlotinib150mg day d15 28 PASCO2008 26 a8031 2020 2 28 YMC 41 TimetoDiseaseProgression 1 00 80 60 40 20 024681012141618202224262830323436 Time weeks 3840424446485052545658 76727272646158585852505046373632261514787676766759585650434341352524221687 121098755531054211111110 No atriskErlotinibPlacebo Earlyandconsistentseparationofcurves Log ranktestp 0 0185 HR 0 5695 CI 0 37 0 84 24 1 31 4 PASCO2008 26 a8031 R R 36 8 24 4 Howlongshouldchemotherapybegiven noPDSatmaintenancephase GEMCDDPdose controlarm islessthanusualBetterforthoseCaucasianswhohavehigher ofEGFRwildtype 2020 2 28 YMC 42 FirstlinetreatmentwithEGFR TKIsinthosewithEGFRmutatedpatients 2020 2 28 YMC 43 98ptsunderwentEGFRscreeningandmutationsweredetectedin34 35 EGFRmutations exon19deletions 53 L858R 26 31ptsreceivedgefitinib R R 55 medianprogression freesurvival9 2M Therapywaswelltolerated JClinOncol2008 26 2442 9 2020 2 28 YMC 44 Percentchangeinmeasurabletumoratbestresponse byindividualpatient JClinOncol2008 26 2442 9 2020 2 28 YMC 45 Kaplan Meiercurvesfor A progression freesurvivaland B overallsurvivalamongalltreatedpts JClinOncol2008 26 2442 9 PFS9 2M Sur17 5M 2020 2 28 YMC 46 GefitinibfirstlinetreatmentinenrichedEGFR mutatedNSCLCinNTUH N 106 adenoca97 non adeno9 JCO2008 26 2745 53 2020 2 28 YMC 47 PredictiveFactorsofResponsetoGefitinibin152EGFRmutatedpatientsinNTUH WuJYetal AJRCCM2008 2020 2 28 YMC 48 Nosurvivaldifferencein152chemonaiveorchemo treatedEGFRmutatedpatientsinNTUH WuJYetal AJRCCM2008 2020 2 28 YMC 49 2003 9 15s p4lineC Tsince20010629 PS3FiO250 2003 9 29Iressa2weeksPS1roomair Another1 5year 2020 2 28 YMC 50 Ms ReeHxNo3167688775Y O 20021202SOBformonths PS2 3 NC3L minpreC T 20050804postNGC taxotere underIressa N PS0 2020 2 28 YMC 51 s prenaltransplantationwithadenocarcinoma LUL brain meningealcarcinomatosis Notappropriateforchemotherapy receivefirstlineTarcevawithtotaldisappearanceofmeningealcarcinomatosis brainmetastases brainMRIfollow up6monthsafterTarcevatreatment Tarcevafirstlinetreatment Patientstillaliveatpresent 2020 2 28 YMC 52 T790M Paoetal PLoSMed2005 2 1 11Kwaketal ProNatAcadSciUSA2005 102 7665 708of16TKItreatedhad2ndmutation 7of8wasT790MClinCancerRes2006 12 6494 501 T790Maccountsfor50 acquiredresistancetoEGFR TKIsC METamplificationaccountsfor25 And 2020 2 28 YMC 53 EGFRandMETeachindependentlyactivateErbB3intheresistantcells AKT P13KP110 P85 P P P AdaptedfromreviewbyC1ArteagaNatureMedicile 2007 EGFR ErbB3 Met EduSessionASCO2008 2020 2 28 YMC 54 TheIGF IRpathwayisactivatedbyalossofIGFBindingProteins IGFBPs CellSurvival CellDeath EGFR ErbB3 IGF IGF IR IGF BPs EGFR gefitinib gefitinib ErbB3 IGF IR P13kp110 p85 p IRS 1 AKT p Parental Sensitive Resistant EduSessionASCO2008 2020 2 28 YMC 55 AcquiredResistancetoEGFRInhibitors Heterogenicityofresistancema