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

Epidermalgrowthfactorreceptor-tyrosinekinaseinhibitorinnon-small-celllungcancerYuh-MinChen,MD,PhD.ChestDept.,TaipeiVGH.6/9/20231YMCSurvival

(anti-apoptosis)PI3-KActivationoftheepidermalgrowthfactorreceptortyrosinekinase(EGFR-TK):apivotaldriverofcarcinogenesisEGFR-TKEGFRLigandRASRAFSOSGRB2PTENAKTSTAT3MEKGenetranscriptionCell-cycleprogressionDNAMycMycCyclinD1JunFosPPMAPKProliferation/

maturationChemotherapy/

radiotherapy

resistanceAngiogenesisMetastasisBalabanetal1996;Akimotoetal1999;Wells1999;Woodburn1999;

Hanahan2000;Raymondetal2000CyclinD1pYpYpY.6/9/20232YMCRppRExtracellularIntracellularMembranepKpKpppTGFaSubstrateSubstrateSignallingMoleculesProliferationInhibitApoptosisAngiogenesisMetastasisNucleusMonoclonalAntibodiesEGFRTyrosineKinaseInhibitors.6/9/20233YMCIDEAL1and2trialdesignGefitinib250mg/dayGefitinib

500mg/dayContinuegefitinibuntildisease

progressionorunacceptabletoxicityIDEAL,IressaTMDoseEvaluationinAdvancedLungcancer

RandomisationIDEAL1(n=209)

1or2priorregimensIDEAL2(n=216)

>2priorregimens

PrimaryendpointsObjectivetumourresponseSymptomimprovement(IDEAL2)Safety(IDEAL1).6/9/20234YMCMediantimetoimprovement-symptomsandQOL*Timeof1stassessmentMediantimetoimprovement,days

Symptom/QOLmeasureLCSFACT-L8*29*.6/9/20235YMCIDEAL1and2:overallsurvival

bysymptomimprovement(250mg/day)Probability1.00.80.60.40.20.0IDEAL1MonthsfromrandomisationImprovementNoimprovement2740183013.33.5Patients

(n)Deaths

(n)Median(months)024681012141618204458265613.63.7Patients(n)Deaths

(n)Median(months)1.00.80.60.40.20.0ProbabilityIDEAL2Monthsfromrandomisation02468101214161820Douillardetal2002;Lynchetal2003.6/9/20236YMCISEL(IRESSASurvivalEvaluationinLungCancer):

ClinicalTrialDesignRandomisationGefitinib(250mg)+*BSCPlacebo+*BSCSURVIVALSecondary:TTF,ORQoL,safetyPrimary

endpoint:ENDBENEFIT2:1ratio

AdoubleblindPhaseIIIsurvivalstudycomparingIRESSA(250mg)plusBSCvs.placeboplusBSCinpatientswithadvancedNSCLCwhohavereceived1–2priorchemotherapyregimensandarerefractoryorintoleranttotheirmostrecentregimen1692patientsin210centresacross28countries342patientsoforientaloriginNoJapanese/USsites*BSC=BestSupportiveCareLancet2005;366:1527-37.6/9/20237YMCISEL-OverallSurvivalPercentsurvivingTime(months)Atrisk:Gefitinib112910239017615884553252451751137645199

——

IRESSA

------PlaceboPlacebo563517446382289220160115774428201242GefitinibplaceboMedian(months)5.65.11yrsurvival27%21%HR=0.89(0.77,1.02),p=0.0871StratifiedlogranktestN=1692,deaths=976Coxanalysis,p=0.0299.6/9/20238YMCISELSurvival:OrientalsPercentsurvivingTime(months)Atrisk:Gefitinib235221199179145119957864514025128

——

IRESSA

------Placebo

Placebo107978474564335292213873115.5M9.5M.6/9/20239YMCJChemother2005;17:679.6/9/202310YMCRESULTS3CR,9PR,withaR.R.of33.3%

SD14,controlrateof72.2%Alltreatment-relatedtoxicitieswerefewandmildinseverity,exceptonepatientsufferedfromreversiblegrade3interstitialpneumonitis

JChemother2005;17:679.6/9/202311YMC%SurvivalMediansurvival:9.5monthsOne-yearsurvivalrate:45.1%JChemother2005;17:679.6/9/202312YMC%SurvivalFig.10102030405060708090100036912151821MonthsCompleteorpartialresponse(n=12)median20.1MStableorprogressivedisease(n=24)median4.7MSurvivalaccordingtoresponseornot15.4月JChemother2005;17:679.6/9/202313YMCStudyDesignofBR.21

Stratifiedby:CentrePS(0/1vs2/3)Responsetoprior

treatment(CR/PR:SD:PD)

Priorregimens(1vs2)Priorplatinum

(yesvsno)Tarceva

150mgdailyPlaceboRANDOMISEPS=performancestatus21NEnglJMed2005;353:123–32.6/9/202314YMCBR.21:Significant

clinicalpredictorsofresponsetoTarcevaTarceva

treatedpts(n)R.R.(%)

pvalue*GenderFemale(146)14.40.006Male(281)6.1HistologyAdenocarcinoma(209)13.9<0.001Other(218)4.1EthnicityAsian(53)18.90.02Other(374)7.5Eversmoked**Yes(311)3.8<0.001No(93)24.7Unknown(23)13.0*Significancebetweensubgroups**DatacollectedretrospectivelyInmultiplelogistic-regressionanalyses,onlyneverhavingsmoked(p<0.001)andadenocarcinomahistology(p=0.01)wereassociatedwithresponseShepherdetal.NEJM2005;353:123.6/9/202315YMCImprovementinSurvivalwithTarceva42.5%improvementinmediansurvivalSurvivaldistributionfunctionSurvivaltime(months)HR=0.73,p<0.001*1.000.750.500.2500 5 10 15 20 25 30TarcevaPlaceboNEnglJMed2005;353:123–32

Tarceva

(n=488)

Placebo

(n=243)

Mediansurvival(months)

6.7

4.7

1-yearsurvival(%)

31

21

.6/9/202316YMCBR.21:Timetosymptomdeterioration(months)

Placebo

Tarceva179

179

153

n348

353

298

n1.9

(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,unadjustedformultiplesymptomsBezjakA,etal.JClinOncol2006;24:3831–7ShepherdF,etal.NEnglJMed2005;353:123–32.6/9/202317YMCTRUST:TarcevaMO18109

AnexpandedaccessclinicalprogramofTarceva(erlotinib)inptswithadvancedstageIIIB/IVNSCLC

LungCancer2008.6/9/202318YMCPatientPopulation&ResponseFromMay2005toJuly2006,300patientswereenteredfrom14hospitalsinTaiwan.Thisanalysiswasbasedon299patientswhoreceivedatleastonedoseofTarceva..6/9/202319YMCResponserateandcontrolratebypretreatmentcharacteristicsandskintoxicityPatientcharacteristicsPatientnumberResponserate(%)p-valueControlrate(%)p-valueGenderMaleFemale1401332037.60.001363.682.70.0004Age<65

6516011334.420.40.011573.172.60.9185Performancestatus0/123226351228.822.941.70.46910.339272.671.483.30.88850.4124StageIIIBIV5621517.931.20.049269.673.50.5651HistologyAdenocarcinomaSquamouscellcarcinoma1904834.712.50.00277960.40.0079PresenttreatmentasSecondlineThirdline16710229.926.50.541370.776.50.2983SmokingstatusNon-smokerFormerorcurrentsmoker15811533.521.70.03379.164.40.0067Skintoxicity-1NorashRash2924410.330.70.021641.476.6<0.0001Skintoxicity-2Norashorgrade1Rashgrade2,3,or411915419.335.70.00361.381.80.0002Thebestresponserateswerea29%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..6/9/202320YMC0.000.250.500.751.00Progressionfreesurvival(Months)061020CensoredobservationsFig.1Freefromprogression8421214161822Timetodiseaseprogressionof299NSCLCptstreatedwitherlotinib.Themediantimetodiseaseprogressionwas5.6months(95%C.I.:4.4–6.5months,45ptscensored).6/9/202321YMCEGFR-TKIvs.chemotherapeuticagentsinsalvagechemotherapy.6/9/202322YMCInconclusion,bothchemotherapeuticagents,suchasdocetaxelaloneorgemcitabine+vinorelbine,andgefitinib,areappropriatesalvageregimensforChineseNSCLCptswhohavefailedpreviouschemotherapy.However,gefitinibhasabettersafetyprofileandprobablybettersurvivalthanthechemotherapeuticagents,andwouldbeanappropriatealternativechoiceforsalvagechemotherapy,eveninasecond-linesettingforChinesepts.

JThoracOncol2006;1:545-50.6/9/202323YMCEfficacyofSalvageTherapyinNSCLCTrialScheduleR.R.,%MTP,MMSur,M1-Yr,%SingleagentGemcitabine1200mg/m2D1,8,15q4wks12.52.17.540Docetaxel3535mg/m2D1,8,15q4wks17.24.28.433.44040mg/m2D1,8q3wks10.93.57.4357575mg/m2D1q3wks6.12.87.830.3Gefitinib250mgdaily33.34.79.340.8DoubletDocetaxel+IfosfamideD60mg/m2+I3gm/m2D1q3wks1058.226.1Docetaxel+GemcitabineD30mg/m2+G800mg/m2D1,8q3wks36.13.85.733.3Vinorelbine+GemcitabineV20mg/m2+G800mg/m2D1,8,15q4wks31.34.68.334.3Vinorelbine+CisplatinV20mg/m2D1,8,15+C50mg/m2D1q4wks9.53.77.619.7.6/9/202324YMCSalvageChemotherapy(n=342)Grade¾Neutroopenia.6/9/202325YMCSalvageChemotherapy(n=342)Grade¾FatigueDocetaxel40andvinorelbinepluscisplatininducedmorefrequentseverefatiguethanotherregimens.Patientsthatreceivedsingle-agentgemcitabineandgefitinibreportednoseverefatiguesensation..6/9/202326YMCInterestINTEREST(gefitinibvs.docetaxelinptswithLAormeta.NSCLCpre-treatedwithplatinum-basedchemotherapyWCLC20071466ptsfromMar2004toFeb2006.6/9/202327YMCInterestQoFandsymptomimprovementWCLC2007.6/9/202328YMCInterestWCLC2007.6/9/202329YMCInterestOverallsurvival.6/9/202330YMCClinicalcharacteristics&responserate(ptnumber=1974)IntJClinOncol2006;11:190–8.6/9/202331YMCEGFRMutationEurJCancer2006:17-23NEnglJMed2004;350:2129-39.6/9/202332YMCFailureofDoubletChemotherapyplusEGFR-TKIINTACTI,IITRIBUTE,TALENT.6/9/202333YMCGiaccone.JCO2004;22:777OverallSurvivalofINTACT-1inEachTreatmentGroup(GEM+CDDPc/sIressa)PoorsurvivalforthoseuseIressawithGEM+CDDP.6/9/202334YMCCanwefurtherprolongdisease-freesurvivalandoverallsurvival?FailureofdoubletchemotherapyplusTKIINTACTI,II(Gefitinib);TRIBUTE,TALENT(Erlotinib)MajorityperformedinCaucasianptsUnknownforAsianptswithhighEGFRmutationrateToassesstheefficacyofaddingchronicintermittentlow-dosevinorelbinetogefitinibtreatmentforadenocarcinomaoflungwhofailedtwoormoreregimensofchemotherapy.

.6/9/202335YMC.6/9/202336YMCConclusionsAdditionoflow-dosevinorelbinetogefitinibhasshownhighefficacyinadenocarcinomalungcancerpatientswhohavefailedtwopreviousregimensofchemotherapy.GiventhefactthattherearefournegativephaseIIIrandomizedtrialsofEGFRTKI'swithchemotherapy(INTACTIandII,TRIBUTE,TALENT),

onlystudiesinselectedEGFRmutation-enrichedpatientpopulationscanbejustifiedatthistimeforfurtherclinicaltrialscombiningchemotherapywithEGFRTKIs..6/9/202337YMC%FreefromProgression1-yearprogression-freesurvivalratewas57.1%intheGVarmand21.2%intheGarm(p=0.008).6/9/202338YMCErlotinibinducesG1arrestwhichcanblockM-phaseactivityofdocetaxelDocetaxelinducesM-phasearrestandapoptosisthatisenhancedbyerlotinibSequence–specificInteractionClinLungCancer2006;7:385.6/9/202339YMCFirst-lineAsianSequentialTarcevaplusChemotherapyTrial(FAST-ACT):StudyDesignPlaceboErlotinib150mg/dayPreviouslyuntreatedstageIIIB/IVNSCLC(n=150)R11PDSixcyclesgemcitabine+cisplatinorcarboplatin+placebo;q4wksSixcyclesgemcitabine(d1,8)+cisplatin(d1)orcarboplatin(d1)+erlotinib(d15–28);q4wksPDStratifiedbycentre,stage,

histology,smokingstatusStudytreatmentPost-treatmentScreeningPost-studyGemcitabine1250mg/m2(d1,8);cisplatin75mg/m2ORcarboplatin5×AUC(d1);erlotinib150mg/day(d15–28)PASCO2008;26:a8031.6/9/202340YMCTimetoDiseaseProgression1.00.80.60.40.20

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36Time(weeks)

38 40 42 44 46 48 50 52 54 56 58

76 72 72 72 64 61 58 58 58 52 50 50 46 37 36 32 26 15 14 78 76 76 76 67 59 58 56 50 43 43 41 35 25 24 22 16 8 7

12 10 9 8 7 5 5 5 3 1 0 5 4 2 1 1 1 1 1 1 1 0No.atriskErlotinibPlaceboEarlyandconsistentseparationofcurvesMedianTTP

(weeks)GC-erlotinib31.4GC-placebo24.1Log-ranktestp=0.0185HR=0.5695%CI:0.37–0.8424.131.4PASCO2008;26:a8031R.R.36.8%24.4%Howlongshouldchemotherapybegiven(noPDSatmaintenancephase)GEMCDDPdose(controlarm)islessthanusualBetterforthoseCaucasianswhohavehigher%ofEGFRwildtype.6/9/202341YMCFirstlinetreatmentwithEGFR-TKIsinthosewithEGFRmutatedpatients.6/9/202342YMC98ptsunderwentEGFRscreeningandmutationsweredetectedin34(35%).EGFRmutations:exon19deletions(53%),L858R(26%)31ptsreceivedgefitinib,R.R.55%,medianprogression-freesurvival9.2M.Therapywaswelltolerated.JClinOncol2008;26:2442-9.6/9/202343YMCPercentchangeinmeasurabletumoratbestresponse,byindividualpatientJClinOncol2008;26:2442-9.6/9/202344YMCKaplan-Meiercurvesfor(A)progression-freesurvivaland(B)overallsurvivalamongalltreatedptsJClinOncol2008;26:2442-9PFS9.2MSur17.5M.6/9/202345YMCGefitinibfirstlinetreatmentinenrichedEGFR-mutatedNSCLCinNTUHN=106(adenoca97,non-adeno9)PtNoRR,%DCR,%MedianTTF,MMedianOS,MAll10650.982.15.522.4EGFRmutated556987.3824wildtype352068.63.412.9notdone1656.393.85.6NRJCO2008;26:2745-53PtNoRR,%MedianTTF,MExon19deletion20958.9Exon21L858R2373.99.1.6/9/202346YMCPredictiveFactorsofResponsetoGefitinibin152EGFRmutatedpatientsinNTUHVariablesNoResponserates(%)UnivariatePMultivariatePN=152L858R7565.30.646

DelinExon197768.8

Chemonaive9175.80.0050.006Chemo-treated6154.1

Female11071.80.0450.053Male4254.8

Smoker2254.60.175

Non-smoker13069.2

<=65years7017.90.789>65years8213.7

WuJYetal.AJRCCM2008.6/9/202347YMCNosurvivaldifferencein152chemonaiveorchemo-treatedEGFRmutatedpatientsinNTUHChmonaïvegefitinib(n=91)Chemotherapytreatedgefitinib(n=61)logrankChmonaïvegefitinib(n=91)Chemotherapytreatedgefitinib(n=61)logrank=0.24WuJYetal.AJRCCM2008.6/9/202348YMC2003.9.15s/p4lineC/Tsince20010629,PS3FiO250%2003.9.29Iressa2weeksPS1roomairAnother1.5year.6/9/202349YMCMs.ReeHxNo3167688775Y/O20021202SOBformonths,PS2-3,NC3L/minpreC/T20050804postNGC;taxotere;underIressa-N,PS0.6/9/202350YMCs/prenaltransplantationwith

adenocarcinoma,LUL,&brain,meningealcarcinomatosisNotappropriateforchemotherapy,receivefirstlineTarcevawithtotaldisappearanceofmeningealcarcinomatosis&brainmetastases(brainMRIfollow-up6monthsafterTarcevatreatment)TarcevafirstlinetreatmentPatientstillaliveatpresent.6/9/202351YMCT790MPaoetal.PLoSMed2005;2:1-11Kwaketal.ProNatAcadSciUSA2005;102:7665-708of16TKItreatedhad2ndmutation:7of8wasT790M

ClinCancerRes2006;12:6494-501T790Maccountsfor50%acquiredresistancetoEGFR-TKIsC-METamplificationacco