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.12/18/20221YMCEpidermalgrowthfactorreceptSurvival

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

maturationChemotherapy/

radiotherapy

resistanceAngiogenesisMetastasisBalabanetal1996;Akimotoetal1999;Wells1999;Woodburn1999;

Hanahan2000;Raymondetal2000CyclinD1pYpYpY.12/18/20222YMCSurvival

(anti-apoptosis)PI3-KRppRExtracellularIntracellularMembranepKpKpppTGFaSubstrateSubstrateSignallingMoleculesProliferationInhibitApoptosisAngiogenesisMetastasisNucleusMonoclonalAntibodiesEGFRTyrosineKinaseInhibitors.12/18/20223YMCRppRExtracellularIntracellularIDEAL1and2trialdesignGefitinib250mg/dayGefitinib

500mg/dayContinuegefitinibuntildisease

progressionorunacceptabletoxicityIDEAL,IressaTMDoseEvaluationinAdvancedLungcancer

RandomisationIDEAL1(n=209)

1or2priorregimensIDEAL2(n=216)

>2priorregimens

PrimaryendpointsObjectivetumourresponseSymptomimprovement(IDEAL2)Safety(IDEAL1).12/18/20224YMCIDEAL1and2trialdesignGefiMediantimetoimprovement-symptomsandQOL*Timeof1stassessmentMediantimetoimprovement,days

Symptom/QOLmeasureLCSFACT-L8*29*.12/18/20225YMCMediantimetoimprovement-*TIDEAL1and2:overallsurvival

bysymptomimprovement(250mg/day)Probability1.00.20.0IDEAL1MonthsfromrandomisationImprovementNoimprovement2740183013.33.5Patients

(n)Deaths

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

(n)Median(months)1.00.20.0ProbabilityIDEAL2Monthsfromrandomisation02468101214161820Douillardetal2002;Lynchetal2003.12/18/20226YMCIDEAL1and2:overallsurvivaISEL(IRESSASurvivalEvaluationinLungCancer):

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

endpoint:ENDBENEFIT2:1ratio

AdoubleblindPhaseIIIsurvivalstudycomparingIRESSA(250mg)plusBSCvs.placeboplusBSCinpatientswithadvancedNSCLCwhohavereceived1–2priorchemotherapyregimensandarerefractoryorintoleranttotheirmostrecentregimen1692patientsin210centresacross28countries342patientsoforientaloriginNoJapanese/USsites*BSC=BestSupportiveCareLancet2005;366:1527-37.12/18/20227YMCISEL(IRESSASurvivalEvaluatiISEL-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=0.0299.12/18/20228YMCISEL-OverallSurvivalPercentISELSurvival:OrientalsPercentsurvivingTime(months)Atrisk:Gefitinib235221199179145119957864514025128

——

IRESSA

------Placebo

Placebo107978474564335292213873115.5M9.5M.12/18/20229YMCISELSurvival:OrientalsPercenJChemother2005;17:679.12/18/202210YMCJChemother2005;17:679.12/14/RESULTS3CR,9PR,withaR.R.of33.3%

SD14,controlrateof72.2%Alltreatment-relatedtoxicitieswerefewandmildinseverity,exceptonepatientsufferedfromreversiblegrade3interstitialpneumonitisJChemother2005;17:679.12/18/202211YMCRESULTS3CR,9PR,withaR.R.%SurvivalMediansurvival:9.5monthsOne-yearsurvivalrate:45.1%JChemother2005;17:679.12/18/202212YMC%SurvivalMediansurvival:9.5%SurvivalFig.10102030405060708090100036912151821MonthsCompleteorpartialresponse(n=12)median20.1MStableorprogressivedisease(n=24)median4.7MSurvivalaccordingtoresponseornot15.4月JChemother2005;17:679.12/18/202213YMC%SurvivalFig.101020304050607StudyDesignofBR.21

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

treatment(CR/PR:SD:PD)

Priorregimens(1vs2)Priorplatinum

(yesvsno)Tarceva

150mgdailyPlaceboRANDOMISEPS=performancestatus21NEnglJMed2005;353:123–32.12/18/202214YMCStudyDesignofBR.21StratifBR.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;353:123.12/18/202215YMCBR.21:SignificantclinicalprImprovementinSurvivalwithTarceva42.5%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

.12/18/202216YMCImprovementinSurvivalwithTBR.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;353:123–32.12/18/202217YMCBR.21:TimetosymptomdeterioTRUST:TarcevaMO18109

AnexpandedaccessclinicalprogramofTarceva(erlotinib)inptswithadvancedstageIIIB/IVNSCLC

LungCancer2008.12/18/202218YMCTRUST:TarcevaMO18109

AnexpaPatientPopulation&ResponseFromMay2005toJuly2006,300patientswereenteredfrom14hospitalsinTaiwan.Thisanalysiswasbasedon299patientswhoreceivedatleastonedoseofTarceva..12/18/202219YMCPatientPopulation&ResponseFResponserateandcontrolratebypretreatmentcharacteristicsandskintoxicityPatientcharacteristicsPatientnumberResponserate(%)p-valueControlrate(%)p-valueGenderMaleFemale1401332037.60.001363.682.70.0004Age<65

6516011334.420.40.0115185Performancestatus0/123226351228.822.941.70.46910.339272.671.483.30.88850.4124StageIIIBIV5621517.931.20.049269.673.50.5651HistologyAdenocarcinomaSquamouscellcarcinoma1904834.712.50.00277960.40.0079PresenttreatmentasSecondlineThirdline16710229.926.50.541370.776.50.2983SmokingstatusNon-smokerFormerorcurrentsmoker15811533.521.70.033067Skintoxicity-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..12/18/202220YMCResponserateandcontrolrate0.000.250.500.751.00Progressionfreesurvival(Months)061020CensoredobservationsFig.1Freefromprogression8421214161822Timetodiseaseprogressionof299NSCLCptstreatedwitherlotinib.Themediantimetodiseaseprogressionwas5.6months(95%C.I.:4.4–6.5months,45ptscensored).12/18/202221YMC0.000.250.500.751.00ProgressioEGFR-TKIvs.chemotherapeuticagentsinsalvagechemotherapy.12/18/202222YMCEGFR-TKIvs.chemotherapeuticInconclusion,bothchemotherapeuticagents,suchasdocetaxelaloneorgemcitabine+vinorelbine,andgefitinib,areappropriatesalvageregimensforChineseNSCLCptswhohavefailedpreviouschemotherapy.However,gefitinibhasabettersafetyprofileandprobablybettersurvivalthanthechemotherapeuticagents,andwouldbeanappropriatealternativechoiceforsalvagechemotherapy,eveninasecond-linesettingforChinesepts.

JThoracOncol2006;1:545-50.12/18/202223YMCInconclusion,bothchemotheraEfficacyofSalvageTherapyinNSCLCTrialScheduleR.R.,%MTP,MMSur,M1-Yr,%SingleagentGemcitabine1200mg/m2D1,8,15q4wks40Docetaxel3535mg/m2D1,8,15q4wks33.44040mg/m2D1,8q3wks357575mg/m2D1q3wks30.3Gefitinib250mgdaily40.8DoubletDocetaxel+IfosfamideD60mg/m2+I3gm/m2D1q3wks1058.226.1Docetaxel+GemcitabineD30mg/m2+G800mg/m2D1,8q3wks33.3Vinorelbine+GemcitabineV20mg/m2+G800mg/m2D1,8,15q4wks34.3Vinorelbine+CisplatinV20mg/m2D1,8,15+C50mg/m2D1q4wks19.7.12/18/202224YMCEfficacyofSalvageTherapyinSalvageChemotherapy(n=342)Grade¾Neutroopenia.12/18/202225YMCSalvageChemotherapy(n=342).1SalvageChemotherapy(n=342)Grade¾FatigueDocetaxel40andvinorelbinepluscisplatininducedmorefrequentseverefatiguethanotherregimens.Patientsthatreceivedsingle-agentgemcitabineandgefitinibreportednoseverefatiguesensation..12/18/202226YMCSalvageChemotherapy(n=342)DoInterestINTEREST(gefitinibvs.docetaxelinptswithLAormeta.NSCLCpre-treatedwithplatinum-basedchemotherapyWCLC20071466ptsfromMar2004toFeb2006.12/18/202227YMCInterestINTEREST(gefitinibvsInterestQoFandsymptomimprovementWCLC2007.12/18/202228YMCInterestQoFandsymptomimprovInterestWCLC2007.12/18/202229YMCInterestWCLC2007.12/14/202229InterestOverallsurvival.12/18/202230YMCInterestOverallsurvival.12/14Clinicalcharacteristics&responserate(ptnumber=1974)IntJClinOncol2006;11:190–8.12/18/202231YMCClinicalcharacteristics&resEGFRMutationEurJCancer2006:17-23NEnglJMed2004;350:2129-39.12/18/202232YMCEGFRMutationEurJCancer2006FailureofDoubletChemotherapyplusEGFR-TKIINTACTI,IITRIBUTE,TALENT.12/18/202233YMCFailureofDoubletChemotherapGiaccone.JCO2004;22:777OverallSurvivalofINTACT-1inEachTreatmentGroup(GEM+CDDPc/sIressa)PoorsurvivalforthoseuseIressawithGEM+CDDP.12/18/202234YMCGiaccone.JCO2004;22:777OveraCanwefurtherprolongdisease-freesurvivalandoverallsurvival?FailureofdoubletchemotherapyplusTKIINTACTI,II(Gefitinib);TRIBUTE,TALENT(Erlotinib)MajorityperformedinCaucasianptsUnknownforAsianptswithhighEGFRmutationrateToassesstheefficacyofaddingchronicintermittentlow-dosevinorelbinetogefitinibtreatmentforadenocarcinomaoflungwhofailedtwoormoreregimensofchemotherapy.

.12/18/202235YMCCanwefurtherprolongdisease.12/18/202236YMC.12/14/202236YMCConclusionsAdditionoflow-dosevinorelbinetogefitinibhasshownhighefficacyinadenocarcinomalungcancerpatientswhohavefailedtwopreviousregimensofchemotherapy.GiventhefactthattherearefournegativephaseIIIrandomizedtrialsofEGFRTKI'swithchemotherapy(INTACTIandII,TRIBUTE,TALENT),

onlystudiesinselectedEGFRmutation-enrichedpatientpopulationscanbejustifiedatthistimeforfurtherclinicaltrialscombiningchemotherapywithEGFRTKIs..12/18/202237YMCConclusionsAdditionoflow-dos%FreefromProgression1-yearprogression-freesurvivalratewas57.1%intheGVarmand21.2%intheGarm(p=0.008).12/18/202238YMC%FreefromProgression1-yearErlotinibinducesG1arrestwhichcanblockM-phaseactivityofdocetaxelDocetaxelinducesM-phasearrestandapoptosisthatisenhancedbyerlotinibSequence–specificInteractionClinLungCancer2006;7:385.12/18/202239YMCErlotinibinducesG1arrestwhFirst-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:a8031.12/18/202240YMCFirst-lineAsianSequentialTaTimetoDiseaseProgression1.00.20

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.12/18/202241YMCTimetoDiseaseProgression1.0FirstlinetreatmentwithEGFR-TKIsinthosewithEGFRmutatedpatients.12/18/202242YMCFirstlinetreatmentwithEGFR98ptsunderwentEGFRscreeningandmutationsweredetectedin34(35%).EGFRmutations:exon19deletions(53%),L858R(26%)31ptsreceivedgefitinib,R.R.55%,medianprogression-freesurvival9.2M.Therapywaswelltolerated.JClinOncol2008;26:2442-9.12/18/202243YMC98ptsunderwentEGFRscreeninPercentchangeinmeasurabletumoratbestresponse,byindividualpatientJClinOncol2008;26:2442-9.12/18/202244YMCPercentchangeinmeasurabletKaplan-Meiercurvesfor(A)progression-freesurvivaland(B)overallsurvivalamongalltreatedptsJClinOncol2008;26:2442-9PFS9.2MSur17.5M.12/18/202245YMCKaplan-Meiercurvesfor(A)pGefitinibfirstlinetreatmentinenrichedEGFR-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,MExon19deletion20958.9Exon21L858R232/18/202246YMCGefitinibfirstlinetreatmentPredictiveFactorsofResponsetoGefitinibin152EGFRmutatedpatientsinNTUHVariablesNoResponserates(%)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.AJRCCM2008.12/18/202247YMCPredictiveFactorsofResponseNosurvivaldifferencein152chemonaiveorchemo-treatedEGFRmutatedpatientsinNTUHChmonaïvegefitinib(n=91)Chemotherapytreatedgefitinib(n=61)logrankChmonaïvegefitinib(n=91)Chemotherapytreatedgefitinib(n=61)logrank=0.24WuJYetal.AJRCCM2008.12/18/202248YMCNosurvivaldifferencein1522003.9.15s/p4lineC/Tsince20010629,PS3FiO250%2003.9.29Iressa2weeksPS1roomairAnother1.5year.12/18/202249YMC2003.9.15s/p4lineC/TsincMs.ReeHxNo3167688775Y/O20021202SOBformonths,PS2-3,NC3L/minpreC/T20050804postNGC;taxotere;underIressa-N,PS0.12/18/202250YMCMs.ReeHxNo3167688775Y/Os/prenaltransplantationwith

adenocarcinoma,LUL,&brain,meningealcarcinomatosisNotappropriateforchemotherapy,receivefirstlineTarcevawithtotaldisappearanceofmeningealcarcinomatosis&brainmetastases(brainMRIfollow-up6monthsafterTarcevatreatment)TarcevafirstlinetreatmentPatientstillaliveatpresent.12/18/202251YMCs/prenaltransplantationwithT790MPaoetal.PLoSMed2005;2:1-11Kwaketal.ProNatAcadSciUSA2005;102:7665-708of16TKItreatedhad2ndmutation:7of8wasT790M

ClinCancerRes2006;12:6494-501T790Maccountsfor50%acquiredresistancetoEGFR-TKIsC-METamplificationaccountsfor25%And….12/18/202252YMCT790MPaoetal.PLoSMed2005;EGFRandMETeachindependentlyactivateErbB3intheresistantcellsAKTP13KP110P85PPPAdaptedfromreviewbyC1ArteagaNatureMedicile.2007EGFRErbB3MetEduSessionASCO2008.12/18/202253YMCEGFRandMETeachindependentlTheIGF-IRpathwayisactivatedbyalossofIGFBindingProteins(IGFBPs)CellSurvivalCellDeathEGFRErbB3IGFIGF-IRIGF-BPsEGFRgefitinibgefitinibErbB3IGF-IRP13kp110p85pIRS-1AKTpParental(Sensitive)ResistantEduSessionASCO2008.12/18/202254YMCTheIGF-IRpathwayisactivateAcquiredResistancetoEGFRInhibitorsMechanismTreatmentT790MIrreversibleEGFRinhibitorsMETamplificationsMET+EGFRinhibitorsIGF-1RactivationIGF-1R(orPI3K)+EGFRinhibitorsHeterogenicityofresistancemaynecessitatecombinations(eg.IrreversibleEGFR&METinhibitors)ShouldthesecombinationsbemovedtoinitialtherapytoproducegreaterTTPsimilartostrategyforHIVandTB?EduSessionASCO2008.12/18/202255YMCAcquiredResistancetoEGFRInConclusions:ClinicalPredictorsofEGFR-TKIsResponsivenessResponserate,%*Setting1stline2ndline3rdlineChemotherapy(singleordoublet)20-4510-20<10TKI(EastAsianpopulation)20-3520-3520-35TKI(Caucasian)101010TKI(EGFRmutation+)60-8060-8060-80TKI(EGFRmutation-)10-1510-1510-15*ResponsetoEGFR-TKItreatmentcorrelatedwellwithpatientsurvival..12/18/202256YMCConclusions:ClinicalPredictoSummaryEGFR-TKIiseffectivesalvagetreatmentagainstNSCLC,especiallyinAsian,non-smoker,andadenocarcinoma.PreliminaryresultsofEGFR-TKIinfirst-linesettingofselectedpatients,eg.EGFRmutatedadenoca,areencouraging.HowtointegrateEGFR-TKIintoorreplaceconventionalstandardtreatmentfordifferentstagesofNSCLCremainstoberesolved..12/18/202257YMCSummaryEGFR-TKIiseffectivesEpidermalgrowthfactorreceptor-tyrosinekinaseinhibitorinnon-small-celllungcancerYuh-MinChen,MD,PhD.ChestDept.,TaipeiVGH.12/18/202258YMCEpidermalgrowthfactorreceptSurvival

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

maturationChemotherapy/

radiotherapy

resistanceAngiogenesisMetastasisBalabanetal1996;Akimotoetal1999;Wells1999;Woodburn1999;

Hanahan2000;Raymondetal2000CyclinD1pYpYpY.12/18/202259YMCSurvival

(anti-apoptosis)PI3-KRppRExtracellularIntracellularMembranepKpKpppTGFaSubstrateSubstrateSignallingMoleculesProliferationInhibitApoptosisAngiogenesisMetastasisNucleusMonoclonalAntibodiesEGFRTyrosineKinaseInhibitors.12/18/202260YMCRppRExtracellularIntracellularIDEAL1and2trialdesignGefitinib250mg/dayGefitinib

500mg/dayContinuegefitinibuntildisease

progressionorunacceptabletoxicityIDEAL,IressaTMDoseEvaluationinAdvancedLungcancer

RandomisationIDEAL1(n=209)

1or2priorregimensIDEAL2(n=216)

>2priorregimens

PrimaryendpointsObjectivetumourresponseSymptomimprovement(IDEAL2)Safety(IDEAL1).12/18/202261YMCIDEAL1and2trialdesignGefiMediantimetoimprovement-symptomsandQOL*Timeof1stassessmentMediantimetoimprovement,days

Symptom/QOLmeasureLCSFACT-L8*29*.12/18/202262YMCMediantimetoimprovement-*TIDEAL1and2:overallsurvival

bysymptomimprovement(250mg/day)Probability1.00.20.0IDEAL1MonthsfromrandomisationImprovementNoimprovement2740183013.33.5Patients

(n)Deaths

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

(n)Median(months)1.00.20.0ProbabilityIDEAL2Monthsfromrandomisation02468101214161820Douillardetal2002;Lynchetal2003.12/18/202263YMCIDEAL1and2:overallsurvivaISEL(IRESSASurvivalEvaluationinLungCancer):

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

endpoint:ENDBENEFIT2:1ratio

AdoubleblindPhaseIIIsurvivalstudycomparingIRESSA(250mg)plusBSCvs.placeboplusBSCinpatientswithadvancedNSCLCwhohavereceived1–2priorchemotherapyregimensandarerefractoryorintoleranttotheirmostrecentregimen1692patientsin210centresacross28countries342patientsoforientaloriginNoJapanese/USsites*BSC=BestSupportiveCareLancet2005;366:1527-37.12/18/202264YMCISEL(IRESSASurvivalEvaluatiISEL-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=0.0299.12/18/202265YMCISEL-OverallSurvivalPercentISELSurvival:OrientalsPercentsurvivingTime(months)Atrisk:Gefitinib235221199179145119957864514025128

——

IRESSA

------Placebo

Placebo107978474564335292213873115.5M9.5M.12/18/202266YMCISELSurvival:OrientalsPercenJChemother2005;17:679.12/18/202267YMCJChemother2005;17:679.12/14/RESULTS3CR,9PR,withaR.R.of33.3%

SD14,controlrateof72.2%Alltreatment-relatedtoxicitieswerefewandmildinseverity,exceptonepatientsufferedfromreversiblegrade3interstitialpneumonitisJChemother2005;17:679.12/18/202268YMCRESULTS3CR,9PR,withaR.R.%SurvivalMediansurvival:9.5monthsOne-yearsurvivalrate:45.1%JChemother2005;17:679.12/18/202269YMC%SurvivalMediansurvival:9.5%SurvivalFig.10102030405060708090100036912151821MonthsCompleteorpartialresponse(n=12)median20.1MStableorprogressivedisease(n=24)median4.7MSurvivalaccordingtoresponseornot15.4月JChemother2005;17:679.12/18/202270YMC%SurvivalFig.101020304050607StudyDesignofBR.21

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

treatment(CR/PR:SD:PD)

Priorregimens(1vs2)Priorplatinum

(yesvsno)Tarceva

150mgdailyPlaceboRANDOMISEPS=performancestatus21NEnglJMed2005;353:123–32.12/18/202271YMCStudyDesignofBR.21StratifBR.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;353:123.12/18/202272YMCBR.21:SignificantclinicalprImprovementinSurvivalwithTarceva42.5%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

.12/18/202273YMCImprovementinSurvivalwithTBR.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;353:123–32.12/18/202274YMCBR.21:TimetosymptomdeterioTRUST:TarcevaMO18109

AnexpandedaccessclinicalprogramofTarceva(erlotinib)inptswithadvancedstageIIIB/IVNSCLC

LungCancer2008.12/18/202275YMCTRUST:TarcevaMO18109

AnexpaPatientPopulation&ResponseFromMay2005toJuly2006,300patientswereenteredfrom14hospitalsinTaiwan.Thisanalysiswasbasedon299patientswhoreceivedatleastonedoseofTarceva..12/18/202276YMCPatientPopulation&ResponseFResponserateandcontrolratebypretreatmentcharacteristicsandskintoxicityPatientcharacteristicsPatientnumberResponserate(%)p-valueControlrate(%)p-valueGenderMaleFemale1401332037.60.001363.682.70.0004Age<65

6516011334.420.40.0115185Performancestatus0/123226351228.822.941.70.46910.339272.671.483.30.88850.4124StageIIIBIV5621517.931.20.049269.673.50.5651HistologyAdenocarcinomaSquamouscellcarcinoma1904834.712.50.00277960.40.0079PresenttreatmentasSecondlineThirdline16710229.926.50.541370.776.50.2983SmokingstatusNon-smokerFormerorcurrentsmoker15811533.521.70.033067Skintoxicity-1NorashRash2924410.330.70.021641.476.6<0.0001Skintoxicity-2Norashorgrade1Rashgrade2,3,or411915419.335.70.00361.381.80.0002Thebestresponserateswerea29%partialresponseand