非小细胞肺癌表皮生长因子受体酪氨酸激酶抑制剂英文文档.pptx

2024/4/3YMC1Survival(anti-apoptosis)PI3-KActivationoftheepidermalgrowthfactorreceptortyrosineActivationoftheepidermalgrowthfactorreceptortyrosinekinase(EGFR-TK):apivotaldriverofcarcinogenesiskinase(EGFR-TK):apivotaldriverofcarcinogenesisEGFR-TKEGFRLigandRASRAFSOSGRB2PTENAKTSTAT3MEKGene transcriptionCell-cycle progressionDNAMycMycCyclin D1JunFosP PMAPKProliferation/maturationChemotherapy/radiotherapyresistanceAngiogenesisMetastasisBalaban et al 1996;Akimoto et al 1999;Wells 1999;Woodburn 1999;Hanahan 2000;Raymond et al 2000 Cyclin D1pYpYpY2024/4/3YMC2RppRExtracellularIntracellularMembranepKpKpppTGFaSubstrateSubstrateSignallingMoleculesProliferationInhibit ApoptosisAngiogenesisMetastasisNucleusMonoclonalAntibodiesEGFRTyrosineKinaseInhibitors2024/4/3YMC3IDEAL1and2trialdesignGefitinib250 mg/dayGefitinib500 mg/dayContinue gefitinib until diseaseprogression or unacceptable toxicityIDEAL,IressaTM Dose Evaluation in Advanced Lung cancerRandomisationlIDEAL 1(n=209)1 or 2 prior regimenslIDEAL 2(n=216)2 prior regimensPrimary endpointslObjective tumour responselSymptom improvement(IDEAL 2)lSafety(IDEAL 1)2024/4/3YMC4Median time to improvement-symptoms and QOL*Time of 1st assessmentMedian time toimprovement,daysSymptom/QOLmeasureLCSFACT-L8*29*2024/4/3YMC5IDEAL1and2:overallsurvivalbysymptomimprovement(250mg/day)Probability 1.00.80.60.40.20.0IDEAL 1Months from randomisationImprovementNo improvement2740183013.33.5Patients(n)Deaths(n)Median(months)0 2 4 6 8 101214 1618204458265613.63.7Patients(n)Deaths(n)Median(months)1.00.80.60.40.20.0ProbabilityIDEAL 2Months from randomisation02 4 6 8 10 1214 16 1820Douillard et al 2002;Lynch et al 20032024/4/3YMC6ISEL(IRESSA Survival Evaluation in Lung Cancer):Clinical Trial DesignRandomisation Gefitinib(250 mg)+*BSCPlacebo+*BSC SURVIVALSecondary:TTF,ORQoL,safetyPrimaryendpoint:ENDBENEFIT2:1ratioA double blind Phase III survival study comparing IRESSA(250mg)plus BSC vs.placebo plus BSC in patients with advanced NSCLC who have received 12 prior chemotherapy regimens and are refractory or intolerant to their most recent regimen1692 patients in 210 centres across 28 countries 342 patients of oriental origin No Japanese/US sites*BSC=Best Supportive CareLancet 2005;366:1527-37 2024/4/3YMC7ISEL-OverallSurvivalPercentsurvivingTime(months)At risk:Gefitinib 1129 1023 901 761 588 455 325 245 175 113 76 45 19 9 IRESSA -PlaceboPlacebo 563 517 446 382 289 220 160 115 77 44 28 20 12 4 2GefitinibplaceboMedian(months)5.65.11yrsurvival27%21%HR=0.89(0.77,1.02),p=0.0871StratifiedlogranktestN=1692,deaths=976Coxanalysis,p=0.02992024/4/3YMC8ISELSurvival:OrientalsPercentsurvivingTime(months)At risk:Gefitinib 235 221 199 179 145 119 95 78 64 51 40 25 12 8 IRESSA -Placebo Placebo 107 97 84 74 56 43 35 29 22 13 8 7 3 1 15.5 M5.5 M9.5 M9.5 M2024/4/3YMC9J Chemother 2005;17:6792024/4/3YMC10RESULTS3CR,9PR,withaR.R.of 33.3%SD14,control rate of 72.2%Alltreatment-relatedtoxicitieswerefewandmildinseverity,exceptonepatientsufferedfromreversiblegrade3interstitialpneumonitisJ Chemother 2005;17:6792024/4/3YMC11%SurvivalMedian survival:9.5 months One-year survival rate:45.1%J Chemother 2005;17:6792024/4/3YMC12%SurvivalFig.10102030405060708090100036912151821MonthsCompleteorpartialresponse(n=12)median20.1MStableorprogressivedisease(n=24)median4.7MSurvival according to response or not15.4月月J Chemother 2005;17:6792024/4/3YMC13StudyDesignofBR.21 Stratified by:Centre PS (0/1 vs 2/3)Response to prior treatment (CR/PR:SD:PD)Prior regimens (1 vs 2)Prior platinum (yes vs no)Tarceva150mg dailyPlaceboRANDOM I SEPS=performance status21 N Engl J Med 2005;353:123322024/4/3YMC14BR.21:BR.21:S Significantignificant clinicalpredictorsofresponsetoclinicalpredictorsofresponsetoTarcevaTarcevaTarcevatreated pts(n)R.R.(%)p value*Gender Female(146)14.4 0.006Male(281)6.1HistologyAdenocarcinoma(209)13.90.001Other(218)4.1EthnicityAsian(53)18.90.02Other(374)7.5Ever smoked*Yes(311)3.80.001No(93)24.7Unknown(23)13.0*Significance between subgroups*Data collected retrospectivelyIn multiple logistic-regression analyses,only never having smoked(p0.001)and adenocarcinoma histology(p=0.01)were associated with responseShepherd et al.NEJM 2005;353:1232024/4/3YMC15ImprovementinSurvivalwithTarceva42.5%improvement in median survivalSurvival distribution functionSurvival time(months)HR=0.73,p0.001*1.000.750.500.250051015202530TarcevaPlacebo N Engl J Med 2005;353:12332 Tarceva(n=488)Placebo(n=243)Median survival(months)6.7 4.7 1-year survival(%)31 21 2024/4/3YMC16BR.21:Timetosymptomdeterioration(months)Placebo Tarceva179179153n348353298n1.9(1.82.8)2.9(24.8)3.7(24.9)Median(95%CI)0.022.8(2.43)Pain0.014.7(3.86.2)Dyspnea0.044.9(3.87.4)Cough p value*Median(95%CI)*Log-rank test,unadjusted for multiple symptoms Bezjak A,et al.J Clin Oncol 2006;24:38317Shepherd F,et al.N Engl J Med 2005;353:123322024/4/3YMC17TRUST:TarcevaMO18109AnexpandedaccessclinicalprogramofTarceva(erlotinib)inptswithadvancedstageIIIB/IVNSCLCLungCancer2008LungCancer20082024/4/3YMC18PatientPopulation&ResponseFromMay2005toJuly2006,300patientswereenteredfrom14hospitalsinTaiwan.Thisanalysiswasbasedon299patientswhoreceivedatleastonedoseofTarceva.2024/4/3YMC19ResponserateandcontrolratebypretreatmentResponserateandcontrolratebypretreatmentcharacteristicsandskintoxicitycharacteristicsandskintoxicityPatient characteristicsPatient numberResponse rate(%)Response rate(%)p-valueControl rate(%)p-valueGender Male Female140133202037.637.60.00130.001363.682.70.0004Age 65 6516011334.434.420.420.40.01150.011573.172.60.9185Performance status 0/123226351228.822.941.70.46910.339272.671.483.30.88850.4124Stage IIIB IV5621517.931.20.049269.673.50.5651Histology Adenocarcinoma Squamous cell carcinoma1904834.734.712.512.50.00270.00277960.40.0079Present treatment as Second line Third line16710229.926.50.541370.776.50.2983Smoking status Non-smoker Former or current smoker15811533.533.521.721.70.0330.03379.164.40.0067Skin toxicity-1No rash Rash2924410.310.330.730.70.02160.021641.476.60.0001Skin toxicity-2 No rash or grade 1 Rash grade 2,3,or 411915419.319.335.735.70.0030.00361.381.80.0002The best response rates were a 29%partial response and 29%partial response and 44%stable44%stable disease in 273 patients who had response data available.Non-smoking(Non-smoking(p p=0.033),adenocarcinoma=0.033),adenocarcinoma/BAC BAC(p p=0.0027),female(=0.0027),female(p p=0.0013),=0.0013),aged less than 65 years(p=0.0115),stage IV(p=0.0492),patients with skin rash skin rash(p p=0.0216),and a higher grade of skin rash(=0.0216),and a higher grade of skin rash(p p=0.003)=0.003)were significantly correlated with response to treatment.2024/4/3YMC200.000.250.500.751.00Progressionfreesurvival(Months)061020CensoredobservationsFig.1Freefromprogression8421214161822Time to disease progression of 299 NSCLC pts treated with erlotinib.The median time to disease progression was 5.6 months5.6 months(95%C.I.:4.4 6.5 months,45 pts censored)2024/4/3YMC21EGFR-TKIvs.chemotherapeuticagentsinsalvagechemotherapy2024/4/3YMC22In conclusion,both chemotherapeutic agents,such as In conclusion,both chemotherapeutic agents,such as docetaxel alone or gemcitabine+vinorelbine,and docetaxel alone or gemcitabine+vinorelbine,and gefitinibgefitinib,are appropriate salvage regimens for Chinese,are appropriate salvage regimens for Chinese NSCLC pts who have failed previous chemotherapy.NSCLC pts who have failed previous chemotherapy.However,However,gefitinibgefitinib has a better safety profile and has a better safety profile and probably better survival than the chemotherapeutic probably better survival than the chemotherapeutic agents,and would be an appropriate alternative choice agents,and would be an appropriate alternative choice for salvage chemotherapy,even in a second-line for salvage chemotherapy,even in a second-line setting for Chinese pts.setting for Chinese pts.J Thorac Oncol 2006;1:545-502024/4/3YMC23EfficacyofSalvageTherapyinNSCLCTrialScheduleR.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/m2D1q4wks9.53.77.619.72024/4/3YMC24Salvage Chemotherapy(n=342)Grade Neutroopenia2024/4/3YMC25Salvage Chemotherapy(n=342)Grade FatigueDocetaxel40 and vinorelbine plus cisplatin induced more frequent severe fatigue than other Docetaxel40 and vinorelbine plus cisplatin induced more frequent severe fatigue than other regimens.Patients that received single-agent gemcitabine and gefitinib reported no severe fatigue regimens.Patients that received single-agent gemcitabine and gefitinib reported no severe fatigue sensation.sensation.2024/4/3YMC26InterestINTEREST(gefitinibvs.docetaxelinptswithLAormeta.NSCLCpre-treatedwithplatinum-basedchemotherapyWCLC 20071466 pts from Mar 2004 to Feb 20062024/4/3YMC27InterestQoFandsymptomimprovementWCLC 20072024/4/3YMC28InterestWCLC 20072024/4/3YMC29InterestOverallsurvival2024/4/3YMC30Clinicalcharacteristics&responserate(ptnumber=1974)Int J Clin Oncol 2006;11:19082024/4/3YMC31EGFRMutationEur J Cancer 2006:17-23N Engl J Med 2004;350:2129-392024/4/3YMC32FailureofDoubletChemotherapyplusEGFR-TKIINTACTI,IITRIBUTE,TALENT2024/4/3YMC33Giaccone.JCO 2004;22:777Overall Survival of INTACT-1 in Each Treatment Group(GEM+CDDP c/s Iressa)Poor survival for those use Iressa with GEM+CDDP2024/4/3YMC34Canwefurtherprolongdisease-freesurvivalandoverallsurvival?FailureofdoubletchemotherapyplusTKIINTACTI,II(Gefitinib);TRIBUTE,TALENT(Erlotinib)MajorityperformedinCaucasianptsMajorityperformedinCaucasianpts UnknownforAsianptswithhighEGFRmutationrateUnknownforAsianptswithhighEGFRmutationrateToassesstheefficacyofaddingchronicToassesstheefficacyofaddingchronicintermittentlow-dosevinorelbinetogefitinibintermittentlow-dosevinorelbinetogefitinibtreatmentforadenocarcinomaoflungwhofailedtreatmentforadenocarcinomaoflungwhofailedtwoormoreregimensofchemotherapy.twoormoreregimensofchemotherapy.2024/4/3YMC352024/4/3YMC36ConclusionsAdditionoflow-dosevinorelbinetogefitinibhasshownhighefficacyinadenocarcinomalungcancerpatientswhohavefailedtwopreviousregimensofchemotherapy.GiventhefactthattherearefournegativephaseIIIrandomizedtrialsofEGFRTKIswithchemotherapy(INTACTIandII,TRIBUTE,TALENT),onlystudiesinselectedEGFRmutation-enrichedpatientpopulationscanbejustifiedatthistimeforfurtherclinicaltrialscombiningchemotherapywithEGFRTKIs.2024/4/3YMC37%Free from Progression1-year progression-free survival rate was 57.1%in the GV arm and 21.2%in the G arm(p=0.008)2024/4/3YMC38Erlotinib induces G1 arrest which can block M-phase activity of docetaxelDocetaxel induces M-phase arrest and apoptosis that is enhanced by erlotinibSequence specific InteractionClin Lung Cancer 2006;7:3852024/4/3YMC39First-line Asian Sequential Tarceva plus First-line Asian Sequential Tarceva plus Chemotherapy Trial(FAST-ACT):Study DesignChemotherapy Trial(FAST-ACT):Study DesignPlaceboErlotinib 150mg/dayPreviously untreated stage IIIB/IV NSCLC(n=150)R11PDSix cycles gemcitabine+cisplatin or carboplatin+placebo;q4wksSix cycles gemcitabine(d1,8)+cisplatin(d1)or carboplatin(d1)+erlotinib(d1528);q4wksPDStratifiedbycentre,stage,histology,smokingstatusStudy treatmentPost-treatmentScreeningPost-studyGemcitabine 1250mg/m2(d1,8);cisplatin 75mg/m2 ORcarboplatin 5AUC(d1);erlotinib 150mg/day(d1528)PASCO 2008;26:a80312024/4/3YMC40TimetoDiseaseProgression1.00.80.60.40.200246810 12 1416 18 20 22 24 26 28 30 32 34 36Time(weeks)38 40 42 44 46 48 50 52 54 56 5876 72 72 72 64 61 58 58 58 52 50 50 46 37 36 32 26 15 1478 76 76 76 67 59 58 56 50 43 43 41 35 25 24 22 16 8712 1098755531054211111110No.at riskErlotinibPlaceboEarly and consistent separation of curvesMedian TTP(weeks)GC-erlotinib31.4GC-placebo24.1Log-rank test p=0.0185HR=0.56 95%CI:0.370.8424.131.4PASCO 2008;26:a8031R.R.36.8%24.4%1.How long should chemotherapy be given(no PDS at maintenance phase)2.GEMCDDP dose(control arm)is less than usual 3.Better for those Caucasians who have higher%of EGFR wild type2024/4/3YMC41FirstlinetreatmentwithEGFR-TKIsinthosewithEGFRmutatedpatients2024/4/3YMC4298 pts underwent EGFR screening and mutations were detected in 34(35%).EGFR mutations:exon 19 deletions(53%),L858R(26%)31 pts received gefitinib,R.R.55%,median progression-free survival 9.2 M.Therapy was well tolerated.J Clin Oncol 2008;26:2442-9 2024/4/3YMC43Percent change in measurable tumor at best response,by individual patientJ Clin Oncol 2008;26:2442-9 2024/4/3YMC44 Kaplan-Meier curves for(A)progression-free survival and(B)overall survival among all treated ptsJ Clin Oncol 2008;26:2442-9 PFS 9.2 MSur 17.5 M2024/4/3YMC45GefitinibfirstlinetreatmentinenrichedEGFR-mutatedNSCLCinNTUHN=106(adenoca97,non-adeno9)Pt NoRR,%DCR,%Median TTF,MMedian OS,MAll10650.982.15.522.4EGFR mutated55696987.382424 wild type35202068.63.412.912.9 not done1656.393.85.6NRJCO 2008;26:2745-53Pt NoRR,%Median TTF,MExon 19 deletion20958.9Exon 21 L858R2373.99.12024/4/3YMC46PredictiveFactorsofResponsetoGefitinibin152EGFRmutatedpatientsinNTUHVariablesNoResponse rates(%)Univariate PMultivariate PN=152L858R7565.30.646DelinExon197768.8 Chemonaive9175.80.0050.006 Chemo-treated6154.1Female11071.80.0450.053Male4254.8Smoker2254.60.175Non-smoker13069.265years8213.7Wu JY et al.AJRCCM 20082024/4/3YMC47No survival difference in 152 chemonaive or No survival difference in 152 chemonaive or chemo-treated EGFR mutated patients in NTUH chemo-treated EGFR mutated patients in NTUH Chmonavegefitinib(n=91)Chemotherapytreatedgefitinib(n=61)logrankChmonavegefitinib(n=91)Chemotherapytreatedgefitinib(n=61)logrank=0.24Wu JY et al.AJRCCM 20082024/4/3YMC482003.9.15 s/p 4 line C/T since 20010629,PS 3 FiO2 50%2003.9.29 Iressa 2 weeks PS 1 room airAnother1.5year2024/4/3YMC49Ms.Ree Hx No 31676887 75 Y/O 20021202SOBformonths,PS2-3,NC3L/minpreC/T20050804postNGC;taxotere;underIressa-N,PS02024/4/3YMC50s/p renal transplantation with s/p renal transplantation with adenocarcinoma,LUL,&brain,meningeal adenocarcinoma,LUL,&brain,meningeal carcinomatosiscarcinomatosisNot appropriate for chemotherapy,receive first line Tarceva with total disappearance of meningeal carcinomatosis&brain metastases(brain MRI follow-up 6 months after Tarceva treatment)Tarceva first line treatmentPatient still alive at present2024/4/3YMC51T790MPao et al.PLoS Med Pao et al.PLoS Med 2005;2:1-112005;2:1-11Kwak et al.Pro Nat Acad Kwak et al.Pro Nat Acad Sci USA 2005;102:7665-Sci USA 2005;102:7665-70708 of 16 TKI treated had 8 of 16 TKI treated had 2nd mutation:7 of 8 2nd mutation:7 of 8 was T790Mwas T790M Clin Cancer Res Clin Cancer Res 2006;12:6494-5012006;12:6494-501T790M accounts for 50%acquired resistance to EGFR-TKIsC-MET amplification accounts for 25%And 2024/4/3YMC52EGFR and MET each independently activate ErbB3 in the resistant cells