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、Epidermal growth factor receptor-tyrosine kinase inhibitor in non-small-cell lung cancerYuh-MinChen,MD,PhD.ChestDept.,TaipeiVGH4/26/20241Survival(anti-apoptosis)PI3-KActivationoftheepidermalgrowthfactorreceptortyrosineActivationoftheepidermalgrowthfactorreceptortyrosinekinase(EGFR-TK):apivotaldriver

2、ofcarcinogenesiskinase(EGFR-TK):apivotaldriverofcarcinogenesisEGFR-TKEGFRLigandRASRAFSOSGRB2PTENAKTSTAT3MEKGene transcriptionCell-cycle progressionDNAMycMycCyclin D1JunFosP PMAPKProliferation/maturationChemotherapy/radiotherapyresistanceAngiogenesisMetastasisBalaban et al 1996;Akimoto et al 1999;Wel

3、ls 1999;Woodburn 1999;Hanahan 2000;Raymond et al 2000 Cyclin D1pYpYpY4/26/20242RppRExtracellularIntracellularMembranepKpKpppTGFaSubstrateSubstrateSignallingMoleculesProliferationInhibit ApoptosisAngiogenesisMetastasisNucleusMonoclonalAntibodiesEGFRTyrosineKinaseInhibitors4/26/20243IDEAL1and2trialdes

4、ignGefitinib250 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 impro

5、vement(IDEAL 2)lSafety(IDEAL 1)4/26/20244Median time to improvement-symptoms and QOL*Time of 1st assessmentMedian time toimprovement,daysSymptom/QOLmeasureLCSFACT-L8*29*4/26/20245IDEAL1and2:overallsurvivalbysymptomimprovement(250mg/day)Probability 1.00.80.60.40.20.0IDEAL 1Months from randomisationIm

6、provementNo 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 20034/26/20246ISEL(IRESSA Survival Eva

7、luation 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 recei

8、ved 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 4/26/20247ISEL-OverallSurvivalPercentsurvivingTime(mon

9、ths)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=0.02994/26/20248ISEL

10、Survival: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 M4/26/20249J Chemother 2005;17:6794/26/202410RESULTS3CR,9PR,withaR.R.of 33.3%SD14,control rate of 72.2%All

11、treatment-relatedtoxicitieswerefewandmildinseverity,exceptonepatientsufferedfromreversiblegrade3interstitialpneumonitisJ Chemother 2005;17:6794/26/202411%SurvivalMedian survival:9.5 months One-year survival rate:45.1%J Chemother 2005;17:6794/26/202412%SurvivalFig.10102030405060708090100036912151821M

12、onthsCompleteorpartialresponse(n=12)median20.1MStableorprogressivedisease(n=24)median4.7MSurvival according to response or not15.4月月J Chemother 2005;17:6794/26/202413StudyDesignofBR.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

13、(yes vs no)Tarceva150mg dailyPlaceboRANDOM I SEPS=performance status21 N Engl J Med 2005;353:123324/26/202414BR.21:BR.21:S Significantignificant clinicalpredictorsofresponsetoclinicalpredictorsofresponsetoTarcevaTarcevaTarcevatreated pts(n)R.R.(%)p value*Gender Female(146)14.4 0.006Male(281)6.1Histo

14、logyAdenocarcinoma(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

15、(p=0.01)were associated with responseShepherd et al.NEJM 2005;353:1234/26/202415ImprovementinSurvivalwithTarceva42.5%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)P

16、lacebo(n=243)Median survival(months)6.7 4.7 1-year survival(%)31 21 4/26/202416BR.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,unadjust

17、ed for multiple symptoms Bezjak A,et al.J Clin Oncol 2006;24:38317Shepherd F,et al.N Engl J Med 2005;353:123324/26/202417TRUST:TarcevaMO18109AnexpandedaccessclinicalprogramofTarceva(erlotinib)inptswithadvancedstageIIIB/IVNSCLCLungCancer20214/26/202418PatientPopulation&ResponseFromMay2005toJuly2006,3

18、00patientswereenteredfrom14hospitalsinTaiwan.Thisanalysiswasbasedon299patientswhoreceivedatleastonedoseofTarceva.4/26/202419ResponserateandcontrolratebypretreatmentResponserateandcontrolratebypretreatmentcharacteristicsandskintoxicitycharacteristicsandskintoxicityPatient characteristicsPatient numbe

19、rResponse 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 IV5621517.931.20.049269.673.5

20、0.5651Histology 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 Rash2

21、924410.310.330.730.70.02160.021641.476.60.0001Skin 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.

22、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 sk

23、in rash(p p=0.003)=0.003)were significantly correlated with response to treatment.4/26/2024200.000.250.500.751.00Progressionfreesurvival(Months)061020CensoredobservationsFig.1Freefromprogression8421214161822Time to disease progression of 299 NSCLC pts treated with erlotinib.The median time to diseas

24、e progression was 5.6 months5.6 months(95%C.I.:4.4 6.5 months,45 pts censored)4/26/202421EGFR-TKIvs.chemotherapeuticagentsinsalvagechemotherapy4/26/202422In conclusion,both chemotherapeutic agents,such as In conclusion,both chemotherapeutic agents,such as docetaxel alone or gemcitabine+vinorelbine,a

25、nd 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 bett

26、er 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 s

27、econd-line for salvage chemotherapy,even in a second-line setting for Chinese pts.setting for Chinese pts.J Thorac Oncol 2006;1:545-504/26/202423EfficacyofSalvageTherapyinNSCLCTrialScheduleR.R.,%MTP,MMSur,M1-Yr,%SingleagentGemcitabine1200mg/m2D1,8,15q4wks12.52.17.540Docetaxel3535mg/m2D1,8,15q4wks17.

28、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/m2D1,8,15q4wks31.34.68.334.3Vinorelb

29、ine+CisplatinV20mg/m2D1,8,15+C50mg/m2D1q4wks9.53.77.619.74/26/202424Salvage Chemotherapy(n=342)Grade Neutroopenia4/26/202425Salvage Chemotherapy(n=342)Grade FatigueDocetaxel40 and vinorelbine plus cisplatin induced more frequent severe fatigue than other Docetaxel40 and vinorelbine plus cisplatin in

30、duced 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.4/26/202426InterestINTEREST(gefitinibv

31、s.docetaxelinptswithLAormeta.NSCLCpre-treatedwithplatinum-basedchemotherapyWCLC 20071466 pts from Mar 2004 to Feb 20064/26/202427InterestQoFandsymptomimprovementWCLC 20074/26/202428InterestWCLC 20074/26/202429InterestOverallsurvival4/26/202430Clinicalcharacteristics&responserate(ptnumber=1974)Int J

32、Clin Oncol 2006;11:19084/26/202431EGFRMutationEur J Cancer 2006:17-23N Engl J Med 2004;350:2129-394/26/202432FailureofDoubletChemotherapyplusEGFR-TKIINTACTI,IITRIBUTE,TALENT4/26/202433Giaccone.JCO 2004;22:777Overall Survival of INTACT-1 in Each Treatment Group(GEM+CDDP c/s Iressa)Poor survival for t

33、hose use Iressa with GEM+CDDP4/26/202434Canwefurtherprolongdisease-freesurvivalandoverallsurvival?FailureofdoubletchemotherapyplusTKIINTACTI,II(Gefitinib);TRIBUTE,TALENT(Erlotinib)MajorityperformedinCaucasianptsMajorityperformedinCaucasianpts UnknownforAsianptswithhighEGFRmutationrateUnknownforAsian

34、ptswithhighEGFRmutationrateToassesstheefficacyofaddingchronicToassesstheefficacyofaddingchronicintermittentlow-dosevinorelbinetogefitinibintermittentlow-dosevinorelbinetogefitinibtreatmentforadenocarcinomaoflungwhofailedtreatmentforadenocarcinomaoflungwhofailedtwoormoreregimensofchemotherapy.twoormo

35、reregimensofchemotherapy.4/26/2024354/26/202436ConclusionsAdditionoflow-dosevinorelbinetogefitinibhasshownhighefficacyinadenocarcinomalungcancerpatientswhohavefailedtwopreviousregimensofchemotherapy.GiventhefactthattherearefournegativephaseIIIrandomizedtrialsofEGFRTKIswithchemotherapy(INTACTIandII,T

36、RIBUTE,TALENT),onlystudiesinselectedEGFRmutation-enrichedpatientpopulationscanbejustifiedatthistimeforfurtherclinicaltrialscombiningchemotherapywithEGFRTKIs.4/26/202437%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)4/26/202438Erlotini

37、b 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;7:3854/26/202439First-line Asian Sequential Tarceva plus First-line Asian Sequential Tarceva plus Chemothera

38、py 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);q4wksPDStra

39、tifiedbycentre,stage,histology,smokingstatusStudy treatmentPost-treatmentScreeningPost-studyGemcitabine 1250mg/m2(d1,8);cisplatin 75mg/m2 ORcarboplatin 5AUC(d1);erlotinib 150mg/day(d1528)PASCO 2021;26:a80314/26/202440TimetoDiseaseProgression1.00.80.60.40.200246810 12 1416 18 20 22 24 26 28 30 32 34

40、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-ran

41、k test p=0.0185HR=0.56 95%CI:0.370.8424.131.4PASCO 2021;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 type4/26/202441FirstlinetreatmentwithEGFR-TKIsint

42、hosewithEGFRmutatedpatients4/26/20244298 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 2021;26:2442-9 4/26/202443Perc

43、ent change in measurable tumor at best response,by individual patientJ Clin Oncol 2021;26:2442-9 4/26/202444 Kaplan-Meier curves for(A)progression-free survival and(B)overall survival among all treated ptsJ Clin Oncol 2021;26:2442-9 PFS 9.2 MSur 17.5 M4/26/202445Gefitinibfirstlinetreatmentinenriched

44、EGFR-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 2021;26:2745-53Pt NoRR,%Median TTF,MExon 19 deletion20958.9Exon 21 L858R2373.99.14/26/202446PredictiveFact

45、orsofResponsetoGefitinibin152EGFRmutatedpatientsinNTUHVariablesNoResponse 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 20214/26

46、/202447No 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

47、=61)logrank=0.24Wu JY et al.AJRCCM 20214/26/2024482003.9.15 s/p 4 line C/T since 20010629,PS 3 FiO2 50%2003.9.29 Iressa 2 weeks PS 1 room airAnother1.5year4/26/202449Ms.Ree Hx No 31676887 75 Y/O 20021202SOBformonths,PS2-3,NC3L/minpreC/T20050804postNGC;taxotere;underIressa-N,PS04/26/202450s/p renal t

48、ransplantation 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

49、 6 months after Tarceva treatment)Tarceva first line treatmentPatient still alive at present4/26/202451T790MPao 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

50、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 4/26/202452EGFR and MET each independently activate ErbB3 in the resist

51、ant cellsAKTP13KP110P85PPPAdaptedfromreviewbyC1ArteagaNatureMedicile.2007EGFRErbB3MetEdu Session ASCO 20214/26/202453The IGF-IR pathway is activated by a loss of IGF Binding Proteins(IGFBPs)CellSurvivalCellDeathEGFRErbB3IGFIGF-IRIGF-BPsEGFRgefitinibgefitinibErbB3IGF-IRP13kp110p85pIRS-1AKTpParental(S

52、ensitive)ResistantEdu Session ASCO 20214/26/202454AcquiredResistancetoEGFRInhibitorsMechanismTreatmentT790MIrreversible EGFR inhibitorsMET amplificationsMET+EGFR inhibitorsIGF-1R activationIGF-1R(or PI3K)+EGFR inhibitorsHeterogenicityofresistancemaynecessitatecombinations(eg.IrreversibleEGFR&METinhi

53、bitors)ShouldthesecombinationsbemovedtoinitialtherapytoproducegreaterTTPsimilartostrategyforHIVandTB?Edu Session ASCO 20214/26/202455Conclusions:Clinical Predictors of EGFR-TKIs ResponsivenessResponse rate,%*Setting1st line2nd line3rd lineChemotherapy(single or doublet)20-4510-2010TKI(East Asian pop

54、ulation)20-3520-3520-35TKI(Caucasian)101010TKI(EGFR mutation+)60-8060-8060-80TKI(EGFR mutation-)10-1510-1510-15*Response to EGFR-TKI treatment correlated well with patient survival.4/26/202456SummaryEGFR-TKIiseffectivesalvagetreatmentagainstNSCLC,especiallyinAsian,non-smoker,andadenocarcinoma.PreliminaryresultsofEGFR-TKIinfirst-linesettingofselectedpatients,eg.EGFRmutatedadenoca,areencouraging.HowtointegrateEGFR-TKIintoorreplaceconventionalstandardtreatmentfordifferentstagesofNSCLCremainstoberesolved.4/26/202457