1、2023/1/22YMC1.2023/1/22YMC2Survival(anti-apoptosis)PI3-KEGFR-TKEGFRLigandRASRAFSOSGRB2PTENAKTSTAT3MEKGene transcriptionCell-cycle progressionDNAMycMycCyclin D1JunFosP PMAPKProliferation/maturationChemotherapy/radiotherapyresistanceAngiogenesisMetastasisBalaban et al 1996;Akimoto et al 1999;Wells 199
2、9;Woodburn 1999;Hanahan 2000;Raymond et al 2000 Cyclin D1pYpYpY.2023/1/22YMC3RppRExtracellularIntracellularMembranepKpKpppTGFaSubstrateSubstrateSignalling MoleculesProliferationInhibit ApoptosisAngiogenesisMetastasisNucleusMonoclonal AntibodiesEGFR Tyrosine Kinase Inhibitors.2023/1/22YMC4Gefitinib25
3、0 mg/dayGefitinib500 mg/dayContinue gefitinib until diseaseprogression or unacceptable toxicityIDEAL,IressaTM Dose Evaluation in Advanced Lung cancerRandomisationl IDEAL 1(n=209)1 or 2 prior regimensl IDEAL 2(n=216)2 prior regimensPrimary endpointsl Objective tumour responsel Symptom improvement(IDE
4、AL 2)l Safety(IDEAL 1).2023/1/22YMC5Median time to improvement-symptoms and QOL*Time of 1st assessmentMedian time toimprovement,daysSymptom/QOLmeasureLCSFACT-L8*29*.2023/1/22YMC6Probability 1.00.80.60.40.20.0IDEAL 1Months from randomisationImprovementNo improvement2740183013.33.5Patients(n)Deaths(n)
5、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 2003.2023/1/22YMC7Randomisation Gefitinib(250 mg)+*BSCPlacebo+*BSC SURVIVALSecondary:TTF,ORQoL,s
6、afetyPrimaryendpoint:ENDBENEFIT2:1 ratio A 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 cent
7、res across 28 countries 342 patients of oriental origin No Japanese/US sites*BSC=Best Supportive CareLancet 2005;366:1527-37.2023/1/22YMC8Percent survivingTime(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 2
8、8 20 12 4 20.00.20.40.60.81.0012345678910 11 12 13 14 15 16GefitinibplaceboMedian(months)5.65.11 yr survival27%21%HR=0.89(0.77,1.02),p=0.0871Stratified log rank testN=1692,deaths=976Cox analysis,p=0.0299.2023/1/22YMC9Percent survivingTime(months)At risk:Gefitinib 235 221 199 179 145 119 95 78 64 51
9、40 25 12 8 IRESSA -Placebo0.00.20.40.60.81.0012345678910 11 12 13 14 15 16 Placebo 107 97 84 74 56 43 35 29 22 13 8 7 3 1 1Stratified log rank 0.70(0.49,0.99)0.046 Log rank 0.65(0.47,0.91)0.012 Cox regression 0.66(0.48,0.91)0.010 Analysis Method HR and 95%CI p-value .2023/1/22YMC10J Chemother 2005;1
10、7:679.2023/1/22YMC11 3 CR,9 PR,with a R.R.of 33.3%SD 14,control rate of 72.2%All treatment-related toxicities were few and mild in severity,except one patient suffered from reversible grade 3 interstitial pneumonitis J Chemother 2005;17:679.2023/1/22YMC12%SurvivalJ Chemother 2005;17:679.2023/1/22YMC
11、13%SurvivalFig.10102030405060708090100036912151821MonthsComplete or partial response(n=12)median 20.1MStable or progressivedisease(n=24)median 4.7MSurvival according to response or not15.4月月J Chemother 2005;17:679.2023/1/22YMC14 Stratified by:Centre PS (0/1 vs 2/3)Response to prior treatment (CR/PR:
12、SD:PD)Prior regimens (1 vs 2)Prior platinum (yes vs no)Tarceva150mg dailyPlaceboRANDOM I SEPS=performance status21 N Engl J Med 2005;353:12332.2023/1/22YMC15Tarcevatreated pts(n)R.R.(%)p value*Gender Female(146)14.4 0.006Male(281)6.1HistologyAdenocarcinoma(209)13.90.001Other(218)4.1EthnicityAsian(53
13、)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;
14、353:123.2023/1/22YMC1642.5%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 .2023/1/22YMC17Placebo
15、 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;353:12332.2023/1/22YMC18.
16、2023/1/22YMC19 From May 2005 to July 2006,300 patients were entered from 14 hospitals in Taiwan.This analysis was based on 299 patients who received at least one dose of Tarceva.2023/1/22YMC20Patient characteristicsPatient numberp-valueControl rate(%)p-valueGender Male Female14013363.682.70.0004Age
17、65 6516011373.172.60.9185Performance status 0/123226351228.822.941.70.46910.339272.671.483.30.88850.4124Stage IIIB IV5621517.931.20.049269.673.50.5651Histology Adenocarcinoma Squamous cell carcinoma190487960.40.0079Present treatment as Second line Third line16710229.926.50.541370.776.50.2983Smoking
18、status Non-smoker Former or current smoker15811579.164.40.0067Skin toxicity-1No rash Rash2924441.476.60.0001Skin toxicity-2 No rash or grade 1 Rash grade 2,3,or 411915461.381.80.0002The best response rates were a disease in 273 patients who had response data available./aged less than 65 years(p=0.01
19、15),stage IV(p=0.0492),patients with were significantly correlated with response to treatment.2023/1/22YMC210.000.250.500.751.00Progression free survival(Months)061020Censored observationsFig.1Free from progression8421214161822Time to disease progression of 299 NSCLC pts treated with erlotinib.The m
20、edian time to disease progression was (95%C.I.:4.4 6.5 months,45 pts censored).2023/1/22YMC22.2023/1/22YMC23J Thorac Oncol 2006;1:545-50.2023/1/22YMC24TrialScheduleR.R.,%MTP,MM Sur,M1-Yr,%Single agent Gemcitabine1200 mg/m2 D1,8,15 q4 wks12.52.17.540 Docetaxel 3535 mg/m2 D1,8,15 q4 wks17.24.28.433.4
21、4040 mg/m2 D1,8 q3 wks10.93.57.435 7575 mg/m2 D 1 q3 wks6.12.87.830.3 Gefitinib250 mg daily33.34.79.340.8Doublet Docetaxel+IfosfamideD 60 mg/m2+I 3 gm/m2 D1 q3 wks1058.226.1 Docetaxel+GemcitabineD 30 mg/m2+G 800 mg/m2 D1,8 q3 wks36.13.85.733.3 Vinorelbine+GemcitabineV 20 mg/m2+G 800 mg/m2 D1,8,15 q4
22、 wks31.3 4.68.334.3 Vinorelbine+CisplatinV 20 mg/m2 D1,8,15+C 50 mg/m2 D1 q4 wks9.53.77.619.7.2023/1/22YMC25Salvage Chemotherapy(n=342)Grade Neutroopenia.2023/1/22YMC26Salvage Chemotherapy(n=342)Grade Fatigue.2023/1/22YMC27InterestWCLC 20071466 pts from Mar 2004 to Feb 2006.2023/1/22YMC28InterestWCL
23、C 2007.2023/1/22YMC29InterestWCLC 2007.2023/1/22YMC30Interest.2023/1/22YMC31Int J Clin Oncol 2006;11:1908.2023/1/22YMC32Eur J Cancer 2006:17-23N Engl J Med 2004;350:2129-39.2023/1/22YMC33INTACT I,IITRIBUTE,TALENT.2023/1/22YMC34Giaccone.JCO 2004;22:777Overall Survival of INTACT-1 in Each Treatment Gr
24、oup(GEM+CDDP c/s Iressa)Poor survival for those use Iressa with GEM+CDDP.2023/1/22YMC35 Failure of doublet chemotherapy plus TKI INTACT I,II(Gefitinib);TRIBUTE,TALENT(Erlotinib).2023/1/22YMC36.2023/1/22YMC37 Addition of low-dose vinorelbine to gefitinib has shown high efficacy in adenocarcinoma lung
25、 cancer patients who have failed two previous regimens of chemotherapy.Given the fact that there are four negative phase III randomized trials of EGFR TKIs with chemotherapy(INTACT I and II,TRIBUTE,TALENT),only studies in selected EGFR mutation-enriched patient populations can be justified at this t
26、ime for further clinical trials combining chemotherapy with EGFR TKIs.2023/1/22YMC38%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).2023/1/22YMC39Erlotinib induces G1 arrest which can block M-phase activity of docetaxelDocetaxel induc
27、es M-phase arrest and apoptosis that is enhanced by erlotinibClin Lung Cancer 2006;7:385.2023/1/22YMC40PlaceboErlotinib 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(d
28、1)+erlotinib(d1528);q4wksPDStratified by centre,stage,histology,smoking statusStudy treatmentPost-treatmentScreeningPost-studyGemcitabine 1250mg/m2(d1,8);cisplatin 75mg/m2 ORcarboplatin 5 AUC(d1);erlotinib 150mg/day(d1528)PASCO 2008;26:a8031.2023/1/22YMC411.00.80.60.40.200246810 12 1416 18 20 22 24
29、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-pla
30、cebo24.1Log-rank test p=0.0185HR=0.56 95%CI:0.370.8424.131.4PASCO 2008;26:a8031R.R.36.8%24.4%How long should chemotherapy be given(no PDS at maintenance phase)GEMCDDP dose(control arm)is less than usual Better for those Caucasians who have higher%of EGFR wild type.2023/1/22YMC42.2023/1/22YMC4398 pts
31、 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;26:2442-9.2023/1/22YMC44Percent change in measurable tumor at best re
32、sponse,by individual patientJ Clin Oncol 2008;26:2442-9.2023/1/22YMC45 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 M.2023/1/22YMC46 N=106(adenoca 97,non-adeno 9)Pt NoRR,%DCR,%Median TTF,MMedian OS,MAll1
33、0650.982.15.522.4EGFR mutated5587.38 wild type3568.63.4 not done1656.393.85.6NRJCO 2008;26:2745-53Pt NoRR,%Median TTF,MExon 19 deletion20958.9Exon 21 L858R2373.99.1.2023/1/22YMC47VariablesNoResponse rates(%)Univariate PMultivariate PN=152 L858R7565.30.646 Del in Exon 197768.8 Chemonaive9175.80.0050.
34、006 Chemo-treated6154.1 Female11071.80.0450.053 Male4254.8 Smoker2254.60.175 Non-smoker13069.2 65 years8213.7Wu JY et al.AJRCCM 2008.2023/1/22YMC48 Chmo nave gefitinib(n=91)Chemotherapy treated gefitinib(n=61)log rank Chmo nave gefitinib(n=91)Chemotherapy treated gefitinib(n=61)log rank=0.24Wu JY et
35、 al.AJRCCM 2008.2023/1/22YMC492003.9.15 s/p 4 line C/T since 20010629,PS 3 FiO2 50%2003.9.29 Iressa 2 weeks PS 1 room airAnother 1.5 year.2023/1/22YMC50Ms.Ree Hx No 31676887 75 Y/O 20021202 SOB for months,PS 2-3,NC 3L/min pre C/T20050804 post NGC;taxotere;under Iressa-N,PS 0.2023/1/22YMC51Not approp
36、riate 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 present.2023/1/22YMC52T790MT790M accounts for 50%acquired resistance to EGFR
37、-TKIsC-MET amplification accounts for 25%And.2023/1/22YMC53EGFR and MET each independently activate ErbB3 in the resistant cellsAKTP13KP110P85PPPAdapted from review by C1 Arteaga Nature Medicile.2007EGFRErbB3MetEdu Session ASCO 2008.2023/1/22YMC54The IGF-IR pathway is activated by a loss of IGF Bind
38、ing Proteins(IGFBPs)Cell SurvivalCell DeathEGFRErbB3IGFIGF-IRIGF-BPsEGFRgefitinibgefitinibErbB3IGF-IRP13kp110p85pIRS-1AKTpParental(Sensitive)ResistantEdu Session ASCO 2008.2023/1/22YMC55MechanismTreatmentT790MIrreversible EGFR inhibitorsMET amplificationsMET+EGFR inhibitorsIGF-1R activationIGF-1R(or
39、 PI3K)+EGFR inhibitors Heterogenicity of resistance may necessitate combinations(eg.Irreversible EGFR&MET inhibitors)Should these combinations be moved to initial therapy to produce greater TTP similar to strategy for HIV and TB?Edu Session ASCO 2008.2023/1/22YMC56Conclusions:Clinical Predictors of
40、EGFR-TKIs ResponsivenessResponse rate,%*Setting1st line2nd line3rd lineChemotherapy(single or doublet)20-4510-2010TKI(East Asian population)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 pati
41、ent survival.2023/1/22YMC57 EGFR-TKI is effective salvage treatment against NSCLC,especially in Asian,non-smoker,and adenocarcinoma.Preliminary results of EGFR-TKI in first-line setting of selected patients,eg.EGFR mutated adenoca,are encouraging.How to integrate EGFR-TKI into or replace conventional standard treatment for different stages of NSCLC remains to be resolved.
