1、2023/1/221Survival(anti-apoptosis)PI3-KEGFR-TKEGFRLigandRASRAFSOSGRB2PTENAKTSTAT3MEKGene transcriptionCell-cycle progressionDNAMycMycCyclin D1JunFosP PMAPKProliferation/maturationChemotherapy/radiotherapyresistanceAngiogenesisMetastasisBalaban et al 1996;Akimoto et al 1999;Wells 1999;Woodburn 1999;H
2、anahan 2000;Raymond et al 2000 Cyclin D1pYpYpY2023/1/222RppRExtracellularIntracellularMembranepKpKpppTGFaSubstrateSubstrateSignalling MoleculesProliferationInhibit ApoptosisAngiogenesisMetastasisNucleusMonoclonal AntibodiesEGFR Tyrosine Kinase Inhibitors2023/1/223Gefitinib250 mg/dayGefitinib500 mg/d
3、ayContinue 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(IDEAL 2)l Safety(IDEAL 1)202
4、3/1/224Median time to improvement-symptoms and QOL*Time of 1st assessmentMedian time toimprovement,daysSymptom/QOLmeasureLCSFACT-L8*29*2023/1/225Probability 1.00.80.60.40.20.0IDEAL 1Months from randomisationImprovementNo improvement2740183013.33.5Patients(n)Deaths(n)Median(months)0 2 4 6 8 101214 16
5、18204458265613.63.7Patients(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 20032023/1/226Randomisation Gefitinib(250 mg)+*BSCPlacebo+*BSC SURVIVALSecondary:TTF,ORQoL,safetyPrimaryendpoint:ENDBENEFIT2:1 ra
6、tio 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 centres across 28 countries 342 patients
7、of oriental origin No Japanese/US sites*BSC=Best Supportive CareLancet 2005;366:1527-37 2023/1/227Percent 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 28 20 12 4 20.00.20.40.60.81.001234567891
8、0 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=0.02992023/1/228Percent survivingTime(months)At risk:Gefitinib 235 221 199 179 145 119 95 78 64 51 40 25 12 8 IRESSA -Placebo0.00.20.40.60.81.0
9、012345678910 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 2023/1/229J Chemother 2005;17:6792023/1/2210 3 CR,9 PR,with a R.R.of 33.3%SD
10、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;17:6792023/1/2211%SurvivalJ Chemother 2005;17:6792023/1/2212%SurvivalFig.10102030405060708090100036912151821MonthsCompl
11、ete 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;17:6792023/1/2213 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)Tarceva150
12、mg dailyPlaceboRANDOM I SEPS=performance status21 N Engl J Med 2005;353:12332Percent survivingResponse to prior treatment3 CR,9 PR,with a R.AngiogenesisBalaban et al 1996;Akimoto et al 1999;Wells 1999;Woodburn 1999;Hanahan 2000;Raymond et al 2000GEMCDDP dose(control arm)is less than usualcarboplatin
13、 5AUC(d1);erlotinib 150mg/day(d1528)Univariate PPS=performance statusPrior platinum (yes vs no)INTACT I,II(Gefitinib);TRIBUTE,TALENT(Erlotinib)Gene transcriptionShould these combinations be moved to initial therapy to produce greater TTP similar to strategy for HIV and TB?Median survival:9.Grade Neu
14、troopeniaN=1692,deaths=976RANDOM I SESafety(IDEAL 1)Unknown(23)Progression free survival(Months)QoF and symptom improvementyear survival(%)2023/1/2214Tarcevatreated 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.
15、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;353:123
16、2023/1/221542.5%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 2023/1/2216Placebo Tarceva1791791
17、53n348353298n1.9(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;353:12332Placebo 107 97 84 74 56 43 35 2
18、9 22 13 8 7 3 1 1Months from randomisationPercent survivingWu JY et al.GC-erlotinibNSCLC pre-treated with platinum-based chemotherapySix cycles gemcitabine+cisplatin or carboplatin+placebo;q4wksChemotherapy treated gefitinib(n=61)log rank=0.Docetaxel induces M-phase arrest and apoptosis that is enha
19、nced by erlotinibProbabilityProgression free survival(Months)Docetaxel+GemcitabinePS=performance status024681012141618202224262830323436Response rate and control rate by pretreatment characteristics and skin toxicityISEL Survival:OrientalsOne-year survival rate:45.From May 2005 to July 2006,300 pati
20、ents were entered from 14 hospitals in Taiwan.Wu JY et al.Censored observationsNon-smoker2023/1/22172023/1/2218 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.2023/1/2219Patient charac
21、teristicsPatient numberp-valueControl rate(%)p-valueGender Male Female14013363.682.70.0004Age 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 carcinoma19048796
22、0.40.0079Present treatment as Second line Third line16710229.926.50.541370.776.50.2983Smoking status Non-smoker Former or current smoker15811579.164.40.0067Skin toxicity-1No rash Rash2924441.476.665 yearsSix cycles gemcitabine+cisplatin or carboplatin+placebo;q4wksEfficacy of Salvage Therapy in NSCL
23、CPatient Population&ResponseProliferation/maturationMedian OS,MDocetaxel40 and vinorelbine plus cisplatin induced more frequent severe fatigue than other regimens.PS=performance status76727272646158585852505046373632261514EGFR-TKI vs.Balaban et al 1996;Akimoto et al 1999;Wells 1999;Woodburn 1999;Han
24、ahan 2000;Raymond et al 200029 Iressa 2 weeks PS 1 room air2023/1/22352023/1/2236 Addition of low-dose vinorelbine to gefitinib has shown high efficacy in adenocarcinoma lung cancer patients who have failed two previous regimens of chemotherapy.Given the fact that there are four negative phase III r
25、andomized 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 time for further clinical trials combining chemotherapy with EGFR TKIs.2023/1/2237%Free from Progression1-year progression-free
26、 survival rate was 57.1%in the GV arm and 21.2%in the G arm(p=0.008)2023/1/2238Erlotinib induces G1 arrest which can block M-phase activity of docetaxelDocetaxel induces M-phase arrest and apoptosis that is enhanced by erlotinibClin Lung Cancer 2006;7:3852023/1/2239PlaceboErlotinib 150mg/dayPrevious
27、ly 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);q4wksPDStratified by centre,stage,histology,smoking statusStudy treatmentPost-treatmentScreeningPost-studyGemcitabine
28、 1250mg/m2(d1,8);cisplatin 75mg/m2 ORcarboplatin 5 AUC(d1);erlotinib 150mg/day(d1528)PASCO 2008;26:a8031Therapy was well tolerated.Probability*BSC=Best Supportive Care54211111110Free from progressionStratified log rank test15 s/p 4 line C/T since 20010629,PS 3 FiO2 50%Vinorelbine+CisplatinMET amplif
29、ications13.342 patients of oriental origin No Japanese/US sitesOther(218)Other(218)Activation of the epidermal growth factor receptor tyrosine kinase(EGFR-TK):a pivotal driver of carcinogenesisAngiogenesis*BSC=Best Supportive CareAt risk:Gefitinib 1129 1023 901 761 588 455 325 245 175 113 76 45 19 9
30、C-MET amplification accounts for 25%Wu JY et al.Median(95%CI)75 mg/m2 D 1 q3 wks2023/1/22401.00.80.60.40.200246810 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 1
31、6 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.GE
32、MCDDP dose(control arm)is less than usual 3.Better for those Caucasians who have higher%of EGFR wild type2023/1/22412023/1/224298 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-f
33、ree survival 9.2 M.Therapy was well tolerated.J Clin Oncol 2008;26:2442-9 2023/1/2243Percent change in measurable tumor at best response,by individual patientJ Clin Oncol 2008;26:2442-9 2023/1/2244 Kaplan-Meier curves for(A)progression-free survival and(B)overall survival among all treated ptsJ Clin
34、 Oncol 2008;26:2442-9 PFS 9.2 MSur 17.5 M2023/1/2245 N=106(adenoca 97,non-adeno 9)Pt NoRR,%DCR,%Median TTF,MMedian OS,MAll10650.982.15.522.4EGFR mutated5587.38 wild type3568.63.4 not done1656.393.85.6NRJCO 2008;26:2745-53Pt NoRR,%Median TTF,MExon 19 deletion20958.9Exon 21 L858R2373.99.12023/1/2246Va
35、riablesNoResponse rates(%)Univariate PMultivariate PN=152 L858R7565.30.646 Del in Exon 197768.8 Chemonaive9175.80.0050.006 Chemo-treated6154.1 Female11071.80.0450.053 Male4254.8 Smoker2254.60.175 Non-smoker13069.2 65 years8213.7Wu JY et al.AJRCCM 20082023/1/2247 Chmo nave gefitinib(n=91)Chemotherapy
36、 treated gefitinib(n=61)log rank Chmo nave gefitinib(n=91)Chemotherapy treated gefitinib(n=61)log rank=0.24Wu JY et al.AJRCCM 20082023/1/22482003.9.15 s/p 4 line C/T since 20010629,PS 3 FiO2 50%2003.9.29 Iressa 2 weeks PS 1 room airAnother 1.5 year2023/1/2249Ms.Ree Hx No 31676887 75 Y/O 20021202 SOB
37、 for months,PS 2-3,NC 3L/min pre C/T20050804 post NGC;taxotere;under Iressa-N,PS 02023/1/2250Not 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 treat
38、mentPatient still alive at present2023/1/2251T790MT790M accounts for 50%acquired resistance to EGFR-TKIsC-MET amplification accounts for 25%And 2023/1/2252EGFR and MET each independently activate ErbB3 in the resistant cellsAKTP13KP110P85PPPAdapted from review by C1 Arteaga Nature Medicile.2007EGFRE
39、rbB3MetEdu Session ASCO 20082023/1/2253The IGF-IR pathway is activated by a loss of IGF Binding Proteins(IGFBPs)Cell SurvivalCell DeathEGFRErbB3IGFIGF-IRIGF-BPsEGFRgefitinibgefitinibErbB3IGF-IRP13kp110p85pIRS-1AKTpParental(Sensitive)ResistantEdu Session ASCO 20082023/1/2254MechanismTreatmentT790MIrr
40、eversible EGFR inhibitorsMET amplificationsMET+EGFR inhibitorsIGF-1R activationIGF-1R(or 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 strateg
41、y for HIV and TB?Edu Session ASCO 2008MET amplifications54211111110Proliferation/maturation21:Time to symptom deterioration(months)Stratified log rank testEGFR mutated adenoca,are encouraging.AJRCCM 2008J Chemother 2005;17:679QoL,safetySix cycles gemcitabine+cisplatin or carboplatin+placebo;q4wksJ C
42、hemother 2005;17:679TRIBUTE,TALENT-PlaceboFirst-line Asian Sequential Tarceva plus Chemotherapy Trial(FAST-ACT):Study Designdocetaxel in pts with LA or meta.Safety(IDEAL 1)40 mg/m2 D1,8 q3 wks5 months,45 pts censored)Patient Population&ResponsePercent surviving033),adenocarcinoma/BAC(p=0.Randomisati
43、on2023/1/2255Conclusions:Clinical Predictors of 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
44、 to EGFR-TKI treatment correlated well with patient survival.2023/1/2256 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 i
45、ntegrate EGFR-TKI into or replace conventional standard treatment for different stages of NSCLC remains to be resolved.2023/1/2257Survival(anti-apoptosis)PI3-KEGFR-TKEGFRLigandRASRAFSOSGRB2PTENAKTSTAT3MEKGene transcriptionCell-cycle progressionDNAMycMycCyclin D1JunFosP PMAPKProliferation/maturationC
46、hemotherapy/radiotherapyresistanceAngiogenesisMetastasisBalaban et al 1996;Akimoto et al 1999;Wells 1999;Woodburn 1999;Hanahan 2000;Raymond et al 2000 Cyclin D1pYpYpY2023/1/2258J Chemother 2005;17:6792023/1/2259%SurvivalJ Chemother 2005;17:6792023/1/226042.5%improvement in median survivalSurvival di
47、stribution 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 2023/1/22610.000.250.500.751.00Progression free survival(Months)061020Censored observation
48、sFig.1Free from progression8421214161822Time to disease progression of 299 NSCLC pts treated with erlotinib.The median time to disease progression was (95%C.I.:4.4 6.5 months,45 pts censored)2023/1/2262Salvage Chemotherapy(n=342)Grade Fatigue2023/1/2263InterestWCLC 2007Patients that received single-
49、agent gemcitabine and gefitinib reported no severe fatigue sensation.Irreversible EGFR inhibitorsN Engl J Med 2005;353:12332The best response rates were a 29%partial response and 44%stable disease in 273 patients who had response data available.Median(months)GemcitabineUnivariate PMedian TTF,MDoceta
50、xel induces M-phase arrest and apoptosis that is enhanced by erlotinibPercent surviving003)were significantly correlated with response to treatment.EGFR mutations:exon 19 deletions(53%),L858R(26%)ProbabilityErlotinib 150mg/day56 95%CI:0.The median time to disease progression was 5.PASCO 2008;26:a803
