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1、2023/2/9,YMC,1,Epidermal growth factor receptor-tyrosine kinase inhibitor in non-small-cell lung cancer,Yuh-Min Chen,MD,PhD.Chest Dept.,Taipei VGH,2023/2/9,YMC,2,Survival(anti-apoptosis),PI3-K,Activation of the epidermal growth factor receptor tyrosine kinase(EGFR-TK):a pivotal driver of carcinogene
2、sis,EGFR-TK,EGFR,Ligand,RAS,RAF,SOS,GRB2,PTEN,AKT,STAT3,MEK,Gene transcriptionCell-cycle progression,DNA,Myc,Myc,Cyclin D1,JunFos,P P,MAPK,Proliferation/maturation,Chemotherapy/radiotherapyresistance,Angiogenesis,Metastasis,Balaban et al 1996;Akimoto et al 1999;Wells 1999;Woodburn 1999;Hanahan 2000;
3、Raymond et al 2000,Cyclin D1,pY,pY,pY,2023/2/9,YMC,3,2023/2/9,YMC,4,IDEAL 1 and 2 trial design,Gefitinib250 mg/day,Gefitinib500 mg/day,IDEAL,IressaTM Dose Evaluation in Advanced Lung cancer,Randomisation,IDEAL 1(n=209)1 or 2 prior regimensIDEAL 2(n=216)2 prior regimens,Primary endpoints,Objective tu
4、mour responseSymptom improvement(IDEAL 2)Safety(IDEAL 1),2023/2/9,YMC,5,Median time to improvement-symptoms and QOL,*Time of 1st assessment,Median time toimprovement,days,Symptom/QOLmeasureLCSFACT-L,8*,29*,2023/2/9,YMC,6,IDEAL 1 and 2:overall survival by symptom improvement(250 mg/day),Probability,1
5、.0,0.8,0.6,0.4,0.2,0.0,IDEAL 1,Months from randomisation,ImprovementNo improvement,2740,1830,13.33.5,Patients(n),Deaths(n),Median(months),0,2,4,6,8,10,12,14,16,18,20,4458,2656,13.63.7,Patients(n),Deaths(n),Median(months),1.0,0.8,0.6,0.4,0.2,0.0,Probability,IDEAL 2,Months from randomisation,0,2,4,6,8
6、,10,12,14,16,18,20,Douillard et al 2002;Lynch et al 2003,2023/2/9,YMC,7,ISEL(IRESSA Survival Evaluation in Lung Cancer):Clinical Trial Design,Randomisation,Gefitinib(250 mg)+*BSC,Placebo+*BSC,SURVIVALSecondary:TTF,ORQoL,safety,Primaryendpoint:,ENDBENEFIT,2:1 ratio,A double blind Phase III survival s
7、tudy 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 regimen,1692 patients in 210 centres across 28 countries 342 patients of oriental origin No Japanese/US site
8、s,*BSC=Best Supportive Care,Lancet 2005;366:1527-37,2023/2/9,YMC,8,ISEL-Overall Survival,Percent surviving,Time(months),At risk:Gefitinib 1129 1023 901 761 588 455 325 245 175 113 76 45 19 9,IRESSA-Placebo,Placebo 563 517 446 382 289 220 160 115 77 44 28 20 12 4 2,2023/2/9,YMC,9,ISEL Survival:Orient
9、als,Percent surviving,Time(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 1,5.5 M,9.5 M,2023/2/9,YMC,10,J Chemother 2005;17:679,2023/2/9,YMC,11,RESULTS,3 CR,9 PR,with a R.R.of 33.3%SD 14,control rate of 72.2%All
10、treatment-related toxicities were few and mild in severity,except one patient suffered from reversible grade 3 interstitial pneumonitis,J Chemother 2005;17:679,2023/2/9,YMC,12,%Survival,Median survival:9.5 months One-year survival rate:45.1%,J Chemother 2005;17:679,2023/2/9,YMC,13,%Survival,Survival
11、 according to response or not,J Chemother 2005;17:679,2023/2/9,YMC,14,Study Design of BR.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 daily,Placebo,RANDOM I SE,PS=performance status,N Engl J Med 2005;353:12
12、332,2023/2/9,YMC,15,BR.21:Significant clinical predictors of response to Tarceva,*Significance between subgroups*Data collected retrospectively,In multiple logistic-regression analyses,only never having smoked(p0.001)and adenocarcinoma histology(p=0.01)were associated with response,Shepherd et al.NE
13、JM 2005;353:123,2023/2/9,YMC,16,Improvement in Survival with Tarceva,42.5%improvement in median survival,Survival distribution function,Survival time(months),HR=0.73,p0.001*,1.000.750.500.250,051015202530,N Engl J Med 2005;353:12332,Tarceva,(n=488),Placebo,(n=,243,),Median survival(months),6.7,4.7,1
14、,-,year survival(%),31,21,2023/2/9,YMC,17,BR.21:Time to symptom deterioration(months),Placebo,Tarceva,179,179,153,n,348,353,298,n,1.9(1.82.8),2.9(24.8),3.7(24.9),Median(95%CI),0.02,2.8(2.43),Pain,0.01,4.7(3.86.2),Dyspnea,0.04,4.9(3.87.4),Cough,p value*,Median(95%CI),*Log-rank test,unadjusted for mul
15、tiple symptoms,Bezjak A,et al.J Clin Oncol 2006;24:38317Shepherd F,et al.N Engl J Med 2005;353:12332,2023/2/9,YMC,18,TRUST:Tarceva MO18109An expanded access clinical program of Tarceva(erlotinib)in pts with advanced stage IIIB/IV NSCLCLung Cancer 2008,2023/2/9,YMC,19,Patient Population&Response,From
16、 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.,2023/2/9,YMC,20,Response rate and control rate by pretreatment characteristics and skin toxicity,The best response rates were a 29%partial r
17、esponse and 44%stable disease in 273 patients who had response data available.Non-smoking(p=0.033),adenocarcinoma/BAC(p=0.0027),female(p=0.0013),aged less than 65 years(p=0.0115),stage IV(p=0.0492),patients with skin rash(p=0.0216),and a higher grade of skin rash(p=0.003)were significantly correlate
18、d with response to treatment.,2023/2/9,YMC,21,Time to disease progression of 299 NSCLC pts treated with erlotinib.The median time to disease progression was 5.6 months(95%C.I.:4.4 6.5 months,45 pts censored),2023/2/9,YMC,22,EGFR-TKI vs.chemotherapeutic agents in salvage chemotherapy,2023/2/9,YMC,23,
19、In conclusion,both chemotherapeutic agents,such as docetaxel alone or gemcitabine+vinorelbine,and gefitinib,are appropriate salvage regimens for Chinese NSCLC pts who have failed previous chemotherapy.However,gefitinib has a better safety profile and probably better survival than the chemotherapeuti
20、c agents,and would be an appropriate alternative choice for salvage chemotherapy,even in a second-line setting for Chinese pts.,J Thorac Oncol 2006;1:545-50,2023/2/9,YMC,24,Efficacy of Salvage Therapy in NSCLC,2023/2/9,YMC,25,Salvage Chemotherapy(n=342)Grade Neutroopenia,2023/2/9,YMC,26,Salvage Chem
21、otherapy(n=342)Grade Fatigue,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 sensation.,2023/2/9,YMC,27,Interest,INTEREST(gefitinib vs.docetaxel in pts with LA
22、 or meta.NSCLC pre-treated with platinum-based chemotherapy,WCLC 2007,1466 pts from Mar 2004 to Feb 2006,2023/2/9,YMC,28,Interest,QoF and symptom improvement,WCLC 2007,2023/2/9,YMC,29,Interest,WCLC 2007,2023/2/9,YMC,30,Interest,Overall survival,2023/2/9,YMC,31,Clinical characteristics&response rate(
23、pt number=1974),Int J Clin Oncol 2006;11:1908,2023/2/9,YMC,32,EGFR Mutation,Eur J Cancer 2006:17-23,N Engl J Med 2004;350:2129-39,2023/2/9,YMC,33,Failure of Doublet Chemotherapy plus EGFR-TKI,INTACT I,IITRIBUTE,TALENT,2023/2/9,YMC,34,Giaccone.JCO 2004;22:777,Overall Survival of INTACT-1 in Each Trea
24、tment Group(GEM+CDDP c/s Iressa),Poor survival for those use Iressa with GEM+CDDP,2023/2/9,YMC,35,Can we further prolong disease-free survival and overall survival?,Failure of doublet chemotherapy plus TKIINTACT I,II(Gefitinib);TRIBUTE,TALENT(Erlotinib)Majority performed in Caucasian ptsUnknown for
25、Asian pts with high EGFR mutation rateTo assess the efficacy of adding chronic intermittent low-dose vinorelbine to gefitinib treatment for adenocarcinoma of lung who failed two or more regimens of chemotherapy.,2023/2/9,YMC,36,2023/2/9,YMC,37,Conclusions,Addition of low-dose vinorelbine to gefitini
26、b 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 randomized trials of EGFR TKIs with chemotherapy(INTACT I and II,TRIBUTE,TALENT),only studies in selected EGFR mutation-enriche
27、d patient populations can be justified at this time for further clinical trials combining chemotherapy with EGFR TKIs.,2023/2/9,YMC,38,%Free from Progression,1-year progression-free survival rate was 57.1%in the GV arm and 21.2%in the G arm(p=0.008),2023/2/9,YMC,39,Erlotinib induces G1 arrest which
28、can block M-phase activity of docetaxel,Docetaxel induces M-phase arrest and apoptosis that is enhanced by erlotinib,Sequence specific Interaction,Clin Lung Cancer 2006;7:385,2023/2/9,YMC,40,First-line Asian Sequential Tarceva plus Chemotherapy Trial(FAST-ACT):Study Design,Placebo,Erlotinib 150mg/da
29、y,Previously untreated stage IIIB/IV NSCLC(n=150),R,1,1,PD,Six cycles gemcitabine+cisplatin or carboplatin+placebo;q4wks,Six cycles gemcitabine(d1,8)+cisplatin(d1)or carboplatin(d1)+erlotinib(d1528);q4wks,PD,Stratified by centre,stage,histology,smoking status,Study treatment,Post-treatment,Screening
30、,Post-study,Gemcitabine 1250mg/m2(d1,8);cisplatin 75mg/m2 ORcarboplatin 5AUC(d1);erlotinib 150mg/day(d1528),PASCO 2008;26:a8031,2023/2/9,YMC,41,Time to Disease Progression,1.00.80.60.40.20,024681012141618202224262830323436,Time(weeks),3840424446485052545658,767272726461585858525050463736322615147876
31、76766759585650434341352524221687,121098755531054211111110,No.at riskErlotinibPlacebo,Early and consistent separation of curves,Log-rank test p=0.0185,HR=0.56 95%CI:0.370.84,24.1,31.4,PASCO 2008;26:a8031,R.R.36.8%24.4%,How long should chemotherapy be given(no PDS at maintenance phase)GEMCDDP dose(con
32、trol arm)is less than usual Better for those Caucasians who have higher%of EGFR wild type,2023/2/9,YMC,42,First line treatment with EGFR-TKIs in those with EGFR mutated patients,2023/2/9,YMC,43,98 pts underwent EGFR screening and mutations were detected in 34(35%).EGFR mutations:exon 19 deletions(53
33、%),L858R(26%)31 pts received gefitinib,R.R.55%,median progression-free survival 9.2 M.Therapy was well tolerated.,J Clin Oncol 2008;26:2442-9,2023/2/9,YMC,44,Percent change in measurable tumor at best response,by individual patient,J Clin Oncol 2008;26:2442-9,2023/2/9,YMC,45,Kaplan-Meier curves for(
34、A)progression-free survival and(B)overall survival among all treated pts,J Clin Oncol 2008;26:2442-9,PFS 9.2 M,Sur 17.5 M,2023/2/9,YMC,46,Gefitinib first line treatment in enriched EGFR-mutated NSCLC in NTUH,N=106(adenoca 97,non-adeno 9),JCO 2008;26:2745-53,2023/2/9,YMC,47,Predictive Factors of Resp
35、onse to Gefitinib in 152 EGFR mutated patients in NTUH,Wu JY et al.AJRCCM 2008,2023/2/9,YMC,48,No survival difference in 152 chemonaive or chemo-treated EGFR mutated patients in NTUH,Wu JY et al.AJRCCM 2008,2023/2/9,YMC,49,2003.9.15 s/p 4 line C/T since 20010629,PS 3 FiO2 50%,2003.9.29 Iressa 2 week
36、s PS 1 room air,Another 1.5 year,2023/2/9,YMC,50,Ms.Ree Hx No 31676887 75 Y/O,20021202 SOB for months,PS 2-3,NC 3L/min pre C/T,20050804 post NGC;taxotere;under Iressa-N,PS 0,2023/2/9,YMC,51,s/p renal transplantation with adenocarcinoma,LUL,&brain,meningeal carcinomatosis,Not appropriate for chemothe
37、rapy,receive first line Tarceva with total disappearance of meningeal carcinomatosis&brain metastases(brain MRI follow-up 6 months after Tarceva treatment),Tarceva first line treatment,Patient still alive at present,2023/2/9,YMC,52,T790M,Pao et al.PLoS Med 2005;2:1-11Kwak et al.Pro Nat Acad Sci USA
38、2005;102:7665-708 of 16 TKI treated had 2nd mutation:7 of 8 was T790M Clin Cancer Res 2006;12:6494-501,T790M accounts for 50%acquired resistance to EGFR-TKIsC-MET amplification accounts for 25%And,2023/2/9,YMC,53,EGFR and MET each independently activate ErbB3 in the resistant cells,AKT,P13KP110,P85,
39、P,P,P,Adapted from review by C1 Arteaga Nature Medicile.2007,EGFR,ErbB3,Met,Edu Session ASCO 2008,2023/2/9,YMC,54,The IGF-IR pathway is activated by a loss of IGF Binding Proteins(IGFBPs),Cell Survival,Cell Death,EGFR,ErbB3,IGF,IGF-IR,IGF-BPs,EGFR,gefitinib,gefitinib,ErbB3,IGF-IR,P13kp110,p85,p,IRS-
40、1,AKT,p,Parental(Sensitive),Resistant,Edu Session ASCO 2008,2023/2/9,YMC,55,Acquired Resistance to 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 str
41、ategy for HIV and TB?,Edu Session ASCO 2008,2023/2/9,YMC,56,Conclusions:Clinical Predictors of EGFR-TKIs Responsiveness,*Response to EGFR-TKI treatment correlated well with patient survival.,2023/2/9,YMC,57,Summary,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.,
