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按一下以編輯母片標題樣式,按一下以編輯母片,第二層,第三層,第四層,第五層,*,YMC,*,Epidermal growth factor receptor-tyrosine kinase inhibitor in non-small-cell lung cancer,Yuh-Min Chen, MD, PhD.,Chest Dept., Taipei VGH,8/26/2024,1,YMC,Epidermal growth factor recept,Survival(anti-apoptosis),PI3-K,Activation of the epidermal growth factor receptor tyrosine kinase (EGFR-TK): a pivotal driver of carcinogenesis,EGFR-TK,EGFR,Ligand,RAS,RAF,SOS,GRB2,PTEN,AKT,STAT,3,MEK,Gene transcription,Cell-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; Raymond et al 2000,Cyclin D1,pY,pY,pY,8/26/2024,2,YMC,Survival(anti-apoptosis)PI3-K,R,p,p,R,Extracellular,Intracellular,Membrane,p,K,p,K,p,p,p,TGF,a,Substrate,Substrate,Signalling Molecules,Proliferation,Inhibit Apoptosis,Angiogenesis,Metastasis,Nucleus,Monoclonal Antibodies,EGFR Tyrosine Kinase Inhibitors,8/26/2024,3,YMC,RppRExtracellularIntracellular,IDEAL 1 and 2,trial design,Gefitinib,250 mg/day,Gefitinib500 mg/day,Continue gefitinib until diseaseprogression or unacceptable toxicity,IDEAL, Iressa,TM,Dose Evaluation in Advanced Lung cancer,Randomisation,IDEAL 1 (n=209)1 or 2 prior regimens,IDEAL 2 (n=216),2 prior regimens,Primary endpoints,Objective tumour response,Symptom improvement (IDEAL 2),Safety (IDEAL 1),8/26/2024,4,YMC,IDEAL 1 and 2 trial designGefi,Median time to improvement -,symptoms and QOL,*,Time of 1st assessment,Median time to,improvement, days,Symptom/QOL,measure,LCS,FACT-L,8*,29*,8/26/2024,5,YMC,Median time to improvement -*T,IDEAL 1 and 2: overall survival by symptom improvement (250 mg/day),Probability,1.0,0.8,0.6,0.4,0.2,0.0,IDEAL 1,Months from randomisation,Improvement,No improvement,27,40,18,30,13.3,3.5,Patients(n),Deaths(n),Median (months),0,2,4,6,8,1,0,12,14,16,18,2,0,44,58,26,56,13.6,3.7,Patients (n),Deaths(n),Median (months),1.0,0.8,0.6,0.4,0.2,0.0,Probability,IDEAL 2,Months from randomisation,0,2,4,6,8,1,0,12,14,16,18,2,0,Douillard et al 2002; Lynch et al 2003,8/26/2024,6,YMC,IDEAL 1 and 2: overall surviva,ISEL (,I,RESSA,S,urvival,E,valuation in,L,ung Cancer):,Clinical Trial Design,Randomisation,Gefitinib,(250 mg) + *BSC,Placebo + *BSC,SURVIVAL,Secondary:,TTF, OR,QoL, safety,Primaryendpoint:,END,BENEFIT,2:1 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 regimen,1692,patients in 210 centres across 28 countries,342 patients of oriental origin No Japanese/US sites,*,BSC= Best Supportive Care,Lancet 2005;366:1527-37,8/26/2024,7,YMC,ISEL (IRESSA Survival Evaluati,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,Gefitinib,placebo,Median (months),5.6,5.1,1,yr survival,27%,21%,HR=0.89 (0.77, 1.02), p=0.0871,Stratified log rank test,N=1692, deaths=976,Cox analysis, p=0.0299,8/26/2024,8,YMC,ISEL - Overall SurvivalPercent,ISEL Survival: Orientals,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,8/26/2024,9,YMC,ISEL Survival: OrientalsPercen,J Chemother 2005;17:679,8/26/2024,10,YMC,J Chemother 2005;17:6799/1/202,RESULTS,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;17:679,8/26/2024,11,YMC,RESULTS3 CR, 9 PR, with a R.R.,% Survival,Median survival: 9.5 months,One-year survival rate: 45.1%,J Chemother 2005;17:679,8/26/2024,12,YMC,% SurvivalMedian survival: 9.5,% Survival,Fig. 1,0,10,20,30,40,50,60,70,80,90,100,0,3,6,9,12,15,18,21,Months,Complete or partial response,(n=12) median 20.1M,Stable or progressive,disease (n=24) median 4.7M,Survival according to response or not,15.4,月,J Chemother 2005;17:679,8/26/2024,13,YMC,% SurvivalFig. 101020304050607,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,2,1,N Engl J Med 2005;353:12332,8/26/2024,14,YMC,Study Design of BR.21 Stratif,BR.21:,S,ignificant,clinical predictors of response to Tarceva,Tarceva,treated,pts (,n,),R.R. (%),p value*,Gender,Female (146),14.4,0.006,Male (281),6.1,Histology,Adenocarcinoma (209),13.9,0.001,Other (218),4.1,Ethnicity,Asian (53),18.9,0.02,Other (374),7.5,Ever smoked*,Yes (311),3.8,0.001,No (93),24.7,Unknown (23),13.0,*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,JM 2005;353:123,8/26/2024,15,YMC,BR.21: Significant clinical pr,Improvement in,S,urvival with Tarceva,42.5% improvement in median survival,Survival distribution function,Survival time (months),HR=0.73, p0.001*,1.00,0.75,0.50,0.25,0,051015202530,Tarceva,Placebo,N Engl J Med 2005;353:12332,Tarceva,(n=488),Placebo,(n=,243,),Median survival (months),6.7,4.7,1,-,year survival (%),31,21,8/26/2024,16,YMC,Improvement in Survival with T,BR.21: T,ime 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 multiple symptoms,Bezjak A, et al. J Clin Oncol 2006;24:38317,Shepherd F, et al. N Engl J Med 2005;353:12332,8/26/2024,17,YMC,BR.21: Time to symptom deterio,TRUST: Tarceva MO18109An expanded access clinical program of Tarceva (erlotinib) in pts with advanced stage IIIB/IV NSCLC,Lung Cancer 2008,8/26/2024,18,YMC,TRUST: Tarceva MO18109An expa,Patient Population & Response,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.,8/26/2024,19,YMC,Patient Population & ResponseF,Response rate and control rate by pretreatment characteristics and skin toxicity,Patient characteristics,Patient number,Response rate (%),p-value,Control rate (%),p-value,Gender,Male,Female,140,133,20,37.6,0.0013,63.6,82.7,0.0004,Age,65,65,160,113,34.4,20.4,0.0115,73.1,72.6,0.9185,Performance status,0/1,2,3,226,35,12,28.8,22.9,41.7,0.469,1,0.339,2,72.6,71.4,83.3,0.8885,0.4124,Stage,IIIB,IV,56,215,17.9,31.2,0.0492,69.6,73.5,0.5651,Histology,Adenocarcinoma,Squamous cell carcinoma,190,48,34.7,12.5,0.0027,79,60.4,0.0079,Present treatment as,Second line,Third line,167,102,29.9,26.5,0.5413,70.7,76.5,0.2983,Smoking status,Non-smoker,Former or current smoker,158,115,33.5,21.7,0.033,79.1,64.4,0.0067,Skin toxicity-1,No rash,Rash,29,244,10.3,30.7,0.0216,41.4,76.6,0.0001,Skin toxicity-2,No rash or grade 1,Rash grade 2, 3, or 4,119,154,19.3,35.7,0.003,61.3,81.8,0.0002,The best response rates were a,29% partial response 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 correlated with response to treatment.,8/26/2024,20,YMC,Response rate and control rate,0.00,0.25,0.50,0.75,1.00,Progression free survival (Months),0,6,10,20,Censored observations,Fig. 1,Free from progression,8,4,2,12,14,16,18,22,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),8/26/2024,21,YMC,0.000.250.500.751.00Progressio,EGFR-TKI,vs.,chemotherapeutic agents in salvage chemotherapy,8/26/2024,22,YMC,EGFR-TKI vs. chemotherapeutic,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 chemotherapeutic agents, and would be an appropriate alternative choice for salvage chemotherapy, even in a second-line setting for Chinese pts.,J Thorac Oncol 2006;1:545-50,8/26/2024,23,YMC,In conclusion, both chemothera,Efficacy of Salvage Therapy in NSCLC,Trial,Schedule,R.R.,%,MTP, M,M Sur, M,1-Yr, %,Single agent,Gemcitabine,1200 mg/m,2,D1,8,15 q4 wks,12.5,2.1,7.5,40,Docetaxel 35,35 mg/m,2,D1,8,15 q4 wks,17.2,4.2,8.4,33.4,40,40 mg/m,2,D1,8 q3 wks,10.9,3.5,7.4,35,75,75 mg/m,2,D 1 q3 wks,6.1,2.8,7.8,30.3,Gefitinib,250 mg daily,33.3,4.7,9.3,40.8,Doublet,Docetaxel+Ifosfamide,D 60 mg/m,2,+ I 3 gm/m,2,D1 q3 wks,10,5,8.2,26.1,Docetaxel+Gemcitabine,D 30 mg/m,2,+ G 800 mg/m,2,D1,8 q3 wks,36.1,3.8,5.7,33.3,Vinorelbine+Gemcitabine,V 20 mg/m,2,+ G 800 mg/m,2,D1,8,15 q4 wks,31.3,4.6,8.3,34.3,Vinorelbine+Cisplatin,V 20 mg/m,2,D1,8,15 + C 50 mg/m,2,D1 q4 wks,9.5,3.7,7.6,19.7,8/26/2024,24,YMC,Efficacy of Salvage Therapy in,Salvage Chemotherapy (n=342),Grade Neutroopenia,8/26/2024,25,YMC,Salvage Chemotherapy (n=342)9/,Salvage Chemotherapy (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.,8/26/2024,26,YMC,Salvage Chemotherapy (n=342)Do,Interest,INTEREST (gefitinib vs. docetaxel in pts with LA or meta. NSCLC pre-treated with platinum-based chemotherapy,WCLC 2007,1466 pts from Mar 2004 to Feb 2006,8/26/2024,27,YMC,InterestINTEREST (gefitinib vs,Interest,QoF and symptom improvement,WCLC 2007,8/26/2024,28,YMC,InterestQoF and symptom improv,Interest,WCLC 2007,8/26/2024,29,YMC,InterestWCLC 20079/1/202329YMC,Interest,Overall survival,8/26/2024,30,YMC,InterestOverall survival9/1/20,Clinical characteristics & response rate (pt number=1974),Int J Clin Oncol 2006;11:1908,8/26/2024,31,YMC,Clinical characteristics & res,EGFR Mutation,Eur J Cancer 2006:17-23,N Engl J Med 2004;350:2129-39,8/26/2024,32,YMC,EGFR MutationEur J Cancer 2006,Failure of Doublet Chemotherapy plus EGFR-TKI,INTACT I, II,TRIBUTE, TALENT,8/26/2024,33,YMC,Failure of Doublet Chemotherap,Giaccone. JCO 2004;22:777,Overall Survival of INTACT-1 in Each Treatment Group (GEM+CDDP c/s Iressa),Poor survival for those use Iressa with GEM+CDDP,8/26/2024,34,YMC,Giaccone. JCO 2004;22:777Overa,Can we further prolong disease-free survival and overall survival ?,Failure of doublet chemotherapy plus TKI,INTACT I, II (Gefitinib); TRIBUTE, TALENT (Erlotinib),Majority performed in Caucasian pts,Unknown for Asian pts with high EGFR mutation rate,To 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.,8/26/2024,35,YMC,Can we further prolong disease,8/26/2024,36,YMC,9/1/202336YMC,Conclusions,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 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 time for further clinical trials combining chemotherapy with EGFR TKIs.,8/26/2024,37,YMC,ConclusionsAddition of low-dos,% 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),8/26/2024,38,YMC,% Free from Progression1-year,Erlotinib induces G1 arrest which 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;7:385,8/26/2024,39,YMC,Erlotinib induces G1 arrest wh,First-line Asian Sequential Tarceva plus Chemotherapy Trial (FAST-ACT): Study Design,Placebo,Erlotinib 150mg/day,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 (d15,28);,q4wks,PD,S,tratified by,centre, stage,histology, smoking status,Study treatment,Post-treatment,Screening,Post-study,Gemcitabine,1250mg/m,2,(d1,8); cisplatin 75mg/m,2,OR,carboplatin 5AUC (d1); erlotinib 150mg/day (d1528),PASCO 2008;26:a8031,8/26/2024,40,YMC,First-line Asian Sequential Ta,Time to Disease Progression,1.0,0.8,0.6,0.4,0.2,0,024681012141618202224262830323436,Time (weeks),3840424446485052545658,76727272646158585852505046373632261514,787676766759585650434341352524221687,1210987555310,54211111110,No. at risk,Erlotinib,Placebo,Early and consistent separation of curves,Median TTP(weeks),GC-erlotinib,31.4,GC-placebo,24.1,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 (control arm) is less than usual,Better for those Caucasians who have higher % of EGFR wild type,8/26/2024,41,YMC,Time to Disease Progression1.0,First line treatment with EGFR-TKIs in those with EGFR mutated patients,8/26/2024,42,YMC,First line treatment with EGFR,98 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;26:2442-9,8/26/2024,43,YMC,98 pts underwent EGFR screenin,Percent change in measurable tumor at best response, by individual patient,J Clin Oncol 2008;26:2442-9,8/26/2024,44,YMC,Percent change in measurable t,Kaplan-Meier curves for (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,8/26/2024,45,YMC,Kaplan-Meier curves for (A) p,Gefitinib first line treatment in enriched EGFR-mutated NSCLC in NTUH,N=106 (adenoca 97, non-adeno 9),Pt No,RR, %,DCR, %,Median TTF, M,Median OS, M,All,106,50.9,82.1,5.5,22.4,EGFR mutated,55,69,87.3,8,24,wild type,35,20,68.6,3.4,12.9,not done,16,56.3,93.8,5.6,NR,JCO 2008;26:2745-53,Pt No,RR, %,Median TTF, M,Exon 19 deletion,20,95,8.9,Exon 21 L858R,23,73.9,9.1,8/26/2024,46,YMC,Gefitinib first line treatment,Predictive Factors of Response to Gefitinib in 152 EGFR mutated patients in NTUH,Variables,No,Response rates (%),Univariate P,Multivariate P,N = 152,L858R,75,65.3,0.646,Del in Exon 19,77,68.8,Chemonaive,91,75.8,0.005,0.006,Chemo-treated,61,54.1,Female,110,71.8,0.045,0.053,Male,42,54.8,Smoker,22,54.6,0.175,Non-smoker,130,69.2,65 years,82,13.7,Wu JY et al. AJRCCM 2008,8/26/2024,47,YMC,Predictive Factors of Response,No survival difference in 152 chemonaive or chemo-treated EGFR mutated patients in NTUH,Chmo nave gefitinib (n=91),Chemotherapy treated gefitinib (n=61) log rank,Chmo nave gefitinib (n=91),Chemotherapy treated gefitinib (n=61) log rank=0.24,Wu JY et al. AJRCCM 2008,8/26/2024,48,YMC,No survival difference in 152,2003.9.15 s/p 4 line C/T since 20010629, PS 3 FiO2 50%,2003.9.29 Iressa 2 weeks PS 1 room air,Another 1.5 year,8/26/2024,49,YMC,2003.9.15 s/p 4 line C/T sinc,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 0,8/26/2024,50,YMC,Ms. Ree Hx No 31676887 75 Y/O,s/p renal transplantation with adenocarcinoma, LUL, & brain, meningeal carcinomatosis,Not 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 treatment,Patient still alive at present,8/26/2024,51,YMC,s/p renal transplantation with,T790M,Pao et al. PLoS Med 2005;2:1-11,Kwak et al. Pro Nat Acad Sci USA 2005; 102: 7665-70,8 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-TKIs,C-MET amplification accounts for 25%,And ,8/26/2024,52,YMC,T790MPao et al. PLoS Med 2005;,EGFR and MET each independently activate ErbB3 in the resistant cells,AKT,P13K,P110,P85,P,P,P,Adapted from review by C1 Arteaga Nature Medicile.2007,EGFR,ErbB3,Met,Edu Session ASCO 2008,8/26/2024,53,YMC,EGFR and MET each independentl,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,P13k,p110,p85,p,IRS-1,AKT,p,Parental (Sensitive),Resistant,Edu Session ASCO 2008,8/26/2024,54,YMC,The IGF-IR pathway is activate,Acquired Resistance to EGFR Inhibitors,Mechanism,Treatment,T790M,Irreversible EGFR inhibitors,MET amplifications,MET + EGFR inhibitors,IGF-1R activation,IGF-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 strategy for HIV and TB?,Edu Session ASCO 2008,8/26/2024,55,YMC,Acquired Resistance to EGFR In,Conclusions: Clinical Predictors of EGFR-TKIs Responsiveness,Response rate, %*,Setting,1,st,line,2,nd,line,3,rd,line,Chemotherapy (single or doublet),20-45,10-20,10,TKI (East Asian population),20-35,20-35,20-35,TKI (Caucasian),10,10,10,TKI (EGFR mutation+),60-80,60-80,60-80,TKI (EGFR mutation-),10-15,10-15,10-15,*Response to EGFR-TKI treatment correlated well with patient survival.,8/26/2024,56,YMC,Conclusions: Clinical Predicto,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.,8/26/2024,57,YMC,SummaryEGFR-TKI is effective s,
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