非小细胞肺癌表皮生长因子受体酪氨酸激酶抑制剂(英文)(1).ppt
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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
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- 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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