非小细胞肺癌表皮生长因子受体酪氨酸激酶抑制剂(英文).ppt
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1、2019/5/10,YMC,1,Epidermal growth factor receptor-tyrosine kinase inhibitor in non-small-cell lung cancer,Yuh-Min Chen, MD, PhD. Chest Dept., Taipei VGH,2019/5/10,YMC,2,Survival (anti-apoptosis),PI3-K,Activation of the epidermal growth factor receptor tyrosine kinase (EGFR-TK): a pivotal driver of ca
2、rcinogenesis,EGFR-TK,EGFR,Ligand,RAS,RAF,SOS,GRB2,PTEN,AKT,STAT3,MEK,Gene transcription Cell-cycle progression,DNA,Myc,Myc,Cyclin D1,JunFos,P P,MAPK,Proliferation/ maturation,Chemotherapy/ radiotherapy resistance,Angiogenesis,Metastasis,Balaban et al 1996; Akimoto et al 1999; Wells 1999; Woodburn 19
3、99; Hanahan 2000; Raymond et al 2000,Cyclin D1,pY,pY,pY,2019/5/10,YMC,3,2019/5/10,YMC,4,IDEAL 1 and 2 trial design,Gefitinib 250 mg/day,Gefitinib 500 mg/day,IDEAL, IressaTM Dose Evaluation in Advanced Lung cancer,Randomisation,IDEAL 1 (n=209) 1 or 2 prior regimens IDEAL 2 (n=216) 2 prior regimens,Pr
4、imary endpoints,Objective tumour response Symptom improvement (IDEAL 2) Safety (IDEAL 1),2019/5/10,YMC,5,Median time to improvement - symptoms and QOL,*Time of 1st assessment,Median time to improvement, days,Symptom/QOL measure LCS FACT-L,8*,29*,2019/5/10,YMC,6,IDEAL 1 and 2: overall survival by sym
5、ptom 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),0,2,4,6,8,10,12,14,16,18,20,44 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
6、,Probability,IDEAL 2,Months from randomisation,0,2,4,6,8,10,12,14,16,18,20,Douillard et al 2002; Lynch et al 2003,2019/5/10,YMC,7,ISEL (IRESSA Survival Evaluation in Lung Cancer): Clinical Trial Design,Randomisation,Gefitinib (250 mg) + *BSC,Placebo + *BSC,SURVIVAL Secondary: TTF, OR QoL, safety,Pri
7、mary endpoint:,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 cent
8、res across 28 countries 342 patients of oriental origin No Japanese/US sites,*BSC= Best Supportive Care,Lancet 2005;366:1527-37,2019/5/10,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 56
9、3 517 446 382 289 220 160 115 77 44 28 20 12 4 2,2019/5/10,YMC,9,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,2019/5/10,YMC,10,J Chemother 2005
10、;17:679,2019/5/10,YMC,11,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;17:679,2019/5/10,YMC,12,% Survival,Median survi
11、val: 9.5 months One-year survival rate: 45.1%,J Chemother 2005;17:679,2019/5/10,YMC,13,% Survival,Survival according to response or not,J Chemother 2005;17:679,2019/5/10,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
12、2) Prior platinum (yes vs no),Tarceva 150mg daily,Placebo,RANDOM I SE,PS = performance status,N Engl J Med 2005;353:12332,2019/5/10,YMC,15,BR.21: Significant clinical predictors of response to Tarceva,*Significance between subgroups *Data collected retrospectively,In multiple logistic-regression ana
13、lyses, only never having smoked (p0.001) and adenocarcinoma histology (p=0.01) were associated with response,Shepherd et al. NEJM 2005;353:123,2019/5/10,YMC,16,Improvement in Survival with Tarceva,42.5% improvement in median survival,Survival distribution function,Survival time (months),HR=0.73, p0.
14、001*,1.00 0.75 0.50 0.25 0,0 5 10 15 20 25 30,N Engl J Med 2005;353:12332,Tarceva,(n=488),Placebo,(n=,243,),Median survival (months),6.7,4.7,1,-,year survival (%),31,21,2019/5/10,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),
15、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;353:12332,2019/5/10,YMC,18,TRUST: Tarceva MO181
16、09 An expanded access clinical program of Tarceva (erlotinib) in pts with advanced stage IIIB/IV NSCLC Lung Cancer 2008,2019/5/10,YMC,19,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 receiv
17、ed at least one dose of Tarceva.,2019/5/10,YMC,20,Response rate and control rate by pretreatment characteristics and skin toxicity,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 (
18、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.,2019/5/10,YMC,21,Time to disease progression of 299 NSCLC pts treated with er
19、lotinib. The median time to disease progression was 5.6 months (95% C.I.: 4.4 6.5 months, 45 pts censored),2019/5/10,YMC,22,EGFR-TKI vs. chemotherapeutic agents in salvage chemotherapy,2019/5/10,YMC,23,In conclusion, both chemotherapeutic agents, such as docetaxel alone or gemcitabine + vinorelbine,
20、 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
21、 a second-line setting for Chinese pts.,J Thorac Oncol 2006;1:545-50,2019/5/10,YMC,24,Efficacy of Salvage Therapy in NSCLC,2019/5/10,YMC,25,Salvage Chemotherapy (n=342) Grade Neutroopenia,2019/5/10,YMC,26,Salvage Chemotherapy (n=342) Grade Fatigue,Docetaxel40 and vinorelbine plus cisplatin induced m
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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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