《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》由会员分享，可在线阅读，更多相关《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（57页珍藏版）》请在三一文库上搜索。
1、2019/5/21,YMC,1,Epidermal growth factor receptor-tyrosine kinase inhibitor in non-small-cell lung cancer,Yuh-Min Chen, MD, PhD. Chest Dept., Taipei VGH,2019/5/21,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,2019/5/21,YMC,3,2019/5/21,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),2019/5/21,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*,2019/5/21,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 2003,2019/5/21,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;366:1527-37,2019/5/21,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 2,2019/5/21,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,2019/5/21,YMC,10,J Chemother 2005
10、;17:679,2019/5/21,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;17:679,2019/5/21,YMC,12,% Survival,Median survi
11、val: 9.5 months One-year survival rate: 45.1%,J Chemother 2005;17:679,2019/5/21,YMC,13,% Survival,Survival according to response or not,J Chemother 2005;17:679,2019/5/21,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;353:12332,2019/5/21,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;353:123,2019/5/21,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 (%),31,21,2019/5/21,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;353:12332,2019/5/21,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 2008,2019/5/21,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.,2019/5/21,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.,2019/5/21,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),2019/5/21,YMC,22,EGFR-TKI vs. chemotherapeutic agents in salvage chemotherapy,2019/5/21,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;1:545-50,2019/5/21,YMC,24,Efficacy of Salvage Therapy in NSCLC,2019/5/21,YMC,25,Salvage Chemotherapy (n=342) Grade Neutroopenia,2019/5/21,YMC,26,Salvage Chemotherapy (n=342) Grade Fatigue,Docetaxel40 and vinorelbine plus cisplatin induced m
22、ore frequent severe fatigue than other regimens. Patients that received single-agent gemcitabine and gefitinib reported no severe fatigue sensation.,2019/5/21,YMC,27,Interest,INTEREST (gefitinib vs. docetaxel in pts with LA or meta. NSCLC pre-treated with platinum-based chemotherapy,WCLC 2007,1466 p
23、ts from Mar 2004 to Feb 2006,2019/5/21,YMC,28,Interest,QoF and symptom improvement,WCLC 2007,2019/5/21,YMC,29,Interest,WCLC 2007,2019/5/21,YMC,30,Interest,Overall survival,2019/5/21,YMC,31,Clinical characteristics & response rate (pt number=1974),Int J Clin Oncol 2006;11:1908,2019/5/21,YMC,32,EGFR M
24、utation,Eur J Cancer 2006:17-23,N Engl J Med 2004;350:2129-39,2019/5/21,YMC,33,Failure of Doublet Chemotherapy plus EGFR-TKI,INTACT I, II TRIBUTE, TALENT,2019/5/21,YMC,34,Giaccone. JCO 2004;22:777,Overall Survival of INTACT-1 in Each Treatment Group (GEM+CDDP c/s Iressa),Poor survival for those use
25、Iressa with GEM+CDDP,2019/5/21,YMC,35,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 th
26、e efficacy of adding chronic intermittent low-dose vinorelbine to gefitinib treatment for adenocarcinoma of lung who failed two or more regimens of chemotherapy.,2019/5/21,YMC,36,2019/5/21,YMC,37,Conclusions,Addition of low-dose vinorelbine to gefitinib has shown high efficacy in adenocarcinoma lung
27、 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 t
28、his time for further clinical trials combining chemotherapy with EGFR TKIs.,2019/5/21,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),2019/5/21,YMC,39,Erlotinib induces G1 arrest which can block M-phase activity of docetax
29、el,Docetaxel induces M-phase arrest and apoptosis that is enhanced by erlotinib,Sequence specific Interaction,Clin Lung Cancer 2006;7:385,2019/5/21,YMC,40,First-line Asian Sequential Tarceva plus Chemotherapy Trial (FAST-ACT): Study Design,Placebo,Erlotinib 150mg/day,Previously untreated stage IIIB/
30、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,Post-study,Ge
31、mcitabine 1250mg/m2 (d1,8); cisplatin 75mg/m2 OR carboplatin 5AUC (d1); erlotinib 150mg/day (d1528),PASCO 2008;26:a8031,2019/5/21,YMC,41,Time to Disease Progression,1.0 0.8 0.6 0.4 0.2 0,0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36,Time (weeks),38 40 42 44 46 48 50 52 54 56 58,76 72 72 72 64
32、61 58 58 58 52 50 50 46 37 36 32 26 15 14 78 76 76 76 67 59 58 56 50 43 43 41 35 25 24 22 16 8 7,12 10 9 8 7 5 5 5 3 1 0 5 4 2 1 1 1 1 1 1 1 0,No. at risk Erlotinib Placebo,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
33、.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,2019/5/21,YMC,42,First line treatment with EGFR-TKIs in those with EGFR mutated patients,2019/5/21,YMC,43,98 pts
34、 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;26:2442-9,2019/5/21,YMC,44,Percent change in measurable t
35、umor at best response, by individual patient,J Clin Oncol 2008;26:2442-9,2019/5/21,YMC,45,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,2019/5/21,YMC,46,Gefitinib first line treatment in enriched
36、EGFR-mutated NSCLC in NTUH,N=106 (adenoca 97, non-adeno 9),JCO 2008;26:2745-53,2019/5/21,YMC,47,Predictive Factors of Response to Gefitinib in 152 EGFR mutated patients in NTUH,Wu JY et al. AJRCCM 2008,2019/5/21,YMC,48,No survival difference in 152 chemonaive or chemo-treated EGFR mutated patients i
37、n NTUH,Wu JY et al. AJRCCM 2008,2019/5/21,YMC,49,2003.9.15 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,2019/5/21,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-
38、N, PS 0,2019/5/21,YMC,51,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),T
39、arceva first line treatment,Patient still alive at present,2019/5/21,YMC,52,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
40、EGFR-TKIs C-MET amplification accounts for 25% And ,2019/5/21,YMC,53,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 2008,2019/5/21,YMC,54,The IGF-IR pathway is activa
41、ted 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 2008,2019/5/21,YMC,55,Acquired Resistance to EGFR Inhibitors,Heterogenicity of resis
42、tance 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 2008,2019/5/21,YMC,56,Conclusions: Clinical Predictors of EGFR-TKIs Responsiveness,*Response
43、to EGFR-TKI treatment correlated well with patient survival.,2019/5/21,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.,