抑制剂在癌症治疗中的应用课件

mTOR Inhibitors (mTOR抑制剂) in Cancer Therapy RuiRong Yuan, MD, PhD Oncology, Novartis response were observed in previously treated mRCC (uncontrolled phase II study) Better Inhibition of p70S6 Kinase With Daily Schedule 01234567 Tumor 0 50 100 Time, days Inhibition of p70S6 Kinase Activity, % 50 20 70 30 10 5 10 Daily dosing, mg Weekly dosing, mg Continuous target inhibition is predicted to be achievable through the use of daily dosing schedules Tanaka et al., manuscript in preparation 2007. Phase II Trial of RAD001 in mRCC (Amato) Jac et al. ASCO, 2007. Abstract 5107 N=37 N=39 Median = 11.17+(2.00 31.53+) Months Median = 24.17+ Months Progression-Free Survival Overall Survival Time (months) Time (months) Objectives (end Point) Primary: PFS Secondary: Safety; Response; Patients reported outcome; OS RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) 随机III期试验:比较RAD001与安慰剂 (phase III, double-blind, randomized trial of RAD001+ BSC vs Placebo+BSC) RECORD-1 Phase III study design (随机III期试验:比较RAD001与安慰剂) 410 patients randomized between September 2006 and October 2007 Second interim analysis cut-off: October 15, 2007, based on 191 PFS events Independent Data Monitoring Committee recommended termination of study R A N D O M I Z A T I O N 2:1 Placebo + BSC (n = 138)(n = 138) Upon Disease Progression Interim analysis Interim analysis N=410 Stratification Prior VEGFR TKI: 1 or 2 舒尼替尼 或索拉非尼治疗后 进展的患者 MSKCC risk group: favorable, intermediate, or poor = Final analysis Everolimus + BSC (n = 272)(n = 272) Placebo + BSC (n = 138)(n = 138) Everolimus + BSC (n = 272)(n = 272) Placebo + BSC (n=138) RAD001 + BSC (n=272) 透明细胞癌 Treatment given in 28-day cycles Progression-Free Survival by Treatment Central Radiology Review 100 80 60 40 20 0 024681012 Probability, % Hazard ratio = 0.30 95% CI 0.22, 0.40 Median PFS Everolimus: 4.0 mo Placebo: 1.9 mo Log rank P value 詊詊浗綶疲? 犣犣?蠆螮?wL挏蝈挏蝈 ?8 YH旨誘ZGN周k曩OOMOOM G ?*G ?*鰴鰴 ?到jI 惠譬蚶莧?;?搎搎繾晑#ui?賛?瘙?菸潰萺萺n?p躭?!q豕鰦锏锏椡7埭?鈦?WS瘉?(w?9?n韊驥?顂?忺璭璭驥?:-M 袧袧O?E? !, !,顂?鷇禱?賢Y杵蛢蛢侏峌峌Du讂讂?*ec|嶮i#;?鉡磺t ? 8?.瑷鈪瑷鈪 u槄炵槄炵 K?虲虲蛞訢槒槒訉u,a?砱砱%宰类类%?蜭蜭掙j# |?闱傂闱傂 N焮x ?i?i瓗瓗y 教p“4?p“4? 渦?Ur?Ur +奭礛s窯斘T羊_扥扥z洲?磥磥簁 ?鲫鲫fQ艖上;?鄋鄋 嵛嵛8#=EosEos 玓陧陧扎喦喦3殚殚?U6?cFq?弲弲bb转转蕿鯅鯅軋嬸HH 伾 k