mTOR抑制剂在癌症治疗中的应用

1、mtor inhibitors (mtor抑制剂抑制剂) 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 2

2、0 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 = 11.1

3、7+(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

4、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 c

5、ommittee recommended termination of study r a n d o m i z a t i o n 2:1 placebo + bsc upon disease progression interim analysis interim analysis n=410 stratification prior vegfr tki: 1 or 2 舒尼替尼舒尼替尼 或索拉非尼治疗后或索拉非尼治疗后 进展的患者进展的患者 mskcc risk group: favorable, intermediate, or poor = final analysis evero

6、limus + bsc placebo + bsc everolimus + bsc placebo + bsc (n=138) rad001 + bsc (n=272) 透明细胞癌透明细胞癌 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.

7、0 mo placebo: 1.9 mo log rank p value 0.001 everolimus (n = 272) placebo (n = 138) months 延长无进展生存期延长无进展生存期 motzer rj, et al. asco 2008 and lancet 2008; 372: 44956 progression-free survival by treatment investigator assessment 100 80 60 40 20 0 probability (%) 024681012 months hazard ratio = 0.31 95%

8、 ci 0.23, 0.41 median pfs everolimus: 4.6 mo placebo: 1.8 mo log rank p value 0.001 everolimus (n = 272) placebo (n = 138) probability, % motzer rj, et al. asco 2008 and lancet 2008; 372: 44956 subgroup analysis of progression-free survival central radiology review 1. motzer et al. j clin oncol. 200

9、4;22:454-463. hrn central review0.30410 investigator review0.31410 mskcc risk favorable0.35118 intermediate0.25231 poor0.3961 prior tx sorafenib only0.29119 sunitinib only0.30184 both0.28107 age 65 yrs0.32259 65 yrs0.29151 sex male0.29317 female0.3693 region u.s. 372: 44956 treatment-related adverse

10、 events* everolimus %, (n = 269) placebo %, (n = 135) all gradesgrade 3all gradesgrade 3 stomatitis (口腔炎口腔炎) 40 38 0 asthenia / fatigue (疲劳疲劳)37 324 1 rash (皮皮 疹疹)25 14 0 diarrhea (腹泻腹泻)17 13 0 anorexia (厌食厌食)16 16 0 nausea (恶心恶心)15 08 0 mucosal inflammation14 12 0 vomiting 12 04 0 cough12 04 0 edem

11、a peripheral10 03 0 infections10 32 0 pneumonitis8 30 0 dyspnea8 12 0 * 10% of everolimus patients and additional selected aes. significant difference between sum of grade 3/4 events for everolimus and placebo groups (p .05) . conclusions everolimus prolongs progression-free survival in rcc patients

12、 after progression on vegfr-tki therapies everolimus is the first and only agent with established clinical benefit for the treatment of patients with rcc after vegfr-tki therapy everolimus should be standard-of-care in this setting standards for rcc therapy by phase iii trial after asco 2008 setting

13、phase iii treatment- nave good or intermediate risk* sunitinib bevacizumab + ifn-a a poor risk* temsirolimus sunitinib previously treated prior cytokine sorafenib prior vegfr-tki everolimus prior mtor inhibitor *mskcc risk status motzer rj, et al. asco 2008 everolimus : development overview active i

14、n multiple tumor types rcc and net- first indications lymphoma and tsc- pivotal trials coming generally well-tolerated other proof of concept and clinical trials breast cancer, lung, gastric, hcc, crc combination therapy with other chemo/target agents thank you ! majpjmvcyzj21hlfrvy96dv02lppfygxus7i

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