mtor抑制剂在癌症治疗中的应用.ppt

mTOR Inhibitors (mTOR抑制剂) in Cancer TherapyRuiRong Yuan, MD, PhDOncology, Novartis response were observed in previously treated mRCC (uncontrolled phase II study)Better Inhibition of p70S6 Kinase With Daily Schedule01234567Tumor050100Time, daysInhibition of p70S6 Kinase Activity, % 5020703010510Daily dosing, mgWeekly dosing, mgContinuous target inhibition is predicted to be achievable through the use of daily dosing schedulesTanaka et al., manuscript in preparation 2007.Phase II Trial of RAD001 in mRCC (Amato)Jac et al. ASCO, 2007. Abstract 5107N=37N=39Median = 11.17+(2.00 – 31.53+) MonthsMedian = 24.17+ MonthsProgression-Free SurvivalOverall SurvivalTime (months)Time (months)Objectives (end Point)Primary: PFSSecondary: Safety; Response; Patients reported outcome; OSRECORD-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 studyR A N D O M I Z A T I O N2:1Placebo + BSC (n = 138)(n = 138)Upon Disease ProgressionInterim analysisInterim analysisN=410Stratification •Prior VEGFR TKI: 1 or 2舒尼替尼 或索拉非尼治疗疗后 进进展的患者 •MSKCC risk group: favorable, intermediate, or poor=Final analysisEverolimus + 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)透明细细胞癌Treatment given in 28-day cyclesProgression-Free Survival by Treatment Central Radiology Review100806040200024681012Probability, %Hazard ratio = 0.30 95% CI [0.22, 0.40]Median PFS Everolimus: 4.0 mo Placebo: 1.9 moLog rank P value < 0.001Everolimus (n = 272)Placebo (n = 138) Months延长长无进进展生存期Motzer RJ, et al. ASCO 2008 and Lancet 2008; 372: 449–56Progression-Free Survival by Treatment Investigator Assessment100806040200Probability (%)024681012MonthsHazard ratio = 0.31 95% CI [0.23, 0.41]Median PFS Everolimus: 4.6 mo Placebo: 1.8 moLog rank P value < 0.001Everolimus (n = 272)Placebo (n = 138) Probability, %Motzer RJ, et al. ASCO 2008 and Lancet 2008; 372: 449–56Subgroup Analysis of Progression-Free Survival Central Radiology Review1. Motzer et al. J Clin Oncol. 2004;22:454-463.1Motzer RJ, et al. ASCO 2008 and Lancet 2008; 372: 449–56Treatment-Related Adverse Events*Everolimus %, (n = 269)Placebo %, (n = 135) All GradesGrade 3All GradesGrade 3 Stomatitis (口腔炎) †40 38 0 Asthenia / fatigue (疲劳)37 324 1 Rash (皮 疹)25< 14 0 Diarrhea (腹泻)17 13 0 Anorexia (厌食)16< 16 0 Nausea (恶心)15 08 0 Mucosal inflammation14 12 0 Vomiting 12 04 0 Cough12 04 0 Edema peripheral10 03 0 Infections†10 32 0 Pneumonitis†8 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 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 2008SettingPhase III Treatment - naïveGood or intermediate risk*Sunitinib Bevacizumab + IFN-  Poor risk*Temsirolimus Sunitinib Previously treatedPrior cytokine SorafenibPrior VEGFr-TKI Everolimus Prior mTOR inhibitor*MSKCC risk statusMotzer RJ, et al. ASCO 2008Everolimus : Development Overview• Active in 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 agentsThank You ! 。