胃肠胰神经内分泌肿瘤ppt课件.ppt

舒尼替尼的II期临床研究 Carcinoid(N = 41) pNET(N = 66) All patients(N = 107) PR (confirmed) 1 (2) 11 (17) 12 (11) SD 34 (83) 45 (68) 78 (73) PD 1 (2) 5 (8) 6 (6) Not evaluable 5 (12) 5 (8) 10 (9) Kulke MH, et al. J Clin Oncol. 2008; 26:3403-3410. 均为不可切除的晚期NET 舒尼替尼用法： 50 mg/d，连用4周，每6周重复 过去12个月内疾病出现进展的分化良好的PNET Sunitinib 37.5 mg Continuous dosing Placebo 计划入组340例，实际入组170例 1:1 RANDOMIZE 主要研究终点：PFS 1. Raoul J, et al. Presented at: ESMO 2009; Abstract O-6501. 2. Niccoli P, et al. J Clin Oncol. 2010;28(15s suppl):abstract 4000. 舒尼替尼的III期临床研究 结果：研究者报告的PFS 1.0 0.8 0.6 0.4 0.2 0 Proportion of patients 0 5 10 15 20 25 Median PFS Sunitinib 11.4 months (95% CI 7.4, 19.8) Placebo 5.5 months (95% CI 3.6, 7.4) HR = 0.418 (95% CI 0.263, 0.662) P = 0.0001 86 39 19 4 0 85 28 7 2 1 Number at risk Sunitinib Placebo Time (months) Niccoli P, et al. J Clin Oncol. 2010;28(15s suppl):abstract 4000. 0 0 mTOR抑制剂治疗NET的理论基础 mTOR是细胞生长、增殖、代谢和血管生成的主要调节因子 在与PNET有关的遗传性癌症综合症中，观察到mTOR途径被激活 PNET的临床研究发现发现，依维莫司具有抗肿瘤活性 1. O’Reilly T, Transl Oncol. 2010;3(2):65-79. 2. Meric-Bernstam F, J Clin Oncol. 2009;27:2278-2287. 3. Faivre S, . Nat Rev Drug Disc. 2006;5:671-688. 4. Yao JC, Pancreatic Endocrine Tumours. In: DeVita VT, Lawrence TS, Rosenberg SA, eds. Cancer: Principles Practice of Oncology. 8th Edition. Philadelphia, PA: Lippincott Williams Wilkins; 2008:1702-1721. 5. Yao JC, et al. J Clin Oncol. 2008;26:4311-4318. 6. Yao JC, et al. J Clin Oncol. 2010;28:69-76. VHL TSC1/2 PTEN NF1 PI3K ˉ ligand and receptorexpression IGF-1 IGF-1R IGF-1 VEGF VEGFR Metabolism HIF1a mTOR inhibition blocksdownstream tumourigeniceffects of aberrantlyactivated PI3K/AKT/mTORpathway sstr Growth andproliferation Angiogenesis IGF-1R ˉNegative feedback Activated AKT maystimulate pathwaysthat bypass mTOR mTOR AKT Survival X X X X X mTORinhibitor Stratum 1 n=115 RADIANT-1研究（II期） Everolimus 10 mg/d (No Octreotide LAR ≤60d prior to enrollment) Everolimus 10 mg/d+