苹果酸舒尼替尼治疗胰腺神经内分泌肿瘤。

Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.

机构信息

Service Inter-Hospitalier de Cancérologie et Service de Gastroenteropancréatologie, Hôpital Beaujon, Clichy, France.

出版信息

N Engl J Med. 2011 Feb 10;364(6):501-13. doi: 10.1056/NEJMoa1003825.

DOI:10.1056/NEJMoa1003825

PMID:21306237

Abstract

BACKGROUND

The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials.

METHODS

We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety.

RESULTS

The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue.

CONCLUSIONS

Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.).

摘要

背景

多靶点酪氨酸激酶抑制剂舒尼替尼在临床前模型和 1 期和 2 期试验中显示对胰腺神经内分泌肿瘤有活性。

方法

我们进行了一项多中心、随机、双盲、安慰剂对照的舒尼替尼治疗晚期分化良好的胰腺神经内分泌肿瘤患者的 3 期临床试验。所有患者在基线前 12 个月内均有实体瘤反应评价标准定义的疾病进展记录。171 名患者被随机分配（1:1 比例），接受最佳支持治疗，每日 37.5 毫克舒尼替尼或安慰剂。主要终点是无进展生存期；次要终点包括客观缓解率、总生存期和安全性。

结果

独立的数据和安全监测委员会观察到安慰剂组发生更严重的不良事件和死亡，以及舒尼替尼组无进展生存期有优势后，该研究提前终止。舒尼替尼组的中位无进展生存期为 11.4 个月，安慰剂组为 5.5 个月（进展或死亡的风险比为 0.42；95%置信区间[CI]为 0.26 至 0.66；P<0.001）。根据基线特征进行的无进展生存 Cox 比例风险分析表明，舒尼替尼在所有研究的亚组中均有优势。舒尼替尼组的客观缓解率为 9.3%，安慰剂组为 0%。在数据截止点时，舒尼替尼组报告了 9 例死亡（10%），安慰剂组报告了 21 例死亡（25%）（死亡风险比为 0.41；95%CI 为 0.19 至 0.89；P=0.02）。舒尼替尼组最常见的不良反应是腹泻、恶心、呕吐、乏力和疲劳。