Washington University School of Medicine, St Louis, MO, USA.
Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan.
Lancet. 2016 Feb 6;387(10018):545-557. doi: 10.1016/S0140-6736(15)00986-1. Epub 2015 Nov 29.
Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies. We assessed the effect of nanoliposomal irinotecan alone or combined with fluorouracil and folinic acid in a phase 3 trial in this population.
We did a global, phase 3, randomised, open-label trial at 76 sites in 14 countries. Eligible patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned (1:1) using an interactive web response system at a central location to receive either nanoliposomal irinotecan monotherapy (120 mg/m(2) every 3 weeks, equivalent to 100 mg/m(2) of irinotecan base) or fluorouracil and folinic acid. A third arm consisting of nanoliposomal irinotecan (80 mg/m(2), equivalent to 70 mg/m(2) of irinotecan base) with fluorouracil and folinic acid every 2 weeks was added later (1:1:1), in a protocol amendment. Randomisation was stratified by baseline albumin, Karnofsky performance status, and ethnic origin. Treatment was continued until disease progression or intolerable toxic effects. The primary endpoint was overall survival, assessed in the intention-to-treat population. The primary analysis was planned after 305 events. Safety was assessed in all patients who had received study drug. This trial is registered at ClinicalTrials.gov, number NCT01494506.
Between Jan 11, 2012, and Sept 11, 2013, 417 patients were randomly assigned either nanoliposomal irinotecan plus fluorouracil and folinic acid (n=117), nanoliposomal irinotecan monotherapy (n=151), or fluorouracil and folinic acid (n=149). After 313 events, median overall survival in patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid was 6.1 months (95% CI 4.8-8.9) vs 4.2 months (3.3-5.3) with fluorouracil and folinic acid (hazard ratio 0.67, 95% CI 0.49-0.92; p=0.012). Median overall survival did not differ between patients assigned nanoliposomal irinotecan monotherapy and those allocated fluorouracil and folinic acid (4.9 months [4.2-5.6] vs 4.2 months [3.6-4.9]; 0.99, 0.77-1.28; p=0.94). The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]).
Nanoliposomal irinotecan in combination with fluorouracil and folinic acid extends survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy. This agent represents a new treatment option for this population.
Merrimack Pharmaceuticals.
在先前接受基于吉西他滨的治疗的转移性胰腺导管腺癌患者中，纳米脂质体伊立替康在 2 期研究中表现出活性。我们在该人群中进行了 3 期试验，评估了纳米脂质体伊立替康单独或联合氟尿嘧啶和亚叶酸的效果。
我们在 14 个国家的 76 个地点进行了一项全球、3 期、随机、开放性试验。先前接受过基于吉西他滨的治疗的转移性胰腺导管腺癌患者有资格参加，他们通过中央位置的交互式网络响应系统以 1:1 的比例随机分配接受纳米脂质体伊立替康单药治疗（每 3 周 120mg/m2，相当于伊立替康碱 100mg/m2）或氟尿嘧啶和亚叶酸。后来（在方案修正案中）加入了由纳米脂质体伊立替康（80mg/m2，相当于伊立替康碱 70mg/m2）和每 2 周氟尿嘧啶和亚叶酸组成的第三组（1:1:1）。分层随机化基于基线白蛋白、卡诺夫斯基表现状态和种族。治疗持续到疾病进展或不可耐受的毒性作用。主要终点是总生存期，在意向治疗人群中评估。主要分析计划在 305 例事件后进行。在接受研究药物的所有患者中评估安全性。这项试验在 ClinicalTrials.gov 注册，编号为 NCT01494506。
2012 年 1 月 11 日至 2013 年 9 月 11 日，417 名患者被随机分配接受纳米脂质体伊立替康联合氟尿嘧啶和亚叶酸（n=117）、纳米脂质体伊立替康单药治疗（n=151）或氟尿嘧啶和亚叶酸（n=149）。在 313 例事件后，接受纳米脂质体伊立替康联合氟尿嘧啶和亚叶酸治疗的患者中位总生存期为 6.1 个月（95%CI 4.8-8.9），而接受氟尿嘧啶和亚叶酸治疗的患者中位总生存期为 4.2 个月（3.3-5.3）（风险比 0.67，95%CI 0.49-0.92；p=0.012）。接受纳米脂质体伊立替康单药治疗的患者与接受氟尿嘧啶和亚叶酸治疗的患者中位总生存期无差异（4.9 个月[4.2-5.6]与 4.2 个月[3.6-4.9]；0.99，0.77-1.28；p=0.94）。在接受纳米脂质体伊立替康联合氟尿嘧啶和亚叶酸治疗的 117 名患者中，最常发生的 3 级或 4 级不良事件为中性粒细胞减少症（32 [27%]）、腹泻（15 [13%]）、呕吐（13 [11%]）和疲劳（16 [14%]）。
在先前接受基于吉西他滨的治疗的转移性胰腺导管腺癌患者中，纳米脂质体伊立替康联合氟尿嘧啶和亚叶酸延长了生存期，且具有可管理的安全性。这种药物为该人群提供了一种新的治疗选择。
Merrimack Pharmaceuticals。
