尼达尼布治疗难治性转移性结直肠癌患者（LUME-Colon 1）：一项 III 期、国际、随机、安慰剂对照研究。
Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study.
机构信息
Division of Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium.
Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.
出版信息
Ann Oncol. 2018 Sep 1;29(9):1955-1963. doi: 10.1093/annonc/mdy241.
BACKGROUND
Angiogenesis is critical to colorectal cancer (CRC) growth and metastasis. Phase I/II studies have demonstrated the efficacy of nintedanib, a triple angiokinase inhibitor, in patients with metastatic CRC. This global, randomized, phase III study investigated the efficacy and safety of nintedanib in patients with refractory CRC after failure of standard therapies.
PATIENTS AND METHODS
Eligible patients (Eastern Cooperative Oncology Group performance status 0-1, with histologically/cytologically confirmed metastatic/locally advanced CRC adenocarcinoma unamenable to surgery and/or radiotherapy) were randomized 1 : 1 to receive nintedanib (200 mg twice daily) or placebo (twice daily), until disease progression or undue toxicity. Patients were stratified by previous regorafenib, time from onset of metastatic disease to randomization, and region. Co-primary end points were overall survival (OS) and progression-free survival (PFS) by central review. Secondary end points included objective tumor response and disease control by central review.
RESULTS
From October 2014 to January 2016, 768 patients were randomized; 765 were treated (nintedanib n = 384; placebo n = 381). Median follow-up was 13.4 months (interquartile range 11.1-15.7). OS was not improved [median OS 6.4 months with nintedanib versus 6.0 months with placebo; hazard ratio (HR), 1.01; 95% confidence interval (CI), 0.86-1.19; P = 0.8659]. There was a significant but modest increase in PFS with nintedanib versus placebo (median PFS 1.5 versus 1.4 months, respectively; HR 0.58; 95% CI 0.49-0.69; P < 0.0001). There were no complete or partial responses. Adverse events (AEs) occurred in 97% of 384 nintedanib-treated patients and 93% of 381 placebo-treated patients. The most frequent grade ≥3 AEs were liver-related AEs (nintedanib 16%; placebo 8%) and fatigue (nintedanib 9%; placebo 6%).
CONCLUSIONS
The study failed to meet both co-primary end points. Nintedanib did not improve OS and was associated with a significant but modest increase in PFS versus placebo. Nintedanib was well tolerated.
CLINICALTRIALS.GOV NUMBER: NCT02149108 (LUME-Colon 1).
背景
血管生成对于结直肠癌（CRC）的生长和转移至关重要。I/II 期研究已经证实了三重血管激酶抑制剂尼达尼布在转移性 CRC 患者中的疗效。这项全球性、随机、III 期研究调查了尼达尼布在标准治疗失败后患有难治性 CRC 患者中的疗效和安全性。
患者和方法
符合条件的患者（东部肿瘤协作组表现状态 0-1，组织学/细胞学证实不可手术和/或放疗的转移性/局部晚期 CRC 腺癌）按 1:1 随机分配接受尼达尼布（200mg，每日两次）或安慰剂（每日两次）治疗，直至疾病进展或出现无法耐受的毒性。患者按先前接受regorafenib、从转移性疾病发病到随机分组的时间以及地区进行分层。主要共同终点为中央审查的总生存期（OS）和无进展生存期（PFS）。次要终点包括中央审查的客观肿瘤反应和疾病控制。
结果
从 2014 年 10 月到 2016 年 1 月，共随机分配了 768 名患者；765 名患者接受了治疗（尼达尼布 n=384；安慰剂 n=381）。中位随访时间为 13.4 个月（四分位间距 11.1-15.7）。OS 没有改善[尼达尼布组的中位 OS 为 6.4 个月，安慰剂组为 6.0 个月；风险比（HR），1.01；95%置信区间（CI），0.86-1.19；P=0.8659]。与安慰剂相比，尼达尼布组 PFS 有显著但适度的增加（中位 PFS 分别为 1.5 个月和 1.4 个月；HR，0.58；95%CI，0.49-0.69；P<0.0001）。没有完全或部分反应。尼达尼布治疗的 384 名患者中有 97%和安慰剂治疗的 381 名患者中有 93%发生了不良反应（AE）。最常见的≥3 级 AE 是肝脏相关 AE（尼达尼布 16%；安慰剂 8%）和疲劳（尼达尼布 9%；安慰剂 6%）。
结论
该研究未能达到两个共同主要终点。尼达尼布没有改善 OS，与安慰剂相比，PFS 有显著但适度的增加。尼达尼布耐受良好。
临床试验.gov 编号：NCT02149108（LUME-Colon 1）。
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