Department of Medicine, Division of Medical Oncology, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.
Medical Oncology, Royal Hobart Hospital, Hobart, Australia.
Lancet Gastroenterol Hepatol. 2018 Apr;3(4):263-270. doi: 10.1016/S2468-1253(18)30009-8. Epub 2018 Feb 1.
Napabucasin is a first-in-class cancer stemness inhibitor that targets STAT3, which is a poor prognostic factor in colorectal cancer. This study aimed to test napabucasin in advanced colorectal cancer.
This study was a double-blind randomised phase 3 trial done at 68 centres in Canada, Australia, New Zealand, and Japan. Patients with advanced colorectal cancer with a good Eastern Cooperative Oncology Group (ECOG) performance status (0-1) for whom all available standard therapies had failed were eligible for the study. Patients were randomly assigned (1:1) to receive placebo or napabucasin through a web-based system with a permuted block method, after stratification by ECOG performance status, KRAS status, previous VEGF inhibitor treatment, and time from diagnosis of metastatic disease. Napabucasin 480 mg or matching placebo was taken orally every 12 h. All patients received best supportive care. The primary endpoint was overall survival assessed in an intention-to-treat analysis. This is the final analysis of this trial, which is registered at ClinicalTrials.gov, number NCT01830621.
Accrual began on April 15, 2013, and was stopped for futility on May 23, 2014, at which point 282 patients had undergone randomisation (138 assigned to the napabucasin group and 144 to the placebo group). Overall survival did not differ significantly between groups: median overall survival was 4·4 months (95% CI 3·7-4·9) in the napabucasin group and 4·8 months (4·0-5·3) in the placebo group (adjusted hazard ratio [HR] 1·13, 95% CI 0·88-1·46, p=0·34). The safety population included 136 patients in the napabucasin group and 144 patients in the placebo group. More patients who received napabucasin had any grade of treatment-related diarrhoea (108 [79%] of 136 patients), nausea (69 [51%]), and anorexia (52 [38%]) than did patients who received placebo (28 [19%] of 144 patients, 35 [24%], and 23 [16%], respectively). The most common severe (grade 3 or worse) treatment-related adverse events were abdominal pain (five [4%] patients receiving napabucasin vs five [3%] receiving placebo), diarrhoea (21 [15%] vs one [1%]), fatigue (14 [10%] vs eight [6%]), and dehydration (six [4%] vs one [1%]). 251 (89%) patients had data on pSTAT3 expression, of whom 55 (22%) had pSTAT3-positive tumours (29 in the napabucasin group, 26 in the placebo group). In a prespecified biomarker analysis of pSTAT3-positive patients, overall survival was longer in the napabucasin group than in the placebo group (median 5·1 months [95% CI 4·0-7·5] vs 3·0 months [1·7-4·1]; HR 0·41, 0·23-0·73, p=0·0025).
Although there was no difference in overall survival between groups in the overall unselected population, STAT3 might be an important target for the treatment of colorectal cancer with elevated pSTAT3 expression. Nevertheless, these results require validation.
Canadian Cancer Society Research Institute and Boston Biomedical.
Napabucasin 是一种首创的癌症干细胞抑制剂，针对 STAT3，这是结直肠癌预后不良的一个因素。本研究旨在测试 Napabucasin 在晚期结直肠癌中的疗效。
这是一项在加拿大、澳大利亚、新西兰和日本的 68 个中心进行的双盲随机 3 期试验。对于表现状态良好（ECOG 0-1）且所有可用的标准治疗均已失败的晚期结直肠癌患者，符合研究条件。患者通过基于网络的系统以区组随机化（1:1），分层因素包括 ECOG 表现状态、KRAS 状态、先前的 VEGF 抑制剂治疗和转移性疾病诊断后的时间。Napabucasin 480mg 或匹配的安慰剂每天口服 12 小时。所有患者均接受最佳支持治疗。主要终点为在意向治疗分析中评估的总生存期。这是该试验的最终分析，在 ClinicalTrials.gov 上注册，编号为 NCT01830621。
入组于 2013 年 4 月 15 日开始，2014 年 5 月 23 日因无效而停止，此时已有 282 名患者接受了随机分组（Napabucasin 组 138 例，安慰剂组 144 例）。两组的总生存期无显著差异：Napabucasin 组的中位总生存期为 4.4 个月（95%CI 3.7-4.9），安慰剂组为 4.8 个月（4.0-5.3）（调整后的危险比[HR]1.13，95%CI 0.88-1.46，p=0.34）。安全性人群包括 Napabucasin 组 136 例患者和安慰剂组 144 例患者。接受 Napabucasin 治疗的患者中，任何等级的治疗相关腹泻（136 例患者中有 108 例[79%]）、恶心（69 例[51%]）和厌食（52 例[38%]）的发生率均高于接受安慰剂的患者（144 例患者中分别为 28 例[19%]、35 例[24%]和 23 例[16%]）。最常见的严重（等级 3 或更严重）治疗相关不良事件是腹痛（Napabucasin 组 5 例[4%]与安慰剂组 5 例[3%]）、腹泻（21 例[15%]与 1 例[1%]）、疲劳（14 例[10%]与 8 例[6%]）和脱水（6 例[4%]与 1 例[1%]）。251 例（89%）患者有 pSTAT3 表达的数据，其中 55 例（22%）有 pSTAT3 阳性肿瘤（Napabucasin 组 29 例，安慰剂组 26 例）。在 pSTAT3 阳性患者的预设生物标志物分析中，Napabucasin 组的总生存期长于安慰剂组（中位总生存期 5.1 个月[95%CI 4.0-7.5]与 3.0 个月[1.7-4.1]；HR 0.41，0.23-0.73，p=0.0025）。
尽管在总体未选择人群中，两组的总生存期无差异，但 STAT3 可能是结直肠癌治疗中 pSTAT3 表达升高的一个重要靶点。然而，这些结果需要验证。
尽管在总体未选择人群中，两组的总生存期无差异，但 STAT3 可能是结直肠癌治疗中 pSTAT3 表达升高的一个重要靶点。然而，这些结果需要验证。
本译文仅供参考，具体内容请以原文为准。
