Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial
Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial
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DOI：
10.1016/s0140-6736(17)31827-5
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发表时间：
2017-12-02
期刊：
影响因子：
168.9
通讯作者：
Chen, Li-Tzong
中科院分区：
文献类型：
--
作者：
Kang, Yoon-Koo;Boku, Narikazu;Chen, Li-Tzong
背景：对两种或两种以上化疗方案无效或不耐受的晚期胃或胃食道交界部癌患者预后较差，目前的指南并未建议对这些患者进行任何特定的治疗。我们评估了nivolumab的有效性和安全性，nivolumab是一种全人IgG4单抗抑制程序性死亡-1(PD-1)，对以前接受过两种或两种以上化疗方案的进展期胃或胃食道交界处癌症患者的疗效和安全性。=20年不能切除的晚期或复发性胃或胃食道交界部癌，对标准治疗(包括以前的两种或两种以上化疗方案)无效或不耐受，东方合作肿瘤组[ECOG]表现状态为0-1，未接受抗PD-1治疗或其他治疗性抗体和药物治疗以调节T细胞)。患者被随机分配(2：1)，使用交互式网络响应系统，每两周静脉注射3 mg/kg nivolumab或安慰剂，按国家、ECOG表现状态和有转移的器官数量分层。继续进行研究治疗，直到研究人员对进展性疾病进行评估或出现需要永久停止的毒性反应。患者和调查人员被蒙面进行分组分配。主要终点是意向治疗人群的总体存活率。对所有接受至少一剂研究治疗的患者进行了安全性分析。这项研究正在进行中，但没有招募新患者，并在ClinicalTrials.gov注册，编号为NCT02267343。在2014年11月4日至2016年2月26日期间，我们随机分配493名患者接受nivolumab(n=330)或安慰剂(n=163)治疗。在数据截止时(2016年8月13日)，尼伏卢单抗组存活患者的中位随访期为8.87个月(IQR 6.57-12.37)，安慰剂组为8.59个月(5.65-11.37)。尼伏单抗治疗组的中位总生存期为5.26个月(95%可信区间为4.60-6.37)，安慰剂组为4.14个月(风险比为0.63，95%可信区间为0.51-0.78；p<；0.0001)。使用nivolumab的12个月总生存率为26.2%(95%CI 20.7-32.0)，使用安慰剂的12个月总生存率为10.9%(6.2-17.0)。接受nivolumab治疗的330名患者中有34名(10%)发生了与治疗有关的3级或4级不良事件，接受安慰剂治疗的161名患者中有7名(4%)发生了与治疗有关的不良事件；在接受nivolumab治疗的330名患者中有5名(2%)和接受安慰剂治疗的161名患者中有2名(1%)死亡。没有观察到新的安全信号。在这项3期研究中的解释是，生存益处表明nivolumab可能是一种新的治疗方案，用于严重预治疗的晚期胃或胃-食道交界处癌症患者。包括非亚洲患者在内的正在进行的试验正在研究nivolumab在各种环境和更早的治疗路线中用于晚期胃癌或胃-食道交界处癌症。
Background Patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, two or more previous regimens of chemotherapy have a poor prognosis, and current guidelines do not recommend any specific treatments for these patients. We assessed the efficacy and safety of nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), in patients with advanced gastric or gastro-oesophageal junction cancer who had been previously been treated with two or more chemotherapy regimens.Methods In this randomised, double-blind, placebo-controlled, phase 3 trial done at 49 clinical sites in Japan, South Korea, and Taiwan, eligible patients (aged >= 20 years with unresectable advanced or recurrent gastric or gastrooesophageal junction cancer refractory to, or intolerant of, standard therapy [including two or more previous chemotherapy regimens], with an Eastern Cooperative Oncology Group [ECOG] performance status of 0-1, and naive to anti-PD-1 therapy or other therapeutic antibodies and pharmacotherapies for the regulation of T cells) were recruited. Patients were randomly assigned (2: 1) using an interactive web response system to receive 3 mg/kg nivolumab or placebo intravenously every 2 weeks, stratified by country, ECOG performance status, and number of organs with metastases. Study treatment was continued until progressive disease per investigator assessment or onset of toxicities requiring permanent discontinuation. Patients and investigators were masked to group assignment. The primary endpoint was overall survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study treatment. This study is ongoing but not recruiting new patients, and is registered with ClinicalTrials.gov, number NCT02267343.Findings Between Nov 4, 2014, and Feb 26, 2016, we randomly assigned 493 patients to receive nivolumab (n= 330) or placebo (n= 163). At the data cutoff (Aug 13, 2016), median follow-up in surviving patients was 8.87 months (IQR 6.57-12.37) in the nivolumab group and 8.59 months (5.65-11.37) in the placebo group. Median overall survival was 5.26 months (95% CI 4.60-6.37) in the nivolumab group and 4.14 months (3.42-4.86) in the placebo group (hazard ratio 0.63, 95% CI 0.51-0.78; p< 0.0001). 12-month overall survival rates were 26.2% (95% CI 20.7-32.0) with nivolumab and 10.9% (6.2-17.0) with placebo. Grade 3 or 4 treatment-related adverse events occurred in 34 (10%) of 330 patients who received nivolumab and seven (4%) of 161 patients who received placebo; treatment-related adverse events led to death in five (2%) of 330 patients in the nivolumab group and two (1%) of 161 patients in the placebo group. No new safety signals were observed.Interpretation In this phase 3 study, the survival benefits indicate that nivolumab might be a new treatment option for heavily pretreated patients with advanced gastric or gastro-oesophageal junction cancer. Ongoing trials that include non-Asian patients are investigating nivolumab for advanced gastric or gastro-oesophageal junction cancer in various settings and earlier treatment lines.