Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial
Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial
复制标题
DOI：
10.1016/s1470-2045(17)30181-x
复制
发表时间：
2017-05-01
期刊：
影响因子：
51.1
通讯作者：
Kitagawa, Yuko
中科院分区：
文献类型：
--
作者：
Kudo, Toshihiro;Hamamoto, Yasuo;Kitagawa, Yuko
纳武单抗是一种人单克隆IgG 4抗体，可抑制活化T细胞上表达的程序性细胞死亡蛋白1（PD-1）。我们调查了纳武利尤单抗在难治性食管癌患者中的安全性和活性。符合条件的患者患有晚期鳞状细胞癌、腺鳞状细胞癌或食管腺癌，对基于氟尿嘧啶、铂类和紫杉烷的化疗难治或不耐受。患者用3 mg/kg纳武单抗治疗，每2周一次静脉内给药，6周为一个周期。主要终点是根据实体瘤疗效评价标准（第1.1版）集中评估的客观缓解（最佳缓解为完全缓解或部分缓解的患者比例）。在整个研究期间监测不良事件和治疗相关不良事件（定义为无法排除与纳武利尤单抗的因果关系的事件）。在接受至少一剂nivolumab的患者中进行了安全性分析，并在接受至少一剂nivolumab并至少有一次肿瘤反应中心评估的患者中评估了药物活性。本研究注册于clinicaltrials.jp，编号ONO-4538-07/JapicCTI-No.142422。结果2014年2月25日至11月14日期间，65例患者入选，均患有鳞状细胞癌。64例患者可评估主要终点，1例患者因患有多种原发性癌症而被排除;所有患者均可评估安全性。中位随访时间为10.8个月（IQR 4.9-14.3）。64例患者中有11例（17%，95% CI 10-28）达到中心评估的客观缓解。在65例评估不良事件的患者中，最常见的3级或4级事件为4级呼吸困难和低钠血症（各1例[2%]患者），3级肺部感染（5例[8%]患者）、3级食欲减退（2例[3%]患者）、3级血肌酐磷酸激酶升高（2例[3%]患者）和3级脱水（2例[3%]患者）。研究期间发生的严重不良事件为肺部感染（4例[6%]患者）、脱水（2例[3%]）、间质性肺病（2例[3%]）和低钠血症、呼吸困难、疲乏、肝功能异常、腹泻、胆管狭窄、胃肠炎、肺炎、水肿和背痛（各1例[2%]患者）。没有治疗相关的死亡。解释纳武利尤单抗显示出有希望的活性和可管理的安全性。这种药物可能为治疗难治性晚期鳞状细胞癌患者提供一种潜在的新治疗方法。
Background Nivolumab is a human monoclonal IgG4 antibody that inhibits programmed cell death protein 1 (PD-1) expressed on activated T cells. We investigated the safety and activity of nivolumab in patients with treatment-refractory oesophageal cancer.Methods We did an open-label, single-arm, multicentre phase 2 study. Eligible patients had advanced squamous-cell carcinoma, adenosquamous-cell carcinoma, or adenocarcinoma of the oesophagus refractory or intolerant to fluoropyrimidine-based, platinum-based, and taxane-based chemotherapy. Patients were treated with 3 mg/kg nivolumab given intravenously once every 2 weeks in 6-week cycles. The primary endpoint was centrally assessed objective response (the proportion of patients whose best response was complete or partial response), according to the Response Evaluation Criteria In Solid Tumors, version 1.1. Adverse events and treatment-related adverse events (defined as events for which a causal relation to nivolumab could not be ruled out) were monitored throughout the study. The safety analysis was done in patients who received at least one dose of nivolumab, and drug activity was assessed in patients who received at least one dose of nivolumab and had at least one central assessment of tumour response. This study is registered with clinicaltrials.jp, number ONO-4538-07/JapicCTI-No.142422. Follow-up of patients is ongoing.Findings Between Feb 25 and Nov 14, 2014, 65 patients were enrolled, all with squamous-cell carcinoma. 64 patients were assessable for the primary endpoint as one patient was excluded due to having multiple primary cancers; all patients were assessable for safety. Median follow-up was 10.8 months (IQR 4.9-14.3). 11 (17%, 95% CI 10-28) of 64 patients had a centrally assessed objective response. Of the 65 patients assessed for adverse events, the most common grade 3 or 4 events were grade 4 dyspnoea and hyponatraemia (one [2%) patient each), grade 3 lung infection (five [8%] patients), grade 3 decreased appetite (two [3%] patients), grade 3 increased blood creatinine phosphokinase (two [3%] patients), and grade 3 dehydration (two [3%] patients). Serious adverse events that occurred during the study were lung infection (four [6%] patients), dehydration (two [3%]), interstitial lung disease (two [3%]), and hyponatraemia, dyspnoea, fatigue, abnormal hepatic function, diarrhoea, bile duct stenosis, gastroenteritis, pneumonia, oedema, and back pain (one [2%] patient each). There were no treatment-related deaths.Interpretation Nivolumab showed promising activity with a manageable safety profile. This drug could offer a potential new treatment approach for patients with treatment-refractory advanced squamous-cell carcinoma.