Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial
Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial
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DOI：
10.1016/s1470-2045(19)30626-6
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发表时间：
2019-11-01
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：
Kato, Ken;Cho, Byoung Chul;Kitagawa, Yuko
背景晚期食管鳞状细胞癌患者的化疗提供了较差的长期生存前景。我们报告了免疫检查点PD-1抑制剂纳武利尤单抗与化疗在既往接受过治疗的晚期食管鳞状细胞癌患者中的研究的最终分析。方法我们在90家医院和癌症中心进行了一项多中心、随机、开放标签、3期试验（ATTRACTION-3）丹麦、德国、意大利、日本、韩国、台湾、英国和美国。我们招募了年龄在20岁及以上的晚期或复发性食管鳞状细胞癌患者（不考虑PD-L1表达），根据实体瘤疗效评价标准（RECIST）第1.1版至少有一处可测量或不可测量病灶，基线东部肿瘤协作组体力状态为0-1，并且对先前的基于氟嘧啶和基于铂的化疗难治或不耐受，并且预期寿命至少为3个月。患者被随机分配（1：1）接受nivolumab（240 mg，每2周一次，持续30分钟）或研究者选择的化疗（紫杉醇100 mg/m2，每周至少60分钟，持续6周，然后停药1周;或多西他赛75 mg/m2，每3周一次，持续至少60分钟），均静脉给药。治疗持续至研究者根据RECIST 1.1版评估的疾病进展或不可接受的毒性。使用交互式网络应答系统进行随机化，区组大小为4，并根据地理区域（日本vs世界其他地区）、转移器官数量和PD-L1表达进行分层。患者和研究者对治疗分配不设盲。主要终点是总生存期，定义为在包括所有随机分配患者的意向治疗人群中，从随机化至任何原因导致死亡的时间。在接受至少一剂指定治疗的所有患者中评估安全性。该试验在ClinicalTrials.gov注册，编号NCT 02569242，长期结果的随访正在进行中。结果在2016年1月7日至2017年5月25日期间，我们将419名患者分配到治疗组：210名接受nivolumab治疗，209名接受化疗。在2018年11月12日数据截止时，nivolumab组的总生存期中位随访时间为10.5个月（IQR 4.5-19.0），化疗组为8.0个月（4.6-15.2）。最短随访时间（即从最后一名患者随机分配到数据截止的时间）为17.6个月，与化疗组相比，纳武利尤单抗组的总生存期显著改善（中位10.9个月，95% CI 9.2-13.3 vs 8.4个月，7.2-9.9;死亡风险比0.77，95% CI 0.62-0.96; p=0.019）。纳武利尤单抗组209例患者中有38例（18%）发生了3级或4级治疗相关不良事件，而化疗组208例患者中有131例（63%）。最常见的3级或4级治疗相关不良事件是纳武利尤单抗组的贫血（4例[2%]）和化疗组的中性粒细胞计数降低（59例[28%]）。5例死亡被认为与给药相关：纳武利尤单抗组中的两个（间质性肺病和肺炎各1例），化疗组3例（肺炎、脊髓脓肿和间质性肺病各一种）。解释与先前治疗的晚期食管鳞状细胞癌患者中的化疗相比，纳武单抗与总生存期的显著改善和有利的安全性特征相关，并且可能代表这些患者的新的标准二线治疗选择。
Background Chemotherapy for patients with advanced oesophageal squamous cell carcinoma offers poor long-term survival prospects. We report the final analysis from our study of the immune checkpoint PD-1 inhibitor nivolumab versus chemotherapy in patients with previously treated advanced oesophageal squamous cell carcinoma.Methods We did a multicentre, randomised, open-label, phase 3 trial (ATTRACTION-3) at 90 hospitals and cancer centres in Denmark, Germany, Italy, Japan, South Korea, Taiwan, the UK, and the USA. We enrolled patients aged 20 years and older with unresectable advanced or recurrent oesophageal squamous cell carcinoma (regardless of PD-L1 expression), at least one measurable or non-measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a baseline Eastern Cooperative Oncology Group performance status of 0-1, and who were refractory or intolerant to one previous fluoropyrimidine-based and platinum-based chemotherapy and had a life expectancy of at least 3 months. Patients were randomly assigned (1:1) to either nivolumab (240 mg for 30 min every 2 weeks) or investigator's choice of chemotherapy (paclitaxel 100 mg/m(2) for at least 60 min once per week for 6 weeks then 1 week off; or docetaxel 75 mg/m(2) for at least 60 min every 3 weeks), all given intravenously. Treatment continued until disease progression assessed by the investigator per RECIST version 1.1 or unacceptable toxicity. Randomisation was done using an interactive web response system with a block size of four and stratified according to geographical region (Japan vs rest of the world), number of organs with metastases, and PD-L1 expression. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival, defined as the time from randomisation until death from any cause, in the intention-to-treat population that included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT02569242, and follow-up for long-term outcomes is ongoing.Findings Between Jan 7, 2016, and May 25, 2017, we assigned 419 patients to treatment: 210 to nivolumab and 209 to chemotherapy. At the time of data cutoff on Nov 12, 2018, median follow-up for overall survival was 10.5 months (IQR 4.5-19.0) in the nivolumab group and 8.0 months (4.6-15.2) in the chemotherapy group. At a minimum follow-up time (ie, time from random assignment of the last patient to data cutoff) of 17.6 months, overall survival was significantly improved in the nivolumab group compared with the chemotherapy group (median 10.9 months, 95% CI 9.2-13.3 vs 8.4 months, 7.2-9.9; hazard ratio for death 0.77, 95% CI 0.62-0.96; p=0.019). 38 (18%) of 209 patients in the nivolumab group had grade 3 or 4 treatment-related adverse events compared with 131 (63%) of 208 patients in the chemotherapy group. The most frequent grade 3 or 4 treatment-related adverse events were anaemia ( four [2%]) in the nivolumab group and decreased neutrophil count (59 [28%]) in the chemotherapy group. Five deaths were deemed treatment-related: two in the nivolumab group (one each of interstitial lung disease and pneumonitis) and three in the chemotherapy group (one each of pneumonia, spinal cord abscess, and interstitial lung disease).Interpretation Nivolumab was associated with a significant improvement in overall survival and a favourable safety profile compared with chemotherapy in previously treated patients with advanced oesophageal squamous cell carcinoma, and might represent a new standard second-line treatment option for these patients.