Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
Lancet Oncol. 2019 Nov;20(11):1506-1517. doi: 10.1016/S1470-2045(19)30626-6. Epub 2019 Sep 30.
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.
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 for at least 60 min once per week for 6 weeks then 1 week off; or docetaxel 75 mg/m 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.
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).
Nivolumab was associated with a significant improvement in overall survivaland 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.
ONO Pharmaceutical Company and Bristol-Myers Squibb.
对于晚期食管鳞状细胞癌患者，化疗的长期生存预后不佳。我们报告了先前接受过治疗的晚期食管鳞状细胞癌患者中免疫检查点 PD-1 抑制剂纳武单抗与化疗对比的研究最终分析结果。
我们在丹麦、德国、意大利、日本、韩国、中国台湾、英国和美国的 90 家医院和癌症中心进行了一项多中心、随机、开放性、III 期试验（ATTRACTION-3）。我们招募了年龄在 20 岁及以上、无法切除的晚期或复发性食管鳞状细胞癌患者（无论 PD-L1 表达情况如何），至少有一个根据实体瘤反应评价标准（RECIST）1.1 可测量或不可测量的病变，基线东部肿瘤协作组体力状态为 0-1，对氟嘧啶类和铂类化疗药物不耐受或耐药，预期寿命至少为 3 个月。患者随机（1:1）接受纳武单抗（每 2 周静脉滴注 240mg，持续 30 分钟）或研究者选择的化疗药物（紫杉醇 100mg/m，至少 60 分钟，每周一次，持续 6 周，然后休息 1 周；或多西他赛 75mg/m，至少 60 分钟，每 3 周一次），所有药物均静脉滴注。治疗持续到研究者根据 RECIST 1.1 评估疾病进展或出现不可耐受的毒性。随机分组采用交互式网络应答系统进行，分组大小为 4 组，按地理区域（日本与世界其他地区）、转移器官数量和 PD-L1 表达情况分层。患者和研究者对治疗分配不知情。主要终点是总生存期，定义为随机分组至任何原因死亡的时间，意向治疗人群包括所有随机分组的患者。所有接受至少一剂指定治疗的患者均进行安全性评估。该试验在 ClinicalTrials.gov 注册，编号为 NCT02569242，正在进行长期结局的随访。
2016 年 1 月 7 日至 2017 年 5 月 25 日，我们将 419 名患者分配至治疗组：纳武单抗组 210 例，化疗组 209 例。截至 2018 年 11 月 12 日数据截止时，纳武单抗组的中位总生存期为 10.5 个月（四分位距 4.5-19.0），化疗组为 8.0 个月（4.6-15.2）。在随访时间至少为 17.6 个月的最小随访时间时，纳武单抗组的总生存期明显优于化疗组（中位 10.9 个月，95%CI 9.2-13.3 对比 8.4 个月，7.2-9.9；死亡风险比为 0.77，95%CI 0.62-0.96；p=0.019）。纳武单抗组 209 例患者中有 38 例（18%）发生 3 或 4 级治疗相关不良事件，化疗组 208 例患者中有 131 例（63%）发生该级别的不良事件。最常见的 3 或 4 级治疗相关不良事件是纳武单抗组的贫血（4 例[2%]）和化疗组的中性粒细胞减少（59 例[28%]）。有 5 例死亡被认为与治疗相关：纳武单抗组各有 1 例（分别为间质性肺病和肺炎性），化疗组各有 1 例（分别为肺炎、脊髓脓肿和间质性肺病）。
与化疗相比，先前接受过治疗的晚期食管鳞状细胞癌患者中，纳武单抗与显著的总生存期改善和良好的安全性相关，可能成为这些患者新的二线治疗选择。
小野制药株式会社和百时美施贵宝公司。
