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Background: First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone. 晚期或转移性人表皮生长因子受体 2 (HER2) 阴性胃或胃食管交界处腺癌的一线化疗的中位总生存期 (OS) 不到 1 年。我们旨在评估基于程序性细胞死亡 (PD)-1 抑制剂的一线治疗在胃癌、胃食管交界处和食管腺癌中的疗效。我们报告了纳武利尤单抗加化疗与单独化疗的第一个结果。Methods: In this multicentre, randomised, open-label, phase 3 trial (CheckMate 649), we enrolled adults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression from 175 hospitals and cancer centres in 29 countries. Patients were randomly assigned (1:1:1 while all three groups were open) via interactive web response technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more. Safety was assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT02872116. 这项多中心、随机、开放标签、3 期试验 (CheckMate 649) 中，我们招募了既往未经治疗、不可切除、非 HER2 阳性胃癌、胃食管交界处或食管腺癌的成人（≥18 岁），无论来自 29 个国家的 175 家医院和癌症中心的 PD-配体 1 (PD-L1) 表达。患者通过交互式网络响应技术（6 个块大小）被随机分配（1:1:1，而所有三组均开放）接受纳武单抗（每 3 周 360 毫克或每 2 周 240 毫克）加化疗（卡培他滨和奥沙利铂每3 周或亚叶酸、氟尿嘧啶和奥沙利铂每 2 周），纳武单抗加易普利姆玛，或单独化疗。纳武利尤单抗加化疗与单独化疗的主要终点是通过盲法独立中央审查的 OS 或无进展生存期 (PFS)，在 PD-L1 联合阳性评分 (CPS) 为 5 或以上的患者中。在接受至少一剂指定治疗的所有患者中评估安全性。该研究已在 ClinicalTrials.gov 注册，NCT02872116。Findings: From March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7-19·1) for nivolumab plus chemotherapy and 11·1 months (5·8-16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59-0·86]; p<0·0001) and PFS (HR 0·68 [98 % CI 0·56-0·81]; p<0·0001) versus chemotherapy alone in patients with a PD-L1 CPS of five or more (minimum follow-up 12·1 months). Additional results showed significant improvement in OS, along with PFS benefit, in patients with a PD-L1 CPS of one or more and all randomly assigned patients. Among all treated patients, 462 (59%) of 782 patients in the nivolumab plus chemotherapy group and 341 (44%) of 767 patients in the chemotherapy alone group had grade 3-4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥25%) were nausea, diarrhoea, and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-related. No new safety signals were identified. 从 2017 年 3 月 27 日到 2019 年 4 月 24 日，在评估合格的 2687 名患者中，我们同时将 1581 名患者随机分配接受治疗（纳武单抗联合化疗 [n=789, 50%] 或单独化疗 [n=792, 50%] ）。纳武利尤单抗加化疗的中位 OS 随访时间为 13·1 个月 (IQR 6·7-19·1)，单独化疗的中位随访时间为 11·1 个月 (5·8-16·1)。纳武利尤单抗加化疗显着改善了 OS（风险比 [HR] 0·71 [98·4% CI 0·59-0·86]；p<0·0001）和 PFS（HR 0·68 [98 % CI 0·56-0·81]；p<0·0001) 与单独化疗相比，PD-L1 CPS ≥ 5 的患者（最短随访时间 12·1 个月）。其他结果显示，在一名或多名 PD-L1 CPS 患者以及所有随机分配的患者中，OS 显着改善，同时 PFS 获益。在所有接受治疗的患者中，纳武利尤单抗联合化疗组 782 名患者中的 462 名（59%）和单独化疗组 767 名患者中的 341 名（44%）出现 3-4 级治疗相关不良事件。两组最常见的任何级别的治疗相关不良事件（≥25%）是恶心、腹泻和周围神经病变。纳武利尤单抗联合化疗组中的 16 例（2%）死亡和单独化疗组中的 4 例（1%）死亡被认为与治疗相关。没有发现新的安全信号。纳武利尤单抗联合化疗组中的 16 例（2%）死亡和单独化疗组中的 4 例（1%）死亡被认为与治疗相关。没有发现新的安全信号。纳武利尤单抗联合化疗组中的 16 例（2%）死亡和单独化疗组中的 4 例（1%）死亡被认为与治疗相关。没有发现新的安全信号。Interpretation: Nivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients. Nivolumab 是第一个在既往未经治疗的晚期胃癌、胃食管交界处或食管腺癌患者中显示出优越 OS、PFS 益处和可接受的安全性特征的 PD-1 抑制剂，联合化疗与单独化疗相比。纳武利尤单抗加化疗代表了这些患者的新标准一线治疗。
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