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.

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.

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.

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.

Funding

Bristol Myers Squibb, in collaboration with Ono Pharmaceutical.

中文翻译：

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一线纳武单抗联合化疗与单独化疗治疗晚期胃、胃食管交界处和食管腺癌的比较 (CheckMate 649)：一项随机、开放标签 3 期试验

 背景

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腺癌的一线化疗的中位总生存期 (OS) 不到 1 年。我们的目的是评估基于程序性细胞死亡 (PD)-1 抑制剂的胃、胃食管交界处和食管腺癌的一线疗法。我们报告了纳武单抗联合化疗与单独化疗的初步结果。

 方法

在这项多中心、随机、开放标签 3 期试验 (CheckMate 649) 中，我们招募了患有既往未经治疗、不可切除、非 HER2 阳性胃癌、胃食管交界处或食管腺癌的成年人（≥18 岁），无论其是否患有PD-配体 1 (PD-L1) 的表达来自 29 个国家的 175 家医院和癌症中心。通过交互式网络响应技术（块大小为 6 个）将患者随机分配（1:1:1，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（每组卡培他滨和奥沙利铂） 3 周或每 2 周一次甲酰四氢叶酸、氟尿嘧啶和奥沙利铂）、纳武单抗加伊匹单抗或单独化疗。纳武单抗联合化疗与单独化疗的主要终点是通过盲法独立中心审查得出的 OS 或无进展生存期 (PFS)，对象是肿瘤 PD-L1 综合阳性评分 (CPS) 为 5 或以上的患者。对接受至少一剂指定治疗的所有患者进行安全性评估。本研究已在 ClinicalTrials.gov 注册，NCT02872116。

 发现

从 2017 年 3 月 27 日到 2019 年 4 月 24 日，在评估资格的 2687 名患者中，我们同时随机分配 1581 名患者接受治疗（纳武单抗加化疗 [n=789, 50%] 或单独化疗 [n=792, 50%] ）。纳武单抗联合化疗的中位 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)。纳武单抗联合化疗可显着改善 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 PD-L1 CPS 为 5 或以上的患者相比单独化疗（最短随访 12·1 个月）。其他结果显示，一名或多名患有 PD-L1 CPS 的患者以及所有随机分配的患者的 OS 显着改善，并且 PFS 受益。在所有接受治疗的患者中，纳武单抗加化疗组的 782 名患者中有 462 名患者（59%）和单纯化疗组的 767 名患者中有 341 名患者（44%）出现 3-4 级治疗相关不良事件。两组中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。纳武单抗加化疗组中有 16 例 (2%) 死亡，单独化疗组中有 4 例 (1%) 死亡被认为与治疗相关。没有发现新的安全信号。

 解释

Nivolumab 是第一个 PD-1 抑制剂，与化疗相结合，与单独化疗相比，在先前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异的 OS、PFS 益处和可接受的安全性。纳武单抗联合化疗代表了这些患者的新标准一线治疗。

 资金

百时美施贵宝与小野制药合作。