The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China.
The First Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China.
JAMA. 2023 Dec 5;330(21):2064-2074. doi: 10.1001/jama.2023.19918.
Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy.
To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100).
DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021.
Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years.
The primary end point was overall survival time from randomization.
Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%).
Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo.
ClinicalTrials.gov Identifier: NCT03745170.
全球每年有超过 100 万人被诊断出患有不可切除的局部晚期或转移性胃或胃食管交界处癌，而有效的治疗方法却寥寥无几。Sintilimab 是一种与人程序性死亡受体 1（PD-1）结合的重组人 IgG4 单克隆抗体，联合化疗，显示出了有前景的疗效。
比较不可切除的局部晚期或转移性胃或胃食管交界处腺癌患者接受 sintilimab 联合化疗与安慰剂联合化疗的总生存期。同时还比较了 PD 配体 1（PD-L1）联合阳性评分（CPS）为 5 或更高（范围，1-100）的患者亚组。
设计、地点和参与者：在中国 62 家医院进行的随机、双盲、安慰剂对照、III 期临床试验，纳入了 2019 年 1 月 3 日至 2020 年 8 月 5 日期间不可切除的局部晚期或转移性胃或胃食管交界处腺癌患者 650 例。最终随访时间为 2021 年 6 月 20 日。
患者按 1:1 随机分为 sintilimab（n = 327）或安慰剂（n = 323）联合卡培他滨和奥沙利铂（XELOX 方案）每 3 周一次，最多 6 个周期。接受 sintilimab 或安慰剂联合卡培他滨的维持治疗，持续最多 2 年。
主要终点是从随机分组到总生存时间。
在 650 例患者中（平均年龄 59 岁；483 [74.3%] 例男性），327 例随机分配至 sintilimab 联合化疗组，323 例随机分配至安慰剂联合化疗组。在随机分组的患者中，397 例（61.1%）肿瘤的 PD-L1 CPS 为 5 或更高；563 例（86.6%）停止了研究治疗，388 例（59.7%）死亡；1 例（<0.1%）失访。在所有随机患者中，sintilimab 与安慰剂相比，改善了总生存期（中位数，15.2 与 12.3 个月；分层风险比 [HR]，0.77 [95%CI，0.63-0.94]；P = .009）。在 CPS 为 5 或更高的患者中，sintilimab 与安慰剂相比，改善了总生存期（中位数，18.4 与 12.9 个月；HR，0.66 [95%CI，0.50-0.86]；P = .002）。最常见的 3 级或更高级别的治疗相关不良事件是血小板计数降低（sintilimab，24.7%比安慰剂，21.3%），中性粒细胞计数降低（sintilimab，20.1%比安慰剂，18.8%）和贫血（sintilimab，12.5%比安慰剂，8.8%）。
在接受一线化疗的不可切除的局部晚期或转移性胃和胃食管交界处腺癌患者中，sintilimab 与安慰剂相比，显著改善了所有患者以及 CPS 为 5 或更高的患者的总生存期。
ClinicalTrials.gov 标识符：NCT03745170。
