Background

First-line therapy for advanced oesophageal cancer is currently limited to fluoropyrimidine plus platinum-based chemotherapy. We aimed to evaluate the antitumour activity of pembrolizumab plus chemotherapy versus chemotherapy alone as first-line treatment in advanced oesophageal cancer and Siewert type 1 gastro-oesophageal junction cancer.

Methods

We did a randomised, placebo-controlled, double-blind, phase 3 study across 168 medical centres in 26 countries. Patients aged 18 years or older with previously untreated, histologically or cytologically confirmed, locally advanced, unresectable or metastatic oesophageal cancer or Siewert type 1 gastro-oesophageal junction cancer (regardless of PD-L1 status), measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, and Eastern Cooperative Oncology Group performance status of 0–1, were randomly assigned (1:1) to intravenous pembrolizumab 200 mg or placebo, plus 5-fluorouracil and cisplatin (chemotherapy), once every 3 weeks for up to 35 cycles. Randomisation was stratified by geographical region, histology, and performance status. Patients, investigators, and site staff were masked to group assignment and PD-L1 biomarker status. Primary endpoints were overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 combined positive score (CPS) of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients. This trial is registered with ClinicalTrials.gov, NCT03189719, and is closed to recruitment.

Findings

Between July 25, 2017, and June 3, 2019, 1020 patients were screened and 749 were enrolled and randomly assigned to pembrolizumab plus chemotherapy (n=373 [50%]) or placebo plus chemotherapy (n=376 [50%]). At the first interim analysis (median follow-up of 22·6 months), pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more (median 13·9 months vs 8·8 months; hazard ratio 0·57 [95% CI 0·43–0·75]; p<0·0001), oesophageal squamous cell carcinoma (12·6 months vs 9·8 months; 0·72 [0·60–0·88]; p=0·0006), PD-L1 CPS of 10 or more (13·5 months vs 9·4 months; 0·62 [0·49–0·78]; p<0·0001), and in all randomised patients (12·4 months vs 9·8 months; 0·73 [0·62–0·86]; p<0·0001). Pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for progression-free survival in patients with oesophageal squamous cell carcinoma (6·3 months vs 5·8 months; 0·65 [0·54–0·78]; p<0·0001), PD-L1 CPS of 10 or more (7·5 months vs 5·5 months; 0·51 [0·41–0·65]; p<0·0001), and in all randomised patients (6·3 months vs 5·8 months; 0·65 [0·55–0·76]; p<0·0001). Treatment-related adverse events of grade 3 or higher occurred in 266 (72%) patients in the pembrolizumab plus chemotherapy group versus 250 (68%) in the placebo plus chemotherapy group.

Interpretation

Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved overall survival in patients with previously untreated, advanced oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients regardless of histology, and had a manageable safety profile in the total as-treated population.

Funding

Merck Sharp & Dohme.

中文翻译：

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帕博利珠单抗联合化疗对比单独化疗用于晚期食管癌的一线治疗 (KEYNOTE-590)：一项随机、安慰剂对照、3 期研究

背景

晚期食管癌的一线治疗目前仅限于氟嘧啶加铂类化疗。我们旨在评估派姆单抗联合化疗与单独化疗作为晚期食管癌和 Siewert 1 型胃食管交界处癌一线治疗的抗肿瘤活性。

方法

我们在 26 个国家的 168 个医疗中心进行了一项随机、安慰剂对照、双盲、3 期研究。年龄在 18 岁或以上的先前未经治疗、经组织学或细胞学证实、局部晚期、不可切除或转移性食管癌或 Siewert 1 型胃食管结合部癌（无论 PD-L1 状态如何）、根据实体瘤反应评估标准可测量的疾病的患者1.1 版，东部肿瘤协作组体能状态为 0-1，被随机分配 (1:1) 静脉注射派姆单抗 200 mg 或安慰剂，加 5-氟尿嘧啶和顺铂（化疗），每 3 周一次，最多 35 个周期. 随机化按地理区域、组织学和体能状态分层。患者、研究者、和现场工作人员不了解分组分配和 PD-L1 生物标志物状态。主要终点是食管鳞癌患者的总生存期和 PD-L1 联合阳性评分 (CPS) 为 10 或更高，以及食管鳞癌患者的总生存期和无进展生存期，PD-L1 CPS 为 10 或以上更多，并且在所有随机患者中。该试验已在 ClinicalTrials.gov 注册，NCT03189719，现已停止招募。

发现

2017 年 7 月 25 日至 2019 年 6 月 3 日期间，对 1020 名患者进行了筛查，其中 749 名患者被随机分配到派姆单抗加化疗组（n=373 [50%]）或安慰剂加化疗组（n=376 [50%]）。在第一次中期分析（中位随访 22·6 个月）中，对于 PD-L1 CPS 为 10 或更高（中位 13·9个月vs 8·8 个月；风险比 0·57 [95% CI 0·43–0·75]；p<0·0001），食管鳞状细胞癌（12·6 个月vs 9·8 个月；0·72 [0·60–0·88]；p=0·0006)，PD-L1 CPS 为 10 或更多（13·5 个月vs 9·4 个月；0·62 [0·49-0·78]；p <0·0001)，并且在所有随机化患者中（12·4 个月对比9·8个月；0·73 [0·62–0·86]；p<0·0001)。在食管鳞状细胞癌患者的无进展生存期方面，派姆单抗加化疗优于安慰剂加化疗（6·3 个月vs 5·8 个月；0·65 [0·54–0·78]；p<0·0001 )，PD-L1 CPS 为 10 或更多（7·5 个月vs 5·5 个月；0·51 [0·41–0·65]；p<0·0001），并且在所有随机化患者中 (6·3月vs 5·8 个月；0·65 [0·55–0·76]；p<0·0001)。派姆单抗加化疗组 266 名（72%）患者发生 3 级或更高级别的治疗相关不良事件，而安慰剂加化疗组为 250 名（68%）。

解释

与安慰剂加化疗相比，帕博利珠单抗加化疗提高了既往未治疗晚期食管鳞癌患者 PD-L1 CPS ≥10 的总生存期，以及食管鳞癌 PD 患者的总生存期和无进展生存期-L1 CPS 为 10 或更多，并且在所有随机化患者中，无论组织学如何，并且在总治疗人群中具有可控的安全性。

资金

默克夏普和 Dohme。