注：本文由小咖机器人翻译整理

期刊来源：Lancet

文献发表时间：2023-04-16

原文链接：https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00727-4/fulltext

内容如下：

总结

背景

发生于肝内或肝外胆管的胆道癌和胆囊，通常预后不良，并且在世界范围内发病率上升。晚期胆道癌的标准治疗方案是化疗。吉西他滨和顺铂。因为大多数胆道癌都有免疫抑制微环境，免疫检查点抑制剂单药治疗与低客观反应率。我们旨在评估是否添加免疫检查点抑制剂与吉西他滨相比，Pembrolizumab联合吉西他滨和顺铂可改善预后。和单用顺铂治疗晚期胆道癌。

方法

KEYNOTE-966是一项随机、双盲、安慰剂对照的3期临床试验在全球175个医疗中心。符合条件的参与者年龄为18岁或以上；既往未经治疗、无法切除、局部晚期或转移性胆道癌症；根据实体瘤版本中的缓解评估标准，HAD疾病可测量1.1;且东部肿瘤协作组绩效状态为0或1。合格参与者被随机（1：1）分配到Pembrolizumab 200 mg组或安慰剂组每3周静脉给药一次（最多35个周期），与吉西他滨（每3周第1天和第8天静脉注射1000mg/m2；无最长持续时间）和顺铂（25每3周第1天和第8天静脉注射mg/m2；最多8个周期）。随机化是使用中央交互式语音应答系统完成，并按地理位置分层区域、疾病阶段和起源位置，块大小为4。主要终点在意向治疗人群中评估总生存率。次要的在接受治疗的人群中评估安全性终点。本研究已注册ClinicalTrials.gov，NCT04003636。

调查结果

在2019年10月4日至2021年6月8日期间，对1564名患者进行了资格筛选。其中1069名患者被随机分配接受pembrolizumab联合吉西他滨和顺铂治疗（Pembrolizumab组；n=533）或安慰剂加吉西他滨和顺铂（安慰剂组；n=536）。最终分析的中位研究随访时间为25.6个月（IQR 21.7–30.4）。Pembrolizumab组的中位总生存期为12.7个月（95%CI 11.5–13.6）安慰剂组为10.9个月（9.9–11.6）（风险比0.83[95%CI 0.72–0.95]；单侧P=0.0034[显著性阈值，P=0.0200]）。在治疗人群中，的529名参与者中有420名（79%）的最大不良事件等级为3至4级。Pembrolizumab组和400（75%）的534在安慰剂组；369名（70%）参与者在pembrolizumab组和安慰剂组中，有367例（69%）与治疗相关31名（6%）Pembrolizumab受试者出现最大级别为3至4级的不良事件安慰剂组有49例（9%）因不良事件死亡，其中8例Pembrolizumab组有3例（2%）死亡，安慰剂组有3例（1%）死亡治疗相关不良事件。

解释

基于总体上有统计学意义的、有临床意义的改善生存率与吉西他滨和顺铂相比，没有任何新的安全性信号，pembrolizumab加吉西他滨和顺铂可能是一种新的治疗选择未经治疗的转移性或无法切除的胆道癌。

资助

美国新泽西州拉威市默克公司的子公司默沙东公司。

英文原文内容如下：

Summary

Background

Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer.

Methods

KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636.

Findings

Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7–30·4). Median overall survival was 12·7 months (95% CI 11·5–13·6) in the pembrolizumab group versus 10·9 months (9·9–11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72–0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events.

Interpretation

Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer.

Funding

Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.