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. 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/m intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m 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 , . 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. 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. Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

中文翻译：

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派姆单抗联合吉西他滨和顺铂与单用吉西他滨和顺铂治疗晚期胆道癌患者的比较 (KEYNOTE-966)：一项随机、双盲、安慰剂对照 3 期试验

胆道癌起源于肝内或肝外胆管和胆囊，通常预后不良，并且在全球范围内发病率不断上升。晚期胆道癌的标准治疗方法是吉西他滨和顺铂化疗。由于大多数胆道癌具有免疫抑制的微环境，因此免疫检查点抑制剂单一疗法的客观缓解率较低。我们的目的是评估在晚期胆道癌患者中，与单独使用吉西他滨和顺铂相比，在吉西他滨和顺铂中添加免疫检查点抑制剂派姆单抗是否会改善预后。 KEYNOTE-966 是一项在全球 175 个医疗中心进行的随机、双盲、安慰剂对照 3 期试验。符合资格的参与者年龄为 18 岁或以上；既往患有未经治疗、不可切除、局部晚期或转移性胆道癌；根据实体瘤反应评估标准 1.1 版，患有可测量的疾病；东部肿瘤合作组表现状态为 0 或 1。符合条件的参与者被随机分配 (1:1) 接受派姆单抗 200 mg 或安慰剂，两者均每 3 周静脉注射一次（最多 35 个周期），并与吉西他滨（1000 mg）联合用药/m，每 3 周第 1 和第 8 天静脉注射；无最长持续时间）和顺铂（每 3 周第 1 和第 8 天静脉注射 25 mg/m；最多 8 个周期）。随机化是使用中央交互式语音应答系统进行的，并按地理区域、疾病阶段和起源部位进行分层，以四块大小为单位。在意向治疗人群中评估了总体生存的主要终点。在接受治疗的人群中评估了次要安全终点。这项研究注册于，。 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查，其中1069名患者被随机分配至派姆单抗加吉西他滨和顺铂（派姆单抗组；n=533）或安慰剂加吉西他滨和顺铂（安慰剂组；n=533）。 =536）。最终分析的中位研究随访时间为 25·6 个月 (IQR 21·7–30·4)。派姆单抗组的中位总生存期为 12·7 个月 (95% CI 11·5–13·6)，而安慰剂组为 10·9 个月 (9·9–11·6)（风险比 0·83 [95] % CI 0·72–0·95]；单侧 p=0·0034 [显着性阈值，p=0·0200]）。在接受治疗的人群中，派姆单抗组 529 名参与者中的 420 名参与者（79%）和安慰剂组 534 名参与者中的 400 名参与者（75%）最大不良事件等级为 3 至 4 级；派姆单抗组中有 369 名 (70%) 名参与者和安慰剂组中有 367 名 (69%) 名参与者出现了治疗相关不良事件，最高等级为 3 至 4 级。 派姆单抗组中有 31 名 (6%) 名参与者和 49 名 (9%) 名参与者发生了与治疗相关的不良事件。安慰剂组中的 1 名患者因不良事件死亡，其中派姆单抗组中有 8 名患者 (2%) ，安慰剂组中有 3 名患者 (1%) 因治疗相关不良事件死亡。与吉西他滨和顺铂相比，在没有任何新的安全信号的情况下，帕博利珠单抗联合吉西他滨和顺铂在总生存期方面取得了统计学上显着的、有临床意义的改善，因此可能成为先前未经治疗的转移性或不可切除的胆道癌患者的新治疗选择。 Merck Sharp & Dohme 是 Merck & Co 的子公司，位于美国新泽西州拉威。