德国汉诺威医学院Arndt Vogel团队研究了派姆单抗联合吉西他滨和顺铂与单独使用吉西他滨和顺铂相比，治疗晚期胆道癌的疗效与安全性。2023年4月16日出版的《柳叶刀》杂志发表了这项成果。

胆管癌起源于肝内或肝外胆管和胆囊，通常预后不佳，在世界范围内发病率正在上升。晚期胆道癌症的标准治疗方法是吉西他滨和顺铂联合化疗。由于大多数胆道癌都有免疫抑制的微环境，免疫检查点抑制剂单药治疗与低客观缓解率有关。该研究旨在评估在吉西他滨和顺铂中添加免疫检查点抑制剂派姆单抗，与吉西他滨和顺铂单独使用相比，是否会改善晚期胆道癌症患者的预后。

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个医疗中心进行。符合条件的参与者年龄在18岁及以上；曾患有未经治疗、无法切除、局部晚期或转移性胆道癌症；根据实体瘤1.1版的缓解评估标准可衡量疾病；并且具有0或1的东部合作肿瘤组性能状态。符合条件的参与者被随机分配（1:1）服用200 mg派姆单抗或安慰剂，两种药物每3周静脉注射一次（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1000 mg/m²；无最长持续时间）和顺铂（每3周第1天、第8天，静脉注射25 mg/m²；最多8个周期）联合使用。使用中央交互式语音应答系统进行随机分组，并按地理区域、疾病分期和起源地以四个区块的大小进行分层。在意向治疗人群中评估总生存率的主要终点。在接受治疗的人群中评估安全性的次要终点。

2019年10月4日至2021年6月8日，研究组对1564名患者进行了资格筛选，其中1069名被随机分为派姆单抗联合吉西他滨和顺铂组（派姆单抗组；n=533）或安慰剂联合吉西他滨和顺铂组（安慰剂组；n=536）。最终分析时的中位研究随访时间为25.6个月。派姆单抗组的中位总生存期为12.7个月，安慰剂组为10.9个月，危险比为0.83。

在接受治疗的人群中，派姆单抗组529名参与者中的420名（79%）和安慰剂组534名中的400名（75%）患者最大不良事件等级为3-4级；派姆单抗组369名（70%）参与者和安慰剂组367名（69%）参与者出现了最高级别为3至4级的治疗相关不良事件。派姆单抗组有31名（6%）参与者和安慰剂组有49名（9%）参与者死于不良事件，其中派姆单抗组中有8名（2%）、安慰剂组中有3名（1%）参与者死于治疗相关不良事件。

研究结果表明，与吉西他滨和顺铂相比，在没有任何新的安全性信号的情况下，总生存率有统计学意义和临床意义的改善，因此，派姆单抗联合吉西他宾和顺铂可能是先前未经治疗的转移性或无法切除的胆道癌症患者的一种新的治疗选择。

附：英文原文

Title: Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial

Author: Robin Kate Kelley, Makoto Ueno, Changhoon Yoo, Richard S Finn, Junji Furuse, Zhenggang Ren, Thomas Yau, Heinz-Josef Klümpen, Stephen L Chan, Masato Ozaka, Chris Verslype, Mohamed Bouattour, Joon Oh Park, Olga Barajas, Uwe Pelzer, Juan W Valle, Li Yu, Usha Malhotra, Abby B Siegel, Julien Edeline, Arndt Vogel, Mehmet Akce, Immaculada Ales Diaz, Gustavo Alves, Sumitra Anand, Cagatay Arslan, Jamil Asselah, Eric Assenat, Francine Aubin, Li-Yuan Bai, Yuxian Bai, Olga Barajas, Susan Bates, Stephen Begbie, Irit Ben-Aharon, Nina Beri, Marie-Luise Berres, Jean-Frederic Blanc, Ivan Borbath, Robert Bordonaro, Mohamed Bouattour, Giovanni Brandi, Adam Burgoyne, Kritiya Butthongkomvong, Ke Cao, Marcela Carballido, Marcos Camandaroba, Stephan Lam Chang, Jen-Shi Chen, Ming-Huang Chen, Xiaoming Chen, Ashley Cheng, Tai-Jan Chiu, Hye Jin Choi, Hong Jae Chon, Joelle Collignon, Antonio Cubillo Gracian, Sarah Davis, Ricardo Saraiva de Carvalho, D.J.A. de Groot, Anne Demols, Judith De Vos, Maria Diab, Jacob Easaw, Martin Eatock, Julien Edeline, Rawad Elias, Fredericus Eskens, Alfredo Falcone, Plinio Fernandez, Richard Finn, Fabio Franke, Masayuki Furukawa, Junji Furuse, Olumide Gbolahan, Karen Geboes, Keri-Lee Geneser, Zhimin Geng, Ravit Geva, Roopinder Gillmore, Thorsten Goetze, Hongfeng Gou, Julieta Grasselli, Shanzhi Gu, Mahmut Gumus, Nadia Haj Mohammad, Chunyi Hao, Hakan Harputluoglu, Hassan Hatoum, Volker Heinemann, Wang Kwong Ho, Chiun Hsu, Ayala Hubert, Juneul Hwang, Mevlude Inanc, Soledad Iseas, Vaishnavi Jeyasingam, Paula Jimenez Fonseca, Warren Joubert, Jitlada Juengsamarn, Diego Kaen, Masahi Kanai, Stefan Kasper-Virchow, Ghazaleh Kazemi, Fergal Kelleher, Robin Kelley, Jin Won Kim, Jong Gwang Kim, Ana Beatriz Kinupe Abrahao, Heinz Klumpen, Mark Kochenderfer, Fatih Kose, Ho Ching Lam, Choong-kun Lee, Hyun Woo Lee, Margaret Lee, Myung Ah Lee, Wai Man Sarah Lee, Samuel Le Sourd, Dongliang Li, Wei Li, Houjie Liang, Tingbo Liang, Chun Sen Lim, Brian Lingerfelt, Charles Lopez, John Low, Teresa Macarulla Mercade

Issue&Volume: 2023-04-16

Abstract: 

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.

DOI: 10.1016/S0140-6736(23)00727-4

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