胆管癌的新治疗选择

诸平

Immunotherapies for cancer: The body’s own immune defence is specifically supported or activated to seek out and attack cancer cells. Copyright: medJUNGE

据德国汉诺威医学院 (Hannover Medical School简称MHH，Hanover, Germany)2023年4月17日提供的消息，由该院（MHH）阿恩特·沃格尔（Arndt Vogel）教授参与的一项国际研究表明，免疫疗法（immunotherapy）可提高胆管癌是总体生存率（New treatment option for bile duct cancer）。

上述图示就是癌症免疫疗法：人体自身的免疫防御得到特别支持或激活，以寻找和攻击癌细胞。胆管癌（bile duct cancer）也称为胆道肿瘤（biliary tumours）的新病例在世界范围内不断增加。治愈的机会被认为很差。迄今为止，晚期胆管癌的标准疗法是基于化疗药物吉西他滨（gemcitabine）和顺铂（cisplatin）；用人体自身的免疫防御系统治疗这类癌症已经研究了多年。一个由汉诺威医学院(MHH)的阿恩特·沃格尔参与的国际研究团队，现已能够在KEYNOTE-966 研究中证明，加入免疫检查点抑制剂 pembrolizumab 可提高患者的总体生存率。相关研究结果于2023年4月16日已经在《柳叶刀》（The Lancet）杂志网站发表——Prof Robin Kate Kelley, Makoto Ueno, Prof Changhoon Yoo, Prof Richard S Finn, Prof Junji Furuse, Prof Zhenggang Ren, Thomas Yau, Heinz-Josef Klümpen, Prof Stephen L Chan, Masato Ozaka, Prof Chris Verslype, Mohamed Bouattour, Prof Joon Oh Park, Olga Barajas, Uwe Pelzer, Prof Juan W Valle, Li Yu, Usha Malhotra, Abby B Siegel, Prof Julien Edeline, Prof Arndt Vogel. 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. The Lancet, Published: April 16, 2023 DOI: 10.1016/S0140-6736(23)00727-4. https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(23)00727-4.pdf

该研究的共同通讯作者之一、MHH胃肠病学、肝脏病学、传染病和内分泌学系的阿恩特·沃格尔教授说：“我们的研究表明，胆管癌患者的总体生存率在统计学上有明显改善，安全性可控。Pembrolizumab 加吉西他滨（gemcitabine）和顺铂（cisplatin）代表了一种新的一线治疗方案，适用于既往未经治疗的转移性或不可切除的胆管癌患者。” KEYNOTE-966尤其在白种人患者（Caucasian patients）中显示出疗效，并证实免疫疗法现在将成为胆道肿瘤全身治疗的一个组成部分。KEYNOTE-966 研究是迄今为止针对胆道肿瘤开展的规模最大的全球研究。

KEYNOTE-966三期试验在全球175个医疗中心进行，包括1069名患者。研究参与者被随机分配接受pembrolizumab加吉西他滨和顺铂治疗（pembrolizumab plus gemcitabine and cisplatin）或安慰剂加吉西他滨和顺铂（placebo plus gemcitabine and cisplatin）治疗。这种程序被认为是科学中获得可靠结果的“黄金标准”（"gold standard"）。

该结果于 2023  年 4 月 16 日在美国癌症研究协会 (American Association for Cancer Research简称AACR) 年会上首次公布。

上述介绍，仅供参考。欲了解更多信息，敬请注意浏览原文或者相关报道。

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.