引言
胆道恶性肿瘤（biliary tract cancer，BTC）是一种起源于胆道上皮细胞、具有高度侵袭性的恶性肿瘤。根据解剖学来源，BTC 可分为肝内胆管上皮细胞来源的肝内胆管癌、胆囊上皮细胞来源的胆囊癌以及肝外胆管上皮细胞来源的肝外胆管癌。早期 BTC 患者可以通过根治性手术治愈，然而大多数 BTC 患者在就诊时已处于晚期，不仅失去了根治性手术的机会，同时治疗效果和预后极差。
According to anatomical sources, BTC can be divided into liver ovarian cancer from the source of cerebral cells in the liver, cyborg cancer from the source of cyst cells in the gall bladder, and hepatoctic cerebral cancer from the source of the cerebral cells in the liver. Early BTC patients can be cured by root surgery, but most BTC patients are late in treatment, losing not only the opportunity for cerebral surgery, but also very poor treatment and prognosis.
化疗是晚期不可切除 BTC 患者的标准一线治疗手段，但疗效有限，进展后仍缺乏后续的标准化治疗选择，迫切需要寻求新的更有效的治疗策略。近年来，免疫检查点抑制剂（Immune checkpoint inhibitors，ICI）在恶性肿瘤治疗领域取得了显著的突破性进展。国内外研究者也积极进行以 TOPAZ-1 研究和 KEYNOTE-966 研究为代表的多种免疫联合治疗相关的临床试验[1,2]，这些研究显示出免疫治疗的初步疗效，有望为未来针对晚期不可切除 BTC 患者一线、二线治疗策略提供指导与参考依据。
In recent years, Immunene checkpoint inhibitors (ICI) have made remarkable breakthroughs in the field of treatment for malignant tumours. National and international researchers have also been active in conducting clinical trials [1,2]/supp> related to multi-immunotherapy combined treatments, as represented by the TOPAZ-1 study and KEYNOTE-966 studies, which have shown the initial effects of immunotherapy treatment and are expected to provide guidance and a frame of reference for future one- or two-line treatment strategies for BTC patients that cannot be removed at a later stage.
作为全球最负盛名的肿瘤学术会议之一，2024 年美国临床肿瘤学会（ASCO）年会于美国东部时间 5 月 31 日~ 6 月 4 日在芝加哥盛大召开。当地时间 5 月 23 日下午 5 点，ASCO 官网公布其部分摘要内容。
As one of the world’s most famous academic meetings on oncology, the annual meeting of the American Society of Clinical Oncology (ASCO) in 2024 was held in Chicago on May 31–June 4 East Time in the United States. Local time on May 23rd, at 5 p.m., the ASCO Network published part of its summary.
「丁香园肿瘤时间」特整理晚期 BTC 新疗法探索领域的两项研究内容，其中一项为阿替利珠单抗和 varlilumab（CDX-1127）联合或不联合 cobimetinib 用于既往接受过治疗的不可切除 BTC 的随机 II 期研究，另一项为 sitravatinib 联合替雷利珠单抗治疗既往至少 1 种系统治疗失败的晚期 BTC 的 II 期研究[3,4]。
Two studies in the field of new treatment exploration for the "Tincongrete Tumour Time" have been organized specifically for the late-stage BTC, one for the combined or non-combined use of the cobimetinib for the non-cutting BTC that has been treated in the past, and the other for the late-stage BTC II study for the joint sitravatinib for the unsuccessful treatment of at least one system that has failed in the past BTC.[3,4] .
摘要号：4017
标题：A randomized phase 2 study of combination atezolizumab and varlilumab (CDX-1127) with or without addition of cobimetinib in previously treated unresectable biliary tract cancer
Arandomised phrase 2 study of communication atezolozumab and vallilumab (CDX-1127) with or without analysis of cobimetinib in precious treatyable treaty practice possible
阿替利珠单抗和 varlilumab（CDX-1127）联合或不联合 cobimetinib 用于既往接受过治疗的不可切除 BTC 的随机 II 期研究
Random II study for the non-cutting of BTCs that have been treated in the past by the Cobimetinib
讲者：美国范德比尔特-英格拉姆癌症中心 Thatcher Ross Heumann
Speaker at
背景
Background
针对既往经历过一线化疗的晚期 BTC 患者，丝裂原活化蛋白激酶抑制剂（MEKi）联合程序性死亡-配体 1（PD-L1）抑制剂可以明显改善其无进展生存期（PFS）（NCT03201458）。进一步研究表明，尽管 MEKi 可以增强肿瘤的免疫原性，但会损害宿主 T 细胞的激活/成熟。针对体内系统性 MEKi 治疗的情况，添加免疫激动剂（如 CD27 免疫激动剂）可以恢复 T 细胞功能。同时联合使用免疫检查点抑制剂可能有效优化 MEKi 的免疫调节潜力，有望提供更科学高效的治疗策略。
Further research has shown that, in the case of late BTC patients who have undergone first-line chemotherapy, the combined cytological death-composition 1 (PD-L1) inhibitor of the fission protein inhibitor (MEKI) can significantly improve their non-progressive survival (PFS) (NCT03201458). Further studies have shown that, while MEKI can increase the immunogenesis of the tumor, it can damage the activation/maturity of host T cells. In the case of the systemic treatment of MEKI, adding immunosuppressants (e.g. CD27 immunostimulators) can restore T-cell function.
方法
研究团队进行了一项随机的Ⅱ期试验（NCT04941287），旨在评估针对既往经治的不可切除 BTC 患者，使用阿替利珠单抗联合 CD27 免疫激动剂（CDX-1127，即varlilumab）± MEKi（cobimetinib）的疗效。
A random phase II experiment (NCT04941287) was conducted by the research team to assess the efficacy of the treatment of formerly incurable BTC patients using the Altolithone anti-combined CD27 (CDX-1127, or vallilumab) and plusmn; MEKI (cobimetinib).
纳入以下符合条件的患者：病理确诊的 BTC 成人患者；至少接受过一线（不超过二线）系统治疗；有可评估的病灶；ECOG PS 评分为 0 或 1 分；既往接受过PD-（L）1 治疗的患者也可纳入。
The following eligible patients are included: BTC adults diagnosed with pathology; at least one-line (no more than second-line) treatment; there are assessable stoves; ECOG PS scores 0 or 1 points; patients who have previously been treated with PD-(L)1 may also be included.
研究计划招募 64 名可评估受试者，按照 1：1 比例进行随机分配，根据 BTC 的罹患部位，分为 AV 组（阿替利珠单抗：840 mg 静脉注射，第 1、15 天 + varlilumab：3 mg/kg 静脉注射，第1、15天）和 CAV 组（cobimetinib：60 mg 每日口服，第 1—21 天服药、第 22—28 天停药 + 阿替利珠单抗 + varlilumab）两组。
The study plans to recruit 64 assessable candidates, distributed randomly according to 1:1 ratio, divided into AV groups (Atolellium single resistance: 840 mg intravenous injections, days 1, 15 + varlilumab: 3 mg/kg intravenous injections, days 1, 15) and CAV groups (cobimetinib: 60 mg per day oral, 1-21 days drugs, 22-28 days anti-drug stoppages + varlilumab).
研究的主要终点是客观缓解率（ORR）和 PFS。主要相关结果为治疗相关的浸润性 CD8+T 细胞变化。
The main end of the study is the objective mitigation rate (ORR) and the PFS. The main relevant result is the treatment of immersion-related CD8+T cell changes.
结果
基于 ORR 预先计划的中期分析显示，两组均未达到继续治疗的阈值，因此试验无效而提前终止。
A mid-term analysis based on the pre-planned ORR indicated that neither group had met the threshold for continued treatment and therefore the test was invalid and terminated earlier.
共有 57 名 患者入组（CAV 组 29 人，AV 组 28人），其中 67%的患者为肝内胆管癌，33%的患者既往接受过抗 PD-(L)1 治疗。除已经确定的 PD-L1 毒性特性，添加 CD27 免疫激动剂未显著增加免疫毒性。两组方案均耐受良好，无新的安全性信号。
A total of 57 patients were admitted to the group (29 in CAV and 28 in AV), of whom 67% were liver urinary cancers and 33% had been treated with PD-(L)1 in the past. In addition to the PD-L1 toxic properties already identified, the addition of CD27 immunosuppressants did not significantly increase immunotoxicity.
CAV 组和 AV 组的 ORR 分别为 0%和 4%。中位随访时间为 6.2 个月，CAV 组和 AV 组中位 PFS 分别为 2.2 个月和 1.8 个月（HR：0.71，0.40-1.25）。在抗 PD-(L)1 治疗后进展的患者中，CAV 组和 AV 组中位 PFS 分别为 3.6 个月和 1.7 个月（HR：0.44，0.14-1.33）。
The CAV group and the AV group are 0% and 4% respectively. The median follow-up time is 6.2 months, while the CAV group is 2.2 months and the AV group is 1.8 months (HR: 0.71,0.40-1.25). Among patients who have progressed after treatment against PD-(L)1, the CAV group is 3.6 months and the AV group is 1.7 months (HR: 0.44,0.14-1.33).
CAV 组和 AV 组中位总生存期（OS）分别为 10.2 个月和 6.1 个月（HR：0.76，0.37-1.55）。在抗 PD-(L)1 治疗后进展的患者中，CAV 组和 AV 组中位 OS 分别为 6.4 个月和 4.4 个月（HR：0.68，0.19-2.42）。主要的相关终点和更新的生存数据将在 ASCO 年会期间报告。
The median lifetime of CAV and AV groups (OS) is 10.2 months and 6.1 months, respectively (HR: 0.76, 0.37-15.55). Among patients who have advanced after treatment against PD-(L)1, the median of CAV and AV groups are 6.4 months and 4.4 months, respectively (HR: 0.68,0.19-2.42). The main relevant endpoints and updated survival data will be reported during the annual ASCO meeting.
结论
针对晚期 BTC 患者，阿替利珠单抗联合 varlilumab，无论是否添加 cobimetinib，其安全性均得到了验证。然而该治疗策略并未改善后期治疗结果。针对既往接受过免疫治疗的晚期 BTC 患者，与 AV 组相比，CAV 组的 PFS 和 OS 在数值上显示出更有利的治疗。尽管统计学结果并不显著，但这对未来进一步的探索提供了一定的参考依据。
For late-stage BTC patients, the safety of Adelelumab, whether or not a cobimetinib is added, has been verified. However, the treatment strategy does not improve the results of later treatment. For late-stage BTC patients who have been treated with immunization in the past, PFS and OS in the CAV group show a better measure of treatment in numerical terms than the AV group.
摘要号：4018
标题：Phase II study of sitravatinib in combination with tislelizumab in patients with advanced biliary tract cancer who have failed to at least 1 prior systemic treatment
Sitravatinib 联合替雷利珠单抗治疗既往至少 1 种系统治疗失败的晚期胆道恶性肿瘤患者的 II 期研究 Sitravatinib joint study of terminal urinary malignant neoplasms that have failed to treat at least 1 system 讲者：韩国首尔大学医院 Jeesun Yoon
背景
Background
免疫检查点抑制剂（ICI）联合细胞毒性化疗现已成为 TOPAZ-1 和 KN-966 研究支持的标准治疗方案。对此，针对晚期 BTC 患者，探索基于 ICI 的二线及以上治疗方案已成为当前亟待满足的临床需求。抗血管生成药物通过增加肿瘤抗原呈递和促进淋巴细胞浸润、迁移来诱导改善抗肿瘤免疫应答。
In response, exploring second-line treatment based on ICI and above has become a pressing clinical need. Antivascular-generation drugs are used to induce improved anti-cancer immune responses by increasing antigen transmission and promoting lymphocyte immersion, transport, etc.
方法
本研究是一项开放标签的 Ⅱ 期临床试验，旨在探讨 sitravatinib 联合替雷利珠单抗二线治疗晚期 BTC 的疗效（NCT04727996）。本试验纳入既往接受过 ICI 治疗的患者。所有患者均接受 sitravatinib（120 mg/天，口服）联合替雷利珠单抗（200 mg 每 3 周 1 次，静脉给药）治疗，直至疾病进展。主要终点为疾病控制率（DCR），次要终点包括 ORR、PFS、OS 和安全性。组织活检共进行 3 次：筛查、首次疗效评估和确认是否有疾病进展。每个周期采集 1 次血样。
This study is an open-label II clinical trial designed to explore the efficacy of the joint sitravatinib for the late-stage treatment of the Reilly Pearl Single Anti-Second Line (NCT04727996). The experiment includes patients who have been treated by ICI. All patients receive sitravatinib (120 mg/day, oral) joint treatment for the Thunderball Unit (200 mg per 3 weeks, intravenously provided) until the disease progresses. The main end point is disease control (DCR), with secondary endpoints including OrR, PFS, OS and safety.
结果
数据截止日期为 2023 年 7 月 31 日。本研究共纳入 43 例患者。9 例患者既往接受过 ICI 治疗。中位随访时间为 10.5 个月（95%CI，7.0-15.6）。
The deadline is 31 July 2023. The study includes 43 cases. 9 cases have been treated by ICI. The median follow-up period is 10.5 months (95% CI, 7.0-15.6).
本研究的全人群分析达到主要终点，DCR 为 65.1%。在未选择符合方案人群中，ORR 为 20.5%，PFS 为 4.93 个月（95% CI，3.10 - 8.87）。OS 为 10.3 个月（95% CI，6.67-18.2）。
The overall population analysis of this study has reached its main endpoint, with 65.1% DCR, 20.5% ORR and 4.93 months PFS (95% CI, 3.10 - 8.87) for those who did not choose to comply with the programme. OS is 10.3 months (95% CI, 6.67 - 18.2).
最常见的治疗相关不良事件与 sitravatinib 相关；手足综合征（任意级别60.5%，3/4 级 0%）、高血压（任意级别 34.9%，3/4 级 11.6%）。免疫相关不良反应占 46.5%，以 1 ~ 2 级为主。
The most common treatment-related adverse events are related to sitravatinib; foot and foot syndrome (60.5 per cent at any level, 3/4 at 0 per cent), hypertension (34.9 per cent at any level, 3/4 at 11.6 per cent).
探索性分析显示，基线组织 NGS 检测到同源重组缺陷（HRD）的患者（频率为 18.5%）比无 HRD 的患者具有更高的 ORR（60% vs. 13.6%）、更长的 PFS（随访期间未进展 vs. 4.87 个月）和 OS（21.1 个月vs. 8.57 个月）。循环肿瘤 DNA 检测的 HRD 对患者的选择具有辅助作用。RNA 测序显示，筛选和治疗期间的肿瘤组织炎症信号上调而血管生成信号下调。与无 HRD 患者相比，HRD 患者在基线和治疗期间的肿瘤组织显示出更高的炎症信号。
The exploratory analysis shows that the baseline organization NGS detected cogent restructuring defects (HRD) (frequency 18.5%) with higher ORRs (60% vs. 13.6%) than those without HRDs, longer PFSs (no progress during the interview vs. 4.87 months) and OS (21.1 months vs. 8.57 months). The circular oncology DNA testing HRD is complementary to patient selection. The RNA sequence shows that the oncological tissue signs during screening and treatment have been adjusted upwards and downwards in blood vessels.
结论
sitravatinib 联合阿替利珠单抗作为二线治疗晚期 BTC 患者这一治疗策略疗效存在研究意义，同时安全性可接受。值得关注的是，利用 HRD 作为生物标志物对 BTC 患者进行筛选具有研究前景，需要未来进一步探索。
It is interesting to note that the use of HRD as a biomarker to screen BTC patients is promising and needs to be further explored in the future.
总结与展望
本文介绍的两项研究的主要研究对象均为既往接受过治疗的晚期 BTC 患者。第一项研究聚焦免疫疗法优化 MEKi 自身的不良影响从而提高整体的疗效；第二项研究聚焦于靶向联合 ICI 作为二线治疗策略延长晚期 BTC 患者生存时间。尽管第一项研究为阴性结果，收效甚微，但仍然为后续的相关研究探索提供了宝贵价值。而第二项研究探索性发现，是否存在 HRD 与晚期 BTC 人群的疗效具有相关性，同时对未来将 HRD 作为新的生物标志物进行进一步的探索提供坚实的基础。
The two studies presented in this paper are mainly of late-stage BTC patients who have been treated. The first study focuses on optimizing the adverse effects of MEKi and improving the overall effectiveness of the treatment; the second study focuses on targeting ICI as a second-line treatment strategy to extend the survival of BTC patients. While the first study is negative, it still provides valuable value for subsequent research and exploration. The second study found that there is a correlation between the efficacy of HRD and the treatment of the late BTC population, while providing a solid basis for further exploration of HRD as a new biomarker in the future.
BTC 作为异质性恶性肿瘤，总体预后较差。随着肿瘤分子研究的深入和个性化诊疗理念的发展，围绕 BTC 的治疗逐步转向靶向、免疫和化疗联合治疗方案。未来随着更多免疫联合方案相关研究的开展，将助力推动更多新型治疗策略进入临床实践，以延长 BTC 患者生存时间。从现有的研究数据来看，在 BTC 中以 ICI 为基础的免疫联合疗法显示出显著的治愈潜力，未来有望为患者提供更多的治疗选择，并为后续的治疗策略和临床管理提出指导和重要的参考依据。
BTC, as heterogeneous malignant neoplasms, is generally less prognostic. As the concept of ICI-based co-treatment in BTC has developed, treatment around BTC has gradually shifted towards targeted, immuno- and chemotherapy joint treatment programmes. In the future, as more joint immunization programs are developed, it will help to promote more new treatment strategies into clinical practice in order to prolong the survival of BTC patients.
审核专家
杨田 教授
海军军医大学第三附属医院临床研究院院长助理、中心实验室主任
肝外二科副主任、党支部副书记
● 中国临床肿瘤学会 (CSCO) 青年委员会常务委员、肝癌专家委员会委员
• Standing member of the Youth Committee and Expert Committee on Hepatic Cancer, Chinese Clinical Oncology Society (CSCO)
● 国际肝胆胰协会中国分会 (CC-IHPBA) 秘书长
• Secretary-General of the China Section of the International Hepatitis and Insulin Association (CC-IHPBA)
● 中国医师协会外科医师分会肝胆青年专家工作组副组长
• Vice-Chairman of the Working Group of Young Hepatitis Experts of the Surgeons' Association of China
● 师从吴孟超院士，纽约西奈山医学院临床高级访问学者
• Senior Visiting Clinical Scholar, Wu Meng College of Medicine, Sinai Hill, New York
● 中国科技卓越期刊 iLIVER 执行主编，View Medicine, Front Immun 副主编
• Chinese journal of excellence in science and technology, iLIVER Executive Editor-in-Chief, View Medicine, Front Immun Associate Editor-in-Chief
● HBPD Int, HPB, JCTH, eGastro 等 24 本国内外期刊编委
• HBPD Int, HPB, JCTH, eGastro et al.
校审：杨田教授
Revision: Prof. Yangda
整理：王科淳；编辑：Bree
Collating: Wang Ko-sun; Editor: Bree
题图：图虫创意
Title: Ideas of the bug
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