仑伐替尼联合信迪利单抗二线治疗肝内胆管癌的效果和安全性

丁晓燕; 孙巍; 申燕军; 滕颖; 许雅文; 李文东; 陈京龙

doi:10.3969/j.issn.1001-5256.2022.08.018

仑伐替尼联合信迪利单抗二线治疗肝内胆管癌的效果和安全性

DOI: 10.3969/j.issn.1001-5256.2022.08.018

北京地坛医院肿瘤内科，北京 100015

基金项目:

首都临床特色应用研究 (Z181100001718131)

伦理学声明：本研究方案经由北京地坛医院伦理委员会审批，批号为京地伦科字(2021)-043号(2021-12-23)，所纳入患者均签署知情同意书。

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突，特此声明。

作者贡献声明：丁晓燕、陈京龙负责课题设计，资料分析，撰写论文; 孙巍、申燕军、滕颖、丁晓燕、许雅文、李文东参与收集数据，修改论文; 陈京龙负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
陈京龙，cjl6412@ccmu.edu.cn

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出版历程
- 收稿日期: 2022-01-28
- 录用日期: 2022-03-15
- 出版日期: 2022-08-20

Efficacy and safety of lenvatinib combined with sintilimab as the second-line therapy for intrahepatic cholangiocarcinoma

Department of Oncology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China

Research funding:

Foundation of Capital Distinctive Clinical Application Research (Z181100001718131)

More Information

Corresponding author: CHEN Jinglong, cjl6412@ccmu.edu.cn(ORCID: 0000-0003-1640-7115)

摘要

摘要: 目的初步探索仑伐替尼联合信迪利单抗在肝内胆管癌二线治疗中的疗效和安全性。方法回顾性分析北京地坛医院医院2019年10月31日—2021年10月31日收治的无法手术根治的肝内胆管癌二线治疗患者的临床资料，患者使用仑伐替尼联合信迪利单抗治疗。随访患者，采用RECIST1.1标准评价疗效。主要观察终点为至疾病进展时间(TTP)，次要观察终点为肿瘤客观缓解率(ORR)、疾病控制率(DCR)、总生存期(OS)和安全性。Kaplan-Meier法绘制生存曲线，组间差异采用log-rank检验。结果共27例患者入组，其中男15例(55.6%)，女12例(44.4%)，中位年龄58岁(33~73岁)。患者中位TTP为5.5个月(95%CI：1.7~9.3)，13例(48.1%)患者因疾病死亡，中位OS为11.2个月(95%CI：5.0~17.4)。总体ORR为40.7%，DCR为70.3%。66.7%发生了不同程度的不良事件。ALT和AST升高分别为44.4%，高血压37.0%，胆红素升高为29.6%，腹泻29.6%；尿蛋白、食欲下降和乏力分别为25.9%。无治疗相关的死亡；仅有1例发生Ⅳ度免疫相关性肝脏毒性，经激素治疗后缓解，无后遗症，导致信迪利单抗永久性停药。合并淋巴结转移的患者中位TTP与无淋巴结转移患者比较显著缩短(4.5个月 vs 18.8个月，P=0.035), 获得疾病缓解的患者，中位TTP显著延长[11.6个月(95%CI：5.6~17.6) vs 2.8个月(95%CI：1.8~3.8)，P＜0.001];合并淋巴结转移的患者中位OS有缩短趋势[9.6个月(7.9~11.3)vs 21.9个月(95%CI：0~44.9)，P=0.053], 疾病获得缓解的患者中位OS显著延长[16.6个月(95%CI：9.0~24.2) vs 6.9个月(95%CI：3.6~10.2)，P=0.011]。结论仑伐替尼联合信迪利单抗二线治疗肝内胆管癌临床效果显著，严重不良事件发生率低，是一种安全、有效的治疗方案。
- 肝内胆管癌 /
- 仑伐替尼 /
- 信迪利单抗 /
- 治疗学
Abstract: Objective To investigate the efficacy and safety of lenvatinib combined with sintilimab as the second-line therapy for advanced intrahepatic cholangiocarcinoma (ICC). Methods A retrospective analysis was performed for the clinical data of the patients with advanced ICC who were admitted to Beijing Ditan Hospital from October 31, 2019 to October 31, 2021 and could not undergo surgery or experienced metastasis after surgery. All patients were treated with lenvatinib combined with sintilimab as the second-line therapy. The patients were followed up, and the RECIST1.1 criteria were used to assess treatment outcome. The primary endpoint was time to progression (TTP), and the secondary endpoints were tumor objective response rate (ORR), disease control rate (DCR), overall survival (OS) time, and safety. The Kaplan-Meier method was used to plot survival curves, and the log-rank test was used for comparison between groups. Results A total of 27 patients were enrolled, among whom there were15 male patients (55.6%) and 12 female patients (44.4%), with a median age of 58 years (range 33-73 years). The median TTP for these patients was 5.5 (95% confidence interval [CI]: 1.7-9.3) months, and 13 patients (48.1%) died of disease progression, with a median OS time of 11.2 (95%CI: 5.0-17.4) months. The overall ORR and DCR were 40.7% and 70.3%, respectively. Of all patients, 66.7% experienced varying degrees of adverse events, and among these patients, 44.4% had an increase in alanine aminotransferase, 44.4% had an increase in aspartate aminotransferase, 37.0% had hypertension, 29.6% had an increase in bilirubin, 29.6% experienced diarrhea, and 25.9% each experienced proteinuria, anorexia, and weakness. No treatment-related death was observed, and only 1 patient developed grade Ⅳ immune-related hepatotoxicity and was relieved without sequelae after corticosteroid therapy, resulting in permanent withdrawal of sintilimab. The patients with lymph node metastasis had a significantly shorter median TTP than those without lymph node metastasis (4.5 months vs 18.8 months, P=0.035), and the patients who achieved disease remission had a significantly longer median TTP [11.6 months (95%CI: 5.6-17.6) vs 2.8 months (95%CI: 1.8-3.8), P < 0.001]; the patients with lymph node metastasis had a shorter median OS time [9.6 months (95%CI: 7.9-11.3) vs 21.9 months (95%CI: 0-44.9), P=0.053], and the patients who achieved disease remission had a significantly longer median OS time [16.6 months (95%CI: 9.0-24.2) vs 6.9 months (95%CI: 3.6-10.2), P=0.011]. Conclusion Lenvatinib combined with sintilimab has a marked clinical effect and a low incidence rate of serious adverse events as the second-line therapy for advanced ICC, and therefore, it is a safe and effective treatment regimen.
- Intrahepatic Cholangiocarcinoma /
- Lenvatinib /
- Sintilimab /
- Therapeutics

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图 1 肿瘤治疗效果瀑布图

Figure 1. The waterfall plot of patients' responses

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图 2 全组和亚组患者至疾病进展生存时间曲线

注：a, 全组人群；b, 是否合并淋巴结转移的患者；c, 不同肿瘤治疗效果的患者。

Figure 2. Kaplan Meier curve of time to progression for overall patients and subgroup patients

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图 3 全组和亚组患者总生存时间曲线

注：a，全组人群；b, 是否合并淋巴结转移的患者；c, 不同肿瘤治疗效果患者。

Figure 3. Kaplan Meier curve of overall survival for overall patients and subgroup patients

下载: 全尺寸图片幻灯片

表 1 患者基线特征和治疗情况

Table 1. Patients' baseline characteristics and treatment

基本特征	数值
年龄(岁)	58(33~73)
男/女[例(%)]	15(55.6)/12(44.4)
ECOG[例(%)]
0	4(14.8)
1	22(81.5)
2	1(3.7)
合并病毒感染[例(%)]
HBV	12(44.4)
HCV	1(3.7)
肝硬化[例(%)]	4(14.8)
术后转移[例(%)]	7(25.9)
初治无法手术患者分期¹⁾[例(%)]
Ⅱ	3(11.1)
Ⅲ	1(3.7)
Ⅳ	16(59.3)
转移部位[例(%)]
淋巴结	21(77.8)
肺	9(33.3)
骨	6(22.2)
脾脏	1(3.7)
肾脏	1(3.7)
腹膜转移	1(3.7)
治疗前靶病灶(cm)	9.2(1.5~16.8)
基线肿瘤标志物
CEA(ng/mL)	3.7(2.6~21.6)
AFP(ng/mL)	3.98(2.10~20.15)
CA19-9(IU/mL)	151.8(19.5~643.3)
既往一线化疗[例(%)]
无法耐受一线化疗	5(18.5)
替吉奥	4(14.8)
吉西他滨联合奥沙利铂	1(3.7)
一线化疗后进展	22(81.5)
吉西他滨联合注射用紫杉醇(白蛋白结合型)	2(7.4)
吉西他滨联合顺铂	4(14.8)
单药替吉奥	16(59.3)
基线 NLR	3.18(1.22~8.47)
基线 PLR	122.58(46.82~280.00)
注：本院CEA正常值范围0~5 ng/mL，AFP 0~8.78 ng/mL，CA19-9 0 ~37 IU/mL；NLR，粒细胞淋巴细胞比值；PLR，血小板淋巴细胞比值；ECOG：一般体力状态评分; 1)采用AJCC第八版分期标准进行分期。

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表 2 常见不良反应及发生率

Table 2. Common adverse events and frequency

治疗期间出现的不良事件	数值
ALT及AST升高[例(%)]	12(44.4)
Ⅰ/Ⅱ度	11(40.7)
Ⅲ/Ⅳ度	1(3.7)
高血压[例(%)]	10(37.0)
Ⅰ/Ⅱ度	7(25.9)
Ⅲ度	3(11.1)
胆红素升高[例(%)]	8(29.6)
Ⅰ/Ⅱ度	7(25.9)
Ⅲ/Ⅳ度	1(3.7)
腹泻(Ⅰ/Ⅱ度)[例(%)]	8(29.6)
尿蛋白(Ⅰ/Ⅱ度)[例(%)]	7(25.9)
食欲下降(Ⅰ/Ⅱ度)[例(%)]	7(25.9)
乏力(Ⅰ/Ⅱ度)[例(%)]	7(25.9)
发热[例(%)]	6(22.2)
Ⅰ/Ⅱ度	5(18.5)
Ⅲ度	1(3.7)
白细胞和中性粒细胞下降(Ⅰ/Ⅱ度)[例(%)]	6(22.2)
皮疹(Ⅰ/Ⅱ度)[例(%)]	5(18.5)
甲状腺功能减退(Ⅰ/Ⅱ度)[例(%)]	4(14.8)
血小板下降[例(%)]	4(14.8)
Ⅰ/Ⅱ度	3(11.1)
Ⅲ度	1(3.7)
感染[例(%)]	4(14.8)
腹腔感染	2(7.4)
肝脓肿	1(3.7)
急性胆囊炎	1(3.7)
药物暂停[例(%)]	6(22.2)
剂量下调[例(%)]	8(29.6)
Ⅲ度高血压	1(3.7)
Ⅲ度血小板下降	1(3.7)
Ⅳ度转氨酶升高	1(3.7)
乏力	1(3.7)
胆红素升高(Ⅱ/Ⅲ)	2(7.4)
腹泻	2(7.4)

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