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
Efficacy and safety of lenvatinib combined with sintilimab as the second-line therapy for intrahepatic cholangiocarcinoma
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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。 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. -
Key words:
- Intrahepatic Cholangiocarcinoma /
- Lenvatinib /
- Sintilimab /
- Therapeutics
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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。 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) -
[1] KHAN SA, TAVOLARI S, BRANDI G. Cholangiocarcinoma: Epidemiology and risk factors[J]. Liver Int, 2019, 39 (Suppl 1): 19-31. DOI: 10.1111/liv.14095. [2] BERTUCCIO P, MALVEZZI M, CARIOLI G, et al. Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma[J]. J Hepatol, 2019, 71(1): 104-114. DOI: 10.1016/j.jhep.2019.03.013. [3] SQUADRONI M, TONDULLI L, GATTA G, et al. Cholangiocarcinoma[J]. Crit Rev Oncol Hematol, 2017, 116: 11-31. DOI: 10.1016/j.critrevonc.2016.11.012. [4] VALLE J, WASAN H, PALMER DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer[J]. N Engl J Med, 2010, 362(14): 1273-1281. DOI: 10.1056/NEJMoa0908721. [5] VALLE JW, FURUSE J, JITLAL M, et al. Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials[J]. Ann Oncol, 2014, 25(2): 391-398. DOI: 10.1093/annonc/mdt540. [6] LAMARCA A, PALMER DH, WASAN HS, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial[J]. Lancet Oncol, 2021, 22(5): 690-701. DOI: 10.1016/S1470-2045(21)00027-9. [7] FINN RS, IKEDA M, ZHU AX, et. al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma[J]. J Clin Oncol, 2020, 38(26): 2960-2970. DOI: 10.1200/JCO.20.00808. [8] KUDO M, IKEDA M, MOTOMURA K, et al. A phase Ib study of lenvatinib (LEN) plus nivolumab (NⅣ) in patients (pts) with unresectable hepatocellular carcinoma (uHCC): Study 117[J]. J Clin Oncol, 2020, 38(4_suppl): 513. DOI: 10.1200/JCO.2020.38.4_suppl.513. [9] LEE AJ, CHUN YS. Intrahepatic cholangiocarcinoma: the AJCC/UICC 8th edition updates[J]. Chin Clin Oncol, 2018, 7(5): 52. DOI: 10.21037/cco.2018.07.03. [10] MAKAR AB, MCMARTIN KE, PALESE M, et al. Formate assay in body fluids: application in methanol poisoning[J]. Biochem Med, 1975, 13(2): 117-126. DOI: 10.1016/0006-2944(75)90147-7. [11] BRANDI G, RIZZO A, DALL'OLIO FG, et al. Percutaneous radiofrequency ablation in intrahepatic cholangiocarcinoma: a retrospective single-center experience[J]. Int J Hyperthermia, 2020, 37(1): 479-485. DOI: 10.1080/02656736.2020.1763484. [12] YOSHIKAWA D, OJIMA H, IWASAKI M, et al. Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma[J]. Br J Cancer, 2008, 98(2): 418-425. DOI: 10.1038/sj.bjc.6604129. [13] XU YF, YANG XQ, LU XF, et al. Fibroblast growth factor receptor 4 promotes progression and correlates to poor prognosis in cholangiocarcinoma[J]. Biochem Biophys Res Commun, 2014, 446(1): 54-60. DOI: 10.1016/j.bbrc.2014.02.050. [14] BOONJARASPINYO S, BOONMARS T, WU Z, et al. Platelet-derived growth factor may be a potential diagnostic and prognostic marker for cholangiocarcinoma[J]. Tumour Biol, 2012, 33(5): 1785-1802. DOI: 10.1007/s13277-012-0438-8. [15] TOHYAMA O, MATSUI J, KODAMA K, et al. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models[J]. J Thyroid Res, 2014, 2014: 638747. DOI: 10.1155/2014/638747. [16] KIMURA T, KATO Y, OZAWA Y, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model[J]. Cancer Sci, 2018, 109(12): 3993-4002. DOI: 10.1111/cas.13806. [17] FINN RS, IKEDA M, ZHU AX, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma[J]. J Clin Oncol, 2020, 38(26): 2960-2970. DOI: 10.1200/JCO.20.00808. [18] UENO M, IKEDA M, SASAKI T, et al. Phase 2 study of lenvatinib monotherapy as second-line treatment in unresectable biliary tract cancer: primary analysis results[J]. BMC Cancer, 2020, 20(1): 1105. DOI: 10.1186/s12885-020-07365-4. [19] O'MALLEY DM, BARIANI GM, CASSIER PA, et al. Pembrolizumab in patients with microsatellite instability-high advanced endometrial cancer: results from the KEYNOTE-158 study[J]. J Clin Oncol, 2022, 40(7): 752-761. DOI: 10.1200/JCO.21.01874. [20] KIM RD, KIM DW, ALESE OB, et al. A phase lI study of nivolumab in patients with advanced refractory biliary tract cancers (BTC)[J]. J Clin Oncol, 2019, 37(15_suppl): 4097. DOI: 10.1200/JCO.2019.37.15_suppl.4097. [21] LIN J, YANG X, LONG J, et al. Pembrolizumab combined with lenvatinib as non-first-line therapy in patients with refractory biliary tract carcinoma[J]. Hepatobiliary Surg Nutr, 2020, 9(4): 414-424. DOI: 0.21037/bsn-20-338. [22] KATO Y, TABATA K, KIMURA T, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway[J]. PLoS One, 2019, 14(2): e0212513. DOI: 10.1371/journal.pone.0212513. [23] ZHANG Q, LIU X, WEI S, et al. Lenvatinib plus PD-1 inhibitors as first-line treatment in patients with unresectable biliary tract cancer: A single-arm, open-label, phase ii study[J]. Front Oncol, 2021, 11: 751391. DOI: 10.3389/fonc.2021.751391.