卡瑞利珠单抗联合仑伐替尼治疗不可切除肝细胞癌的疗效和安全性

摘要/Abstract

摘要： 目的探讨卡瑞利珠单抗联合仑伐替尼治疗不可切除肝细胞癌(HCC)的效果和安全性。方法将26例不可切除的HCC患者分成两组,对照组11例采用仑伐替尼治疗,观察组15例加用卡瑞利珠单抗治疗。观察两组肿瘤标志物变化,临床疗效、随访和生存指标,主要药物不良反应。结果治疗1个月和3个月时,观察组的血清甲胎蛋白(AFP)和异常凝血酶原(PIVKA-Ⅱ)水平为(502.18±135.90)ng/mL、(436.57±124.63)ng/mL、(634.35±167.18)mAU/mL、(546.07±145.96)mAU/mL,低于对照组的(541.73±156.87)ng/mL、(497.81±136.52)ng/mL、(687.49±185.24)mAU/mL、(604.75±163.28)mAU/mL,差异有统计学意义(t=7.429、6.834、8.182、7.761,均P<0.05)。观察组的客观缓解率(ORR)、局部控制率(DCR)、转化切除率和缓解持续时间(mDR)为46.67%、73.33%、20.0%、6.2(2.1,9.8)个月,高于对照组的27.27%、54.55%,9.091%、4.3(2.1,6.2)个月,差异有统计学意义(χ²=3.826、3.275、3.417,Z=12.738,均P<0.05);观察组应答时间(mRT)为2.6(2.0,3.9)个月,低于对照组的3.7(2.8,4.1)个月,差异有统计学意义(Z=3.265,P<0.05)。观察组的随访时间(mFUP)、总体生存期(mOS)、无进展生存期(mPFS)和靶病灶长径缩小程度为13.4(2.3,24.6)个月、10.7(5.1,16.4)个月、6.7(3.2,9.6)个月、(16.72±4.78)mm,低于对照组的10.9(1.9,20.5)个月、7.4(3.7,12.3)个月、4.4(2.1,7.3)个月、(13.36±4.01)mm,差异有统计学意义(Z=11.752、15.627、17.284,t=8.273,均P<0.05);观察组的病死率为46.67%,低于对照组的63.64%,差异有统计学意义(χ²=9.582,P<0.05)。两组未出现5级不良反应,3～4级不良反应发生率差异无统计学意义(P>0.05)。结论卡瑞丽珠单抗联合仑伐替尼能提高不可切除HCC患者的临床疗效,延长生存时间,使患者获益,安全性较高。

关键词: 肝细胞癌, 不可切除, 卡瑞利珠单抗, 仑伐替尼, 转化率, 生存时间

Abstract: Objective To investigate the efficacy and safety of carrelizumab combined with ramvaritinib in the treatment of unresectable hepatocellular carcinoma (HCC). Methods Twenty-six unresectable HCC patients were divided into a control group and an observation group. The control group was treated with ramvaritinib, and the observation group was treated with carrelizumab. The changes of tumor markers, clinical efficacy, follow-up time, survival indexes and major adverse drug reactions were observed. Results After 1 and 3 months of treatment, the levels of serum alpha-fetoprotein (AFP) and abnormal prothrombin (PIVKA-II) in both groups were decreased compared with those before treatment, and the decrease range in observation group was higher than that in control group (P<0.05). The Objective response rate (ORR), local control rate (DCR) and conversion rate in the observation group were significantly higher than those in the control group, and the median response time (mRT) was shorter and the median duration of response (mDR) was longer than that in the control group (P<0.05). The median follow-up time (mFUP), median overall survival (mOS), median progression-free survival (mPFS) and the extent of long diameter reduction of target lesions in the observation group were significantly higher than those in the control group, and the mortality was lower than that in the control group (P<0.05). There was no grade 5 adverse reactions between the two groups, and there was no significant difference in the incidence of grade 3-4 reactions between the two groups (P>0.05). Conclusion The combination of Caririzumab with ramvaritinib may improve the clinical efficacy of ramvartinib on unresectable HCC patients, prolong the patients' survival with high safety.

Key words: Hepatocellular carcinoma, Unresectable, Carrellizumab, Ramvaratinib, Conversion rate, Survival Time

钱厚龙, 李阳, 朱翔, 路逵. 卡瑞利珠单抗联合仑伐替尼治疗不可切除肝细胞癌的疗效和安全性[J]. 肝脏, 2023, 28(4): 452-456.

QIAN Hou-long, LI Yang, ZHU Xiang, LU Kui. The efficacy and safety of carrilizumab combined with ramvaritinib in the treatment of unresectable hepatocellular carcinoma[J]. Chinese Hepatolgy, 2023, 28(4): 452-456.

参考文献

[1] Cao W,Chen HD,Yu YW,et al.Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020.Chin Med J (Engl),2021,134(7):783-791.
[2] 张大闯,马富权,马富平,等.载药微球与传统C-TACE在治疗乏血供型原发性肝癌中的临床疗效对比.现代消化及介入诊疗,2021,26(6):689-692.
[3] Christopher C,Nicholas B,Dan E,et al.Primary liver cancer: an NCDB analysis of overall survival and margins after hepatectomy. Ann Surg Oncol,2020,27(4):1156-1163.
[4] 张子杰,乔子耘,冯浩,等.系统治疗在肝癌术前新辅助治疗中应用进展.中国实用外科杂志,2021,41(3):326-331.
[5] Greten TF,Lai CW,Li G,et al.Targeted and immune-based therapies for hepatocellular carcinoma.Gastroenterology,2019,156(2):510-524.
[6] Fukumura D,Kloepper J,Amoozgar Z,et al.Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges.Nat Rev Clin Oncol,2018,15(5):325-340.
[7] Yan Z,Yao ZH,Yao SN,et al.Camrelizumab plus apatinib successfully treated a patient with advanced esophageal squamous cell carcinoma.Immunotherapy,2020,12(16):1161-1166.
[8] 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.PLoS One,2019,14(2):e0212513.
[9] 中华人民共和国国家卫生健康委员会医政医管局.原发性肝癌诊疗规范(2019年版).中华肝脏病杂志,2020,28(2):112-128.
[10] Heijde vd D,Joshi A,Pangan A,et al.ASAS40 and ASDAS clinical responses in the ABILITY-1 clinical trial translate to meaningful improvements in physical function, health-related quality of life and work productivity in patients with non-radiographic axial spondyloarthritis.Rheumatology,2016,55(1):80-88.
[11] 徐彬,李小龙,朱小东,等.在接受仑伐替尼联合PD-1抗体治疗的不可切除肝细胞癌患者肝切除术前行门静脉栓塞术的研究.中华肝胆外科杂志,2022,28(1):21-27.
[12] 陈孝强.仑伐替尼联合PD-1抑制剂与索拉非尼一线治疗中晚期原发性肝癌疗效及安全性对比分析.南昌:南昌大学,2021.
[13] Fujita M,Rui Y,Hasegawa T,et al.Classification of primary liver cancer with immunosuppression mechanisms and correlation with genomic alterations.EBioMedicine,2020,53(5):e102659.
[14] Lim H, Ramjeesingh R,Liu D,et al.Optimizing survival by changing the landscape of targeted therapy for intermediate and advanced hepatocellular carcinoma: a systematic review.J Natl Cancer Inst,2020,113(2):123-136.
[15] 李绍雪,张承顺,陈文.血清CEA、AFP、CA72-4联合检测评价胃癌分化程度的效能.现代消化及介入诊疗,2021,26(3):305-308.
[16] Lee QY,Yu XX,Yu WW.The value of PIVKA-Ⅱ versus AFP for the diagnosis and detection of postoperative changes in hepatocellular carcinoma.J Int Med,2021,4(2):77-81.
[17] Chen XW, Yu TJ,Zhang J,et al.CYP4A in tumor-associated macrophages promotes pre-metastatic niche formation and metastasis.Oncogene,2017,36(35):5045-5057.
[18] Liu JQ,Liu Q,Li Y,et al.Efficacy and safety of camrelizumab combined with apatinib in advanced triple-negative breast cancer:an open-label phase Ⅱ trial.J Immunother Cancer,2020,8(1):e000696.
[19] Kimura T,Kato Y,Ozawa Y,et al.Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model.Cancer Sci,2018,109(12):3993-4002.
[20] David O,Daneng L,Noam VW,et al.Geriatric oncology research at the ASCO GI 2020 symposium: Young international society of geriatric oncology perspective paper.J Geriatr Oncol,2020,11(7):1182-1186.
[21] 徐彬,朱小东,黄成,等.仑伐替尼联合程序性死亡受体-1抗体治疗不可切除或进展期肝细胞癌的临床疗效.中华消化外科杂志,2021,20(2):197-204.
[22] Finn RS,Ikeda M,Zhu AX,et al.Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma.J Clin Oncol,2020,38(26):2960-2970.
[23] 刘娟,廖豪杰,袁国盛,等.肝动脉化疗栓塞术联合仑伐替尼治疗中晚期肝细胞肝癌的临床疗效及安全性分析.实用医院临床杂志,2022,19(1):55-59.
[24] 王瑛,袁鹤立,赵利,等.清热利胆自拟方对仑伐替尼联合卡瑞丽珠单抗治疗晚期原发性肝癌患者炎症因子、免疫细胞水平和生活质量的影响.现代中西医结合杂志,2021,30(24):2664-2669.
[25] 滕颖,丁晓燕,李文东,等.程序性细胞死亡受体1抑制剂联合仑伐替尼治疗晚期原发性肝癌的效果及不良反应.临床肝胆病杂志,2021,37(3):606-610.
[26] 王东旭.胆管癌转移相关的基因组特征及其靶向、免疫治疗的临床实践与生物标志物研究.北京:北京协和医学院,2021.