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

Clinical efficacy of combination therapy with lenvatinib and programmed death-1 antibodies in unresectable or advanced hepatocellular carcinoma

目的探讨仑伐替尼联合程序性死亡受体-1(PD-1)抗体治疗不可切除或进展期肝细胞癌(以下简称肝癌)的临床疗效。方法采用回顾性描述性研究方法。收集2018年9月至2020年1月复旦大学附属中山医院收治的59例不可切除或进展期肝癌病人的临床病理资料;男54例,女5例;中位年龄为52岁,年龄范围为25~73岁。59例病人均采用仑伐替尼联合PD-1抗体治疗,其中43例直接进行一线治疗,16例因仑伐替尼或索拉非尼单药治疗发生肿瘤进展或不耐受后进行二线治疗。观察指标:(1)临床疗效。(2)药物不良反应及治疗情况。(3)随访及生存情况。采用门诊和电话方式进行随访,了解病人靶病灶肿瘤长径、总体生存和疾病无进展生存情况。随访时间截至2020年12月。偏态分布的计量资料以M(P25,P75)或M(范围)表示。计数资料以绝对数和(或)百分比表示。采用Kaplan-Meier法计算中位缓解持续时间、中位总体生存时间、中位疾病无进展生存时间和生存率并绘制生存曲线。结果(1)临床疗效:59例肝癌病人治疗后客观缓解率、完全缓解率、部分缓解率、疾病稳定率、疾病进展率、治疗起效时间、中位缓解持续时间分别为37.3%(22/59)、11.9%(7/59)、25.4%(15/59)、37.3%(22/59)、25.4%(15/59)、2.6个月(2.1个月,4.0个月)、6.3个月[95%可信区间(CI)为2.2~10.5个月]。43例进行一线治疗肝癌病人的客观缓解率、完全缓解率、部分缓解率、疾病稳定率、疾病进展率、治疗起效时间分别为41.9%(18/43)、16.3%(7/43)、25.6%(11/43)、37.2%(16/43)、20.9%(9/43)、2.2个月(2.0个月,3.5个月),中位缓解持续时间尚未达到。16例进行二线治疗肝癌病人的客观缓解率、完全缓解率、部分缓解率、疾病稳定率、疾病进展率、治疗起效时间、中位缓解持续时间分别为4/16、0、4/16、6/16、6/16、3.8个月(3.6个月,4.1个月)、4.2个月(95%CI为2.0~6.3个月)。59例肝癌病人中,6例肿瘤转化为可切除肝癌,行R0手术切除,转化切除率为10.2%(6/59)。其中一线治疗病人5例,转化切除率为11.6%(5/43);二线治疗病人1例,转化切除率为1/16。(2)药物不良反应及治疗情况:59例肝癌病人中,25例发生3~4级药物不良反应,发生率为42.4%(25/59)。其中10例病人γ-谷氨酰转移酶>5倍正常值上限(一线治疗、二线治疗病人各5例);9例病人天冬氨酸氨基转移酶>5倍正常值上限(一线治疗病人4例、二线治疗病人5例);5例病人消化道出血(一线治疗病人4例、二线治疗病人1例);4例一线治疗病人白细胞计数<2.0×109/L;4例病人总胆红素>3倍正常值上限(一线治疗病人1例、二线治疗病人3例);3例一线治疗病人中性粒细胞计数<1.0×109/L;3例病人腹腔积液(一线治疗病人2例、二线治疗病人1例);2例病人血小板计数<50.0×109/L(一线治疗、二线治疗病人各1例);2例一线治疗病人丙氨酸氨基转移酶>5倍正常值上限;2例一线治疗病人低钠血症;2例病人肺部感染(一线治疗、二线治疗病人各1例);2例病人1型糖尿病(一线治疗、二线治疗病人各1例);低钾血症、心肌炎、垂体炎、大疱性皮炎、高血压病各1例,均为一线治疗病人。3例发生5级药物不良反应,发生率为5.1%(3/59)。其中1例一线治疗病人为免疫性肝炎;免疫性肺炎、免疫性肠炎各1例,均为二线治疗病人。部分病人同时合并多种药物不良反应。25例发生3~4级药物不良反应病人经药物减量、停药、对症处理和激素治疗后均缓解。3例发生5级药物不良反应病人经大剂量激素冲击和保肝等治疗后仍死亡。(3)随访及生存情况:59例病人均获得随访,随访时间为1.5~25.2个月,中位随访时间为13.3个月。其中一线治疗病人的随访时间为1.9~25.2个月,中位随访时间为13.5个月,随访期间20例病人死亡,病死率为46.5%(20/43);二线治疗病人的随访时间为1.5~24.4个月,中位随访时间为10.8个月,随访期间10例病人死亡,病死率为10/16。截至末次随访,59例病人、一线治疗病人、二线治疗病人靶病灶肿瘤长径分别为75 mm(38 mm,125 mm)、74 mm(36 mm,116 mm)、84 mm(48 mm,150 mm),与基线靶病灶肿瘤长径比率分别为-9.05%(-27.3%,19.7%)、-16.1%(-28.8%,13.6%)、13.2%(-24.7%,23.5%)。一线治疗病人中位总体生存时间、中位疾病无进展生存时间和二线治疗病人的上述指标分别为17.1个月(95%CI为11.0~23.2个月)、10.8个月(95%CI为5.0~16.6个月)和10.8个月(95%CI为9.2~12.4个月)、3.0个月(95%CI为1.6~4.4个月)。结论对于不可切除或进展期肝癌,仑伐替尼联合PD-1抗体一线或二线治疗均可获得有效的抗肿瘤活性和良好的临床疗效。

Objective To investigate the clinical efficacy of the combination therapy of lenvatinib and programmed death-1(PD-1)antibodies in unresectable or advanced hepatocellular carcinoma(HCC).Methods The retrospective and descriptive study was conducted.The clinico-pathological data of 59 patients with unresectable or advanced HCC who were admitted to Zhongshan Hospital of Fudan University from September 2018 to January 2020 were collected.There were 54 males and 5 females,aged from 25 to 73 years,with a median age of 52 years.All 59 patients underwent combination therapy with lenvatinib and PD-1 antibodies including 43 cases undergoing first-line therapy and 16 cases who cannot tolerate first-line therapy or with tumor progressed after first-line therapy undergoing second-line therapy.Observation indicators:(1)clinical efficacy;(2)adverse drug reactions and treatment;(3)follow-up and survival.Follow-up was performed using outpatient examination or telephone interview to detect tumor diameter of the target lesion,overall survival and progression free survival of patients up to December 2020.Measurement data with skewed distribution were expressed as M(P25,P75)or M(range).Count data were represented as absolute numbers and(or)percentages.The Kaplan-Meier method was used to calculate the median duration of response(DoR),median overall survival time,median progression free survival time,survival rates and draw survival curves.Results(1)Clinical efficacy:the objective response rate(ORR),complete response rate(CR),partial response rate(PR),stable disease rate(SD),progression disease rate(PD),time to response(TTR)and median DoR of 59 HCC patients were 37.3%(22/59),11.9%(7/59),25.4%(15/59),37.3%(22/59),25.4%(15/59),2.6 months(2.1 months,4.0 months),6.3 months[95%confidence interval(CI)as 2.2 to 10.5 months],respectively.The ORR,CR,PR,SD,PD and TTR of 43 HCC patients undergoing first-line therapy were 41.9%(18/43),16.3%(7/43),25.6%(11/43),37.2%(16/43),20.9%(9/43),2.2 months(2.0 months,3.5 months),respectively.The median DoR of 43 patients undergoing first-line therapy was not reached.The ORR,CR,PR,SD,PD,TTR and median DoR of 16 HCC patients undergoing second-line therapy were 4/16,0,4/16,6/16,6/16,3.8 months(3.6 months,4.1 months),4.2 months(95%CI as 2.0 to 6.3 months),respectively.Six of 59 HCC patients underwent R0 resection due to tumor converting to resectable HCC with the conversion and resection rate of 10.2%(6/59).Among the 6 patients,5 cases undergoing first-line treatment had the conversion and resection rates of 11.6%(5/43)and 1 case undergoing second-line treatment had the conversion and resection rates of 1/16,respectively.(2)Adverse drug reactions and treatment:25 of 59 HCC patients underwent 3 to 4 grade adverse drug reactions with the incidence of 42.4%(25/59).Among the 25 patients,10 cases including 5 cases undergoing first-line therapy and 5 cases undergoing second-line therapy had the level of gamma glutamyltransferase>5×upper limit of normal(ULN),9 cases including 4 cases undergoing first-line therapy and 5 cases undergoing second-line therapy had the level of aspartate aminotransferase>5×ULN,5 cases including 4 cases undergoing first-line therapy and 1 case undergoing second-line therapy occurred gastrointestinal hemorrhage,4 cases undergoing first-line therapy had the level of white blood cell count<2.0×109/L,4 cases including 1 case undergoing first-line therapy and 3 cases under-going second-line therapy had the level of total bilirubin>3×ULN,3 cases undergoing first-line therapy had the level of neutrophil count<1.0×109/L,3 cases including 2 cases undergoing first-line therapy and 1 case undergoing second-line therapy occurred ascites,2 cases including 1 case undergoing first-line therapy and 1 case undergoing second-line therapy had the level of platelet count<50.0×109/L,2 cases undergoing first-line therapy had the level of alanine aminotransferase>5×ULN,2 cases undergoing first-line therapy occurred hyponatremia,2 cases including 1 case undergoing first-line therapy and 1 case undergoing second-line therapy occurred pulmonary infection,2 cases including 1 case undergoing first-line therapy and 1 case undergoing second-line therapy occurred type 1 diabetes,1 case undergoing first-line therapy occurred hypokalemia,1 case undergoing first-line therapy occurred myocarditis,1 case undergoing first-line therapy occurred hypophysistis,1 case undergoing first-line therapy occurred bullous dermatitis,1 case undergoing first-line therapy occurred hypertension.Three of 59 HCC patients underwent 5 grade adverse drug reactions,with the incidence of 5.1%(3/59),including 1 case undergoing first-line therapy with immune hepatitis,1 case undergoing second-line therapy with immune pneumonia and 1 case undergoing second-line therapy with immune enteritis.Some of patients underwent multiple adverse drug reactions at the same time.Twenty five patients undergoing 3 to 4 grade adverse drug reactions were relieved with the treatment of drug reduction,drug withdrawal,symptomatic treatment or hormone therapy.Three patients undergoing 5 grade adverse drug reactions died after being treated with high-dose hormone shock and hepatoprotective treatment.(3)Follow-up and survival:all 59 patients were followed up for 1.5 to 25.2 months,with a median follow-up time of 13.3 months.Of them,patients undergoing first-line therapy were followed up for 1.9 to 25.2 months,with a median follow-up time of 13.5 months.During follow-up,20 cases undergoing first-line therapy died with the fatality rate of 46.5%(20/43).Patients undergoing second-line therapy were followed up for 1.5 to 24.4 months,with a median follow-up time of 10.8 months.During follow-up,10 cases undergoing second-line therapy died with the fatality rate of 10/16.Up to the latest follow-up,the tumor diameter of the target lesion in all 59 patients,in patients undergoing first-line therapy and in patients undergoing second-line therapy was 75 mm(38 mm,125 mm),74 mm(36 mm,116 mm),84 mm(48 mm,150 mm),respectively.The ratio of tumor diameter of the target lesion at latest follow-up to tumor diameter of the target lesion at baseline were-9.05%(-27.3%,19.7%),-16.1%(-28.8%,13.6%),13.2%(-24.7%,23.5%)for all 59 patients,patients undergoing first-line therapy and patients undergoing second-line therapy,respectively.The median overall survival time and median progression free survival time of patients undergoing first-line therapy and patients undergoing second-line therapy were 17.1 months(95%CI as 11.0 to 23.2 months),10.8 months(95%CI as 5.0 to 16.6 months)and 10.8 months(95%CI as 9.2 to 12.4 months),3.0 months(95%CI as 1.6 to 4.4 months),respectively.Conclusion For unresectable or advanced HCC,combination therapy with lenvatinib and PD-1 antibodies can obtain effective antitumor activity and less incidence of adverse drug reactions.