程序性死亡受体1(PD-1)单抗联合索拉非尼或仑伐替尼治疗肝功能Child-Pugh B级不可切除肝癌患者的效果分析

Efficacy and safety of anti-PD-1 monoclonal antibody combined with sorafenib or lenvatinib in treatment of patients with Child-Pugh class B unresectable hepatocellular carcinoma

目的回顾性分析酪氨酸激酶抑制剂联合免疫检查点抑制剂在肝功能Child-Pugh B级不可切除肝癌(uHCC)患者中的疗效和安全性。方法纳入2020年12月31日—2023年3月30日首都医科大学附属北京地坛医院收治的肝功能Child-Pugh B级的uHCC患者96例,接受仑伐替尼联合程序性细胞死亡-1(PD-1)抑制剂治疗者为L组(63例),接受索拉非尼联合PD-1抑制剂治疗者为S组(33例)。主要终点为客观缓解率(ORR),次要终点包括疾病进展时间(TTP)、总生存期(OS)、毒性、停药率和剂量调整率。符合正态分布的计量资料2组间比较采用成组t检验;非正态分布2组间比较采用Mann-Whitney U检验。计数资料2组间比较采用χ^(2)检验。绘制生存曲线,运用Kaplan-Meier法计算2组患者的生存率,并利用Log-rank检验比较2组差异。通过Cox回归模型计算风险比(HR)和95%置信区间(95%CI),实现预后影响因素的多因素分析。结果96例uHCC患者中,Child-Pugh B级(7分)55例(57.3%),B级(8~9分)41例(42.7%)。L组患者的ORR显著高于S组(46.0%vs 15.2%,P=0.003)。L组和S组中位TTP(6.6个月vs 3.5个月,P=0.48)或OS(13.8个月vs 13.2个月,P=0.95)差异无统计学意义。Child-Pugh B级(7分)患者与Child-Pugh B级(8~9分)患者的中位TTP差异无统计学意义(6.6个月vs 4.8个月,P=0.35),OS具有统计学意义(14.5个月vs 8.8个月,P=0.045)。多因素分析显示,ORR是TTP(HR=0.18,95%CI:0.09~0.36,P<0.001)和OS(HR=0.20,95%CI:0.09~0.43,P<0.001)的保护因素。L组和S组总体不良反应(98.4%vs 97.0%)和≥3级不良反应的发生率(68.3%vs 63.6%)比较,差异均无统计学意义。L组和S组在剂量调整率(84.8%vs 70.2%)或停药率(56.1%vs 72.7%)方面无显著差异。结论与索拉非尼联合PD-1抑制剂方案相比,仑伐替尼联合PD-1抑制剂方案改善了Child-Pugh B级uHCC患者的ORR,但两组总体预后相似,总体安全性相当。

Objective To investigate the safety and efficacy of tyrosine kinase inhibitors combined with immune checkpoint inhibitors in the treatment of patients with Child-Pugh class B unresectable hepatocellular carcinoma(uHCC).Methods A total of 96 patients with Child-Pugh class B uHCC who were admitted to Beijing Ditan Hospital,Capital Medical University,from December 31,2020 to March 30,2023 were enrolled as subjects,among whom 63 patients receiving lenvatinib combined with programmed death-1(PD-1)inhibitor were enrolled as L group and 33 patients receiving sorafenib combined with PD-1inhibitor were enrolled as S group.The primary endpoint was objective response rate(ORR),and secondary endpoints included time to progression(TTP),overall survival(OS),toxicity,drug withdrawal rate,and dose adjustment rate.The The independent-samples t test was used for comparison of normally distributed continuous data between two groups,and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups;the chi-square test was used for comparison of categorical data between two groups.Survival curves were plotted,and the Kaplan-Meier method was used to calculate the survival rate of patients in both groups,while the Log-rank test was used for comparison between the two groups.The Cox regression model was used to calculate hazard ratio(HR)and its 95%confidence interval(CI)and perform the multivariate analysis of influencing factors for prognosis.Results Among the 96 patients with uHCC,55(57.3%)had Child-Pugh class B(7 points)uHCC and 41(42.7%)had Child-Pugh class B(8—9 points)uHCC.The L group had a significantly higher ORR than the S group(46.0%vs 15.2%,P=0.003),and there were no significant differences between the L group and the S group in median TTP(6.6 months vs 3.5 months,P=0.48)or OS(13.8 months vs 13.2 months,P=0.95).There was no significant difference in median TTP between the patients with Child-Pugh class B(7 points)uHCC and those with Child-Pugh class B(8—9 points)uHCC(6.6 months vs 4.8 months,P=0.35),while there was a significant difference in OS between these two groups of patients(14.5 months vs 8.8 months,P=0.045).The multivariate analysis showed that ORR was a protective factor for both TTP(HR=0.18,95%CI:0.09—0.36,P<0.001)and OS(HR=0.20,95%CI:0.09—0.43,P<0.001).There were no significant differences between the L group and the S group in the overall incidence rate of adverse reactions(98.4%vs 97.0%)and the incidence rate of grade≥3 adverse reactions(68.3%vs 63.6%),and there were also no significant differences between the two groups in dose adjustment rate(84.8%vs 70.2%)and drug withdrawal rate(56.1%vs 72.7%).Conclusion Compared with the regimen of sorafenib combined with PD-1 inhibitor,the regimen of lenvatinib combined with PD-1 inhibitor can improve the ORR of patients with Child-Pugh class B uHCC,with similar prognosis and safety profile between the two groups.