PD-1单抗治疗非小细胞肺癌相关不良反应及其与疗效的相关性分析

Analysis of immune-related adverse events and its correlation with efficacy of anti-PD-1 monotherapy in advanced non-small cell lung cancer

背景与目的:随着免疫检查点抑制剂在肺癌中的应用增多,免疫相关不良反应(immune-related adverse event,irAE)受到越来越多的重视。分析使用单药免疫治疗肺癌患者的irAE发生情况及其与免疫治疗效果的相关性。方法:回顾性收集同济大学附属上海市肺科医院2015年6月—2019年1月接受抗程序性死亡[蛋白]-1(programmed death-1,PD-1)免疫治疗的晚期非小细胞肺癌患者的基线临床资料、irAE发生的种类、时间、严重程度、处理、转归以及免疫治疗效果[客观缓解率(objective response rate,ORR)、疾病控制率(disease control rate,DCR)、无进展生存期(progressionfree survival,PFS)]等资料。使用SPSS 23.0软件,探讨irAE与患者免疫治疗效果的相关性。结果:共109例患者入组,中位年龄64岁(32~82岁),男女比例为89∶20,ECOG体能状态评分0、1、2分者分别为4、103、2例,接受一线、二线、三线及以上治疗的患者分别为15、65、29例。63例(57.8%)患者发生irAE,其中43例出现复合irAE,常见irAE为皮肤反应(28例,25.7%)、免疫性肝炎(18例,16.6%)、疲乏(16例,14.7%)、内分泌系统毒性(15例,13.8%)、免疫性肺炎(12例,11.0%)及胃肠道反应(10例,9.2%)等;irAE常见于6~27周,10例(9.2%)患者发生了3~4级irAE,主要为免疫相关性肺炎。总人群ORR为24.7%,DCR为77.9%,中位PFS为4.6个月(95%CI:3.9~5.2)。irAE组对比非irAE组有着较高的ORR(36.5%vs 8.7%,P=0.001)和中位PFS(8.7个月vs 3.5个月,HR=0.294,95%CI:0.184~0.469,P<0.001),其中皮肤不良反应与预后最为相关:中位PFS为12.7和4.3个月(HR=2.332,95%CI:1.184~4.595,P=0.014)。结论:肺癌irAE多见于治疗后6~27周,多为1~2级,其中3~4级irAE多为免疫性肺炎,irAE发生与疗效相关。

Background and purpose:With the increasing application of immune checkpoint inhibitors in lung cancer,immunerelated adverse event(irAE)has attracted more and more attention.This study aimed to analyze the occurrence of irAE in patients receiving single-drug immunotherapy and the correlation between irAE and immunotherapy efficacy.Methods:Data of patients with advanced non-small cell lung cancer(NSCLC)treated with anti-programmed death-1(PD-1)monotherapy in Shanghai Pulmonary Hospital,Tongji University from June 2015 to Janurary 2019 were collected.Patients’baseline clinical data,irAE types,occurrence time,severity,management of irAE,the objective response rate(ORR),disease control rate(DCR)and progression-free survival(PFS)were retrospectively analyzed.And then,we used the SPSS 23.0 software to explore the correlation between irAE and PFS.Results:One hundred and nine advanced NSCLC patients were treated in our hospital.The median age of the patients was 64 years(range 32-82 years).The ratio of male to female was 89∶20.The ECOG performance status scores of 0,1 and 2 were 4,103 and 2 cases respectively.The number of patients who received the first-line,second-line and third-line and above treatment were 15,65 and 29 respectively.At the data cutoff,irAE occurred in 63 patients(57.8%).Among them,43 cases had complex irAE.The most common irAE were skin adverse events(n=28,25.7%).Other irAE were liver dysfunction(n=18,16.6%),fatigue(n=16,14.7%),endocrine toxicity(n=15,13.8%),immune-related pneumonitis(n=12,11.0%)and gastrointestinal toxicity(n=10,9.2%).Most irAE occurred between 6 and 27 weeks.Ten patients(9.2%)had grade 3-4 irAE,mainly immune-related pneumonitis.Among the overall population,ORR was 24.7%,DCR was 77.9%,and median PFS was 4.6 months(95%CI:3.9-5.2).Patients with irAE had significantly higher ORR compared with patients who did not have irAE(36.5%vs 8.7%,P=0.001).Similarly,the median PFS among patients with irAE was longer than patients without irAE(8.7 months vs 3.5 months,HR=0.294,95%CI:0.184-0.469,P<0.001).Among them,skin adverse events were most correlated with prognosis(median PFS:12.7 months vs 4.3 months,HR=2.332,95%CI:1.184-4.595,P=0.014).Conclusion:Most cases of irAE in immunotherapy of lung cancer occurred in 6-27 weeks of treatment,and most of them were grade 1-2.Grade 3-4 irAE were mostly immune-related pneumonitis.Development of irAE was associated with survival outcome.