中国肺癌患者真实世界免疫检查点抑制剂相关性肺炎的流行病学分析

Epidemiological analysis of real-world immune checkpoint inhibitor-related pneumonitis in Chinese patients with lung cancer

背景和目的:临床研究中免疫检查点抑制剂相关性肺炎(checkpoint inhibitor-related pneumonitis,CIP)在程序性死亡[蛋白]-1(programmed cell death-1,PD-1)和程序性死亡[蛋白]配体-1(programmed cell deathligand-1,PD-L1)抑制剂引起的免疫相关不良反应(immune-related adverse event,irAE)致死原因中排第一位,而真实世界CIP的流行病学情况缺乏大宗人群研究报道。本研究旨在了解中国真实世界中肺癌免疫治疗的CIP发病率,并进一步总结其特征、治疗现状和转归。方法:回顾并收集2019年1月—2021年9月在广州医科大学附属第一医院和同济大学附属上海市肺科医院首诊肺癌且接受了免疫检查点抑制剂(immune checkpoint inhibitor,ICI)治疗的患者基本临床信息,以及CIP患者肺炎的发生时间、等级、治疗方案和转归。总结CIP在研究队列以及各亚组CIP的发病率、发病特点、危险因素以及CIP患者接受免疫抑制治疗的临床现状以及转归。结果:共纳入2031例免疫治疗患者,CIP发生率为7.2%(147/2031),重症率为2.6%(52/2031),致死率为0.4%(9/2031)。其中CIP人群中重症率为35.4%(52/147),死亡率为6.1%(9/147)。与非CIP患者相比,CIP多见于男性、老年(>65岁)、联合治疗、晚期二线免疫治疗的患者。在各亚组CIP发病率的对比中,男性、老年(>65岁)、鳞癌、联合治疗、抗PD-1单抗组、晚期一线及二线治疗的患者发病率更高。真实世界CIP的中位发病时间为免疫治疗后148 d,具有双高峰的特点,即免疫治疗后60~90 d及150~210 d是发病的双高峰时间段。CIP发病还具有一定的季节性,秋冬季高发。治疗的患者均使用了糖皮质激素作为一线治疗;本研究中CIP的免疫抑制治疗率为76.2%,治疗后97.9%轻症CIP患者能预后良好,81.2%重症患者能在治疗后有较好的预后,有17.3%重症患者因CIP死亡。结论:真实世界肺癌患者免疫治疗时总人群CIP发生率为7.2%,重症率为2.6%,致死率为0.4%;其中CIP人群重症率为35.4%,死亡率为6.1%。CIP中位发病时间有双高峰特点,且秋冬季高发;男性、老年、鳞癌、联合治疗、抗PD-1单抗组、晚期一线及二线治疗的患者CIP发病率较高。大部分CIP患者经过免疫抑制治疗后转归良好。

Background and purpose:In clinical studies,checkpoint inhibitor-related pneumonitis(CIP)ranks first among the causes of death in programmed cell death protein-1(PD-1)/programmed death ligand-1(PD-L1)inhibitor immune-related adverse events.Real-world CIP situations lack extensive population reports.This study aimed to understand the incidence of CIP in the real world of lung cancer in China,and to summarize its characteristics,treatment status and outcomes.Methods:This study retrospectively collected the essential clinical information of patients with an initral diagnosis of lung cancer who received treatment with immune checkpoint inhibitors(ICIs)at the First Affiliated Hospital of Guangzhou Medical University and Shanghai Pulmonary Hospital between January 2019 and September 2021.For patients with CIP,we also collected the time of its onset,grade,treatment regimen and outcome.The analyses of incidence,patient’s characteristics and the risk factors of CIP in overall and subgroup were carried out.Moreover,we analyzed the outcomes of patients treated with immunosuppressive therapy.Results:A total of 2031 patients with immunotherapy were enrolled,with a CIP incidence rate of 7.2%(147/2031),a severe CIP rate of 2.6%(52/2031)and a mortality rate of 0.4%(9/2031).The rate of severe grade in the population with CIP was 35.4%,and the mortality rate was 6.1%(9/147).Compared with non-CIP patients,more CIP patients were male,older(>65 years),with combination therapy,and on first-and second-line immunotherapy in advanced treatment.In subgroup analyses,the incidence of CIP was higher in men,the elderly(>65 years),squamous cancer,combination therapy,anti-PD-1 inhibitors,and first-and second-line therapy in advanced treatment.The median onset time of CIP in the real world was 148 days,with a double-peak characteristic,that was,60-90 days and 150-210 days after immunotherapy were both the peak time periods for CIP onset.The incidence of CIP was also influenced by seasonality,with a high incidence in autumn and winter.All treated patients used corticosteroids as first-line treatment;the immunosuppressive treatment rate of CIP in this study was 76.2%.After treatment,97.9%of mild CIP patients and 81.2%of severe CIP patients had a good prognosis,and 17.3%of severe CIP patients died due to CIP.Conclusion:In the real world,the incidence of CIP for lung cancer patients was 7.2%,incidence of severe CIP was 2.6%,and mortality rate was 0.4%;the incidence of severe disease in the population with CIP was 35.4%,and mortality rate was 6.1%.The median onset time of CIP was characterized by a double peak,and incidence of CIP was higher in autumn and winter.Men,the elderly,squamous cancer patients,patients on combination therapy,patients who used anti-PD-1 inhibitors,and patients with advanced treatment had higher incidence of CIP.Most patients with CIP had good outcomes after immunosuppressive therapy.