晚期非小细胞肺癌程序性死亡蛋白-1/程序性死亡蛋白配体-1抑制剂治疗免疫相关性肺炎的临床分析

Clinical analysis of immunotherapy-related pneumonitis in advanced non-small cell lung cancer patients treated with programmed death-1/programmed death ligand-1 inhibitors

目的汇总分析晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)程序性死亡蛋白-1(programmed death-1,PD-1)/程序性死亡蛋白配体-1(programmed death ligand-1,PD-L1)抑制剂单药治疗后免疫相关性肺炎的发生、发展、治疗及转归等情况。方法回顾性分析2015年6月至2019年5月同济大学附属上海市肺科医院接受PD-1/PD-L1抑制剂治疗后出现免疫相关性肺炎的晚期NSCLC患者的基线临床资料、免疫相关性肺炎发病率、发生时间、严重程度、影像学表现、治疗、转归等情况。结果共109例患者使用PD-1/PD-L1抑制剂单药治疗,13例(11.9%)患者出现免疫相关性肺炎。免疫相关性肺炎患者的中位年龄和吸烟患者占比均显著高于非免疫相关性肺炎患者(均P<0.05)。发生免疫相关性肺炎的患者中,1~2级免疫相关性肺炎7例(53.8%),3~4级免疫相关性肺炎6例(46.2%);发生时间为免疫治疗后6.3~80.0周,中位发生时间为28.5周。9例(69.2%)患者出现免疫相关性肺炎临床表现,胸闷5例,气促9例,呼吸困难4例,咳嗽咳痰8例,呼吸衰竭5例,伴发热2例;其余4例(30.8%)患者无特征性临床表现。影像学表现:多灶性磨玻璃影1例,双肺斑片影4例,斑片影和结节影混合分布4例,斑片影合并蜂窝肺表现3例,实变影1例。12例患者接受了激素治疗,1例患者未治疗。激素治疗后,11例患者病情好转或稳定,1例患者病情加重。无免疫相关性肺炎导致的死亡病例。治疗好转后4例患者继续使用原免疫方案治疗,未见免疫相关性肺炎复发或加重。结论PD-1/PD-L1抑制剂所致免疫相关性肺炎是一种相对少见但可致命的不良事件,其影像学表现多样,激素治疗有效,密切监测、及时发现和治疗是减少免疫相关性肺炎的关键。

Objective This study summarized and analyzed the occurrence,development,treatment and outcome of immunotherapy-related pneumonitis in advanced non-small cell lung cancer(NSCLC)patients treated with single-drug therapy of programmed death-1(PD-1)/programmed death ligand-1(PD-L1)inhibitors to provide references for the diagnosis and treatment of immunotherapy-related pneumonitis.Method Patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors in Shanghai Pulmonary Hospital,Tongji University from June 2015 to May 2019 were collected.Patients'baseline clinical data,occurrence rate,onset time,severity,imaging manifestations,treatment and outcome of immunotherapy-related pneumonitis were retrospectively analyzed.Result A total of 109 patients were treated with PD-1/PD-L1 inhibitor monotherapy,and 13 patients(11.9%)developed immunotherapy-related pneumonitis.The median age of patients with immunotherapy-related pneumonitis and the proportion of smoking patients were significantly higher than those of patients with non-immunotherapy-related pneumonitis(all P<0.05).In 13 cases of immunotherapy-related pneumonitis,7 patients(53.8%)developed grade 1~2 adverse events,and 6 patients(46.2%)developed grade 3~4 adverse events.The immunotherapy-related pneumonitis occurred at median of 28.5 weeks(ranged from 6.3~80.0 weeks).9 patients(69.2%)showed clinical manifestations of immunotherapy-related pneumonitis,such as chest tightness(5 cases),shortness of breath(9 cases),dyspnea(4 cases),cough,expectoration(8 cases),respiratory failure(5 cases)and fever(2 cases),while the remaining 4 patients(30.8%)showed no characteristic clinical manifestations.CT imaging findings:ground glasses in 1 case,patchy shadows in 4 cases,patchy shadows and consolidation mixing in 4 cases,patch shadow combined with interstitial manifestations in 3 cases,consolidation shadow in 1 case.Twelve patients were received corticosteroids,1 patient with grade 1 without treatment.After treatment,the condition of 11 patients was improved or stable,and the condition of 1 patient was aggravated.No immunotherapy-related pneumonitis deaths occurred.4 patients rechallenged with immunotherapy after recovered to stage 1 adverse events.No immunotherapy-related pneumonitis occurred again in those rechallenged patients.Conclusion Immunotherapyrelated pneumonitis caused by PD-1/PD-L1 inhibitors is a relatively rare but potentially fatal adverse event.Its imaging manifestations are diverse,hormone therapy is effective,and close monitoring,timely detection and treatment are the keys to reduce immunotherapyrelated pneumonitis.