老年肺鳞癌患者免疫治疗疗效及不良反应观察

Clinical observation of immunotherapy efficacy and adverse effects in elderly patients with lung squamous cell carcinoma

目的探讨真实世界中老年肺鳞状细胞癌(肺鳞癌)患者免疫治疗的疗效和不良反应。方法回顾性分析2018年1月至2022年1月就诊于北京医院经病理明确诊断的老年肺鳞癌患者(≥65岁)113例,44例接受手术或微创治疗,69例患者接受内科一线治疗,其中化疗组27例,免疫联合化疗(联合组)24例,免疫组11例,靶向治疗组7例。28例患者接受内科二线治疗,其中化疗组8例,联合组11例,免疫组4例,靶向治疗组5例。比较一线、二线治疗中免疫治疗效果和相关不良反应。评价程序性死亡配体1(PD-L1)表达和肿瘤突变负荷(TMB)作为疗效、预后标志物的价值。采用实体瘤疗效评价标准(RECIST1.1)评价近期疗效,常见不良反应分级评价标准(CTCAE 4.03)评价免疫相关不良反应。Kaplan-Meier法绘制生存曲线,并进行Log-rank检验。Cox风险比例回归模型分析影响预后的因素。结果老年肺鳞癌患者一线联合组总有效率73.7%(14/19),高于化疗组24.0%(6/25),差异有统计学意义(χ^(2)=10.748,P<0.01)。一线联合组、免疫组与化疗组患者比较,中位无进展生存时间(mPFS)延长,且联合组患者中位总生存时间(mOS)更长,但差异无统计学意义(均P>0.05);二线联合组和免疫组患者mOS时间较化疗组延长(均P<0.05)。老年肺鳞癌患者存在高的PD-L1阳性率(≥1%)和高TMB(≥9 mut/Mb)表达率,分别为81.6%(31/38)和57.4%(31/54)。一线联合组PD-L1阳性患者中mPFS优于PD-L1阴性患者(5.10个月比0.93个月,P<0.05)。PD-L1阳性患者中,二线联合组mPFS优于化疗组(7.33个月比2.77个月,P<0.05)。患者mPFS和mOS时间均与TMB表达无关。总体免疫相关不良反应发生率为62.0%(31/50),3级以上26.0%(13/50)。最常见的3级不良反应为皮疹、免疫相关性肺炎和乏力。结论老年肺鳞癌患者一线免疫联合化疗较化疗提高总有效率、mPFS和mOS。二线治疗中,免疫联合化疗与免疫单药均延长mOS,联合治疗较单药免疫无总生存获益。老年患者对单药免疫或联合化疗总体不良反应可控。

Objective To investigate the efficacy and adverse reactions of immunotherapy in elderly patients(≥65 years old)with lung squamous cell carcinoma(LUSC)in Chinese population of real world.Methods A total of 113 elderly LUSC patients(age≥65 years old)underwent pathological diagnosis were involved from January 2018 to January 2022.To compare the efficacy of mono-immunotherapy or combined with chemotherapy to chemotherapy in first-line and second-line treatment.44 patients received surgical or minimally invasive treatment,and 69 patients received first-line medical treatment,including 27 patients in chemotherapy group,24 patients in combined chemotherapy group,and 11 patients in single drug immunization group.7 cases in targeted therapy group.Twenty-eight patients received second-line medical treatment,including 8 patients in chemotherapy group,11 patients in combined immunochemotherapy(combined group),4 patients in single drug immunotherapy group,and 5 patients in targeted therapy group.The therapeutic effects and adverse reactions were compared between the first-line and second-line treatments.The expression of programmed death-ligand 1(PD-L1)and tumor mutational burden(TMB)were evaluated.Response evaluation criteria in solid tumors(RECIST)version 1.1 was used to evaluate the efficacy,and common terminology criteria for adverse events(CTCAE)version 4.03 was used to evaluate immune-related adverse.Kaplan-meier and log-rank test was performed.Cox regression was used in prognostic analysis.Results The total effective rate in the first-line combination group was 73.7%(14/19),higher than that in the chemotherapy group(24.0%,6/25),and the difference was statistically significant(χ^(2)=10.748,P<0.01).Median progression-free survival(mPFS)was longer in the first-line combination group,the immunization group,and the chemotherapy group,and the median overall survival(mOS)was longer in the combination group,but the differences were not statistically significant(all P<0.05);mOS in the second-line combined group were longer than those in the chemotherapy group,both (P<0.01).Elderly patients with lung squamous cell carcinoma had high PD-L1 positive rate(≥1%)and high TMB expression rate(≥9 mut/Mb),81.6%(31/38)and 57.4%(31/54),respectively.mPFS in the PD-L1 positive group(≥1%)was better than that in the PD-L1 negative group(5.10 months vs.0.93 months,P<0.05).Among PD-L1 positive patients,mPFS in the second-line combination group was better than that in the chemotherapy group(7.33 months vs.2.77 months,P<0.05).mPFS and mOS time were not related to TMB expression.The overall incidence of immune-related adverse reactions was 62.0%(31/50),and 26.0%(13/50)with grade 3 or above.The most common grade 3 adverse events were rash,immune-associated pneumonia,and fatigue.Conclusions Immunology combined with chemotherapy increased objective response rate,mPFS and mOS of elderly patients with LUSC group in first-line therapy compared with chemotherapy.In second-line treatment,the mOS was significantly prolonged in both combination therapy and mono-immunotherapy,and the combination therapy exhibited no benefit in OS compared with monotherapy.The adverse effects of immunology in elderly patients with LUSC were controllable.