真实世界老年小细胞肺癌患者一线免疫联合化疗疗效与不良反应观察

Efficacy and adverse effects of first-line immunotherapy combined with chemotherapy in real world elderly patients with small cell lung cancer

目的探讨真实世界中老年小细胞肺癌(SCLC)患者一线免疫联合化疗疗效和不良反应。方法回顾性分析2013年1月至2023年6月就诊于北京医院经穿刺/气管镜活检或手术病理明确诊断SCLC并接受一线内科治疗的广泛期老年患者(≥65岁)148例,其中化疗组103例、免疫联合化疗组(联合组)45例。按年龄分为≥75岁组和<75岁组,比较不同年龄组、一线不同治疗方式的疗效和免疫相关不良反应情况。评价程序性死亡配体1(PD-L1)表达和肿瘤突变负荷(TMB)表达情况及与生存的关系。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(CTCAE4.03)评价免疫相关不良反应。Kaplan-Meier法进行生存曲线分析,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SCLC患者一线联合组总有效率(ORR)79.1%(34/43),高于化疗组63.2%(60/95),但差异未达到统计学意义(χ^(2)=3.451,P=0.063)。≥75岁组患者联合组ORR显著高于化疗组,分别为87.5%(7/8)比48.6%(17/35)(χ^(2)=4.001,P=0.045)。总体患者联合组中位无进展生存时间(mPFS)与化疗组比较差异无统计学意义(5.43个月比6.07个月,P=0.660)。与化疗组相比,联合组延长患者中位总生存时间(mOS),但差异未达到统计学意义(13.63个月比11.97个月,P=0.205)。≥75岁患者中联合组mPFS低于化疗组(2.97个月比6.47个月).但mOS较化疗组延长(13.50个月比11.40个月),差异均未达到统计学意义(均P>0.05)。<75岁患者中联合组与化疗组mPFS和mOS差异均无统计学意义(均P>0.05)。存在严重合并症的老年患者中,联合组mPFS和mOS均低于化疗组(5.40个月比7.30个月、10.70个月比12.27个月,均P>0.05)。不伴有严重合并症患者中,联合组与化疗组mPFS差异无统计学意义(P>0.05),但联合组mOS明显延长(20.57个月比11.57个月,P=0.054)。老年SCLC患者PD-L1肿瘤细胞阳性比例分数(TPS)阳性率(≥1%)23.5%(4/17),高TMB(≥9mut/Mb)表达率69.0%(11/16)。总体免疫相关不良反应发生率为71.0%(32/45),3级以上33.3%(15/45),最常见的3级不良反应有皮疹、免疫相关性肺炎和乏力。结论老年SCLC患者一线免疫联合化疗较单纯化疗提高总有效率和中位总生存时间;≥75岁、不伴有严重合并症患者免疫联合化疗mOS获益更加明显,老年SCLC患者存在低PD-L1阳性率和高TMB表达,老年患者免疫相关不良反应总体可控。

Objective To investigate the efficacy and adverse effects of first-line immunotherapy combined with chemotherapy in elderly patients with small cell lung cancer(SCLC)in population of real world.Methods A total of 148 elderly SCLC patients(age≥65 years old)underwent pathological diagnosis were retrospectively analyzed from January 2013 to June 2023.103 patients received chemotherapy(chemotherapy group),and 45 patients received immunotherapy combined with chemotherapy(combination group).Patients were divided into senior group(≥75 years old)and younger group(<75 years old)by age.To compare the efficacy of different regimens in first-line treatment,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.o3 was used to evaluate immune-related adverse.Kaplan-meier and Log-rank test were performed.Cox regression was used in prognostic analysis.Results The overall response rate(ORR)of the first-line combination group in elderly SCLC patients was 79.1%(34/43),which was higher than that of the chemotherapy group 63.2%(60/95),but the difference did not reach statistical significance(χ^(2)=3.451,P=0.063).ORR was significantly higher in the combination group than in the chemotherapy group for patients in the≥75-year-old group,87.5%(7/8)vs.48.6%(17/35),respectively(χ^(2)=4.001,P=0.045).The difference in median progression-free survival time(mPFS)in the combination group compared with the chemotherapy group was not statistically significant in the overall patients(5.43 months us.6.07 months,P=0.660).The combination group prolonged patients'median overall survival time(mOS)compared with the chemotherapy group,but the difference did not reach statistical significance(13.63 months us.11.97 months,P=0.205).In patients≥75 years old,mPFS was lower in the combination group than in the chemotherapy group(2.97 months us.6.47 months),but mOS was prolonged compared with that in the chemotherapy group(13.50 months us.1l.40 months),and none of the differences reached statistical significance(both P>0.05).The differences in mPFS and mOS between the combination group and the chemotherapy group were not statistically significant in patients<75 years old(both P>0.05).In elderly patients with severe comorbidities,mPFS and mOS were lower in the combination group than in the chemotherapy group(5.40 months us.7.30 months and 10.70 months us.12.27 months,both P>0.05).In patients without severe comorbidities,the difference in mPFS between the combination group and the chemotherapy group was not statistically significant(P>0.05),but the mOS was significantly longer in the combination group(20.57 months s.11.57 months,P=0.054).Elderly SCLC patients had a positive PD-L1 tumor cell positive proportion score(TPS)rate(≥1%)of 23.5%(4/17)and a high TMB(≥9 mut/Mb)expression rate of 69.0%(11/16).The overall incidence of immune-related adverse reactions was 71.0%(32/45),grade 3 or higher 33.3%(15/45),and the most common grade 3 adverse reactions were rash,immune-related pneumonia and malaise.Conclusions First-line immune-combination chemotherapy improves ORR and mOS over chemotherapy in elderly SCLC patients;mOS benefit of immune-combination chemotherapy is more pronounced in patients≥75 years of age without severe comorbidities,low PD-Ll positivity and high TMB expression are present in elderly SCLC patients,and immune-related adverse effects are generally manageable in elderly patients.