联合PD-1/L1免疫检查点抑制剂方案用于EGFR-TKIs耐药后晚期非小细胞肺癌的疗效分析

来源期刊：广州医药 | 1437-1443 发布时间：2025-01-08 收稿时间：2025/11/13 18:42:05 阅读量：53

作者：: 葛建娟,

施向荣,

周艳,

谭清和,

李剑英,

关键词：: PD-1/L1免疫检查点抑制剂 EGFR-TKIs耐药非小细胞肺癌晚期安全性生存质量; PD-1/L1 immune checkpoint inhibitor EGFR-TKIs resistance late stage non small cell lung cancer security quality of life

DOI：: 10.20223/j.cnki.1000-8535.2024.12.008

收稿时间：: 2024-02-27
修订日期：
接收日期：
引用总数：: 2

目的探讨表皮生长因子受体酪氨酸酶抑制剂（EGFR-TKIs）一线治疗耐药后,二线化学治疗（化疗）联合程序性死亡蛋白1及其配体（PD-1/L1）免疫检查点抑制剂方案对晚期非小细胞肺癌（NSCLC）的疗效。方法选取2018年 6月—2022年10月期间就诊于南通大学附属肿瘤医院院的80例有完整临床资料、应用EGFR-TKIs耐药后晚期NSCLC患者进行回顾性分析,依照不同治疗方式将患者分为观察组与对照组,均为40例。对照组一线EGFR-TKIs治疗耐药后进行二线化疗,观察组一线EGFR-TKIs治疗耐药后进行二线化疗联合PD-1/L1免疫检查点抑制剂治疗。对比两组临床疗效及无进展生存期（PFS）,化疗前后血清中人细胞角蛋白21-1片段（Cyfra21-1）、糖类抗原125（CA125）、碱性成纤维细胞生长因子（bFGF）、血管内皮生长因子（VEGF）水平变化,不良反应发生率及生存质量。结果观察组客观缓解率与疾病控制率高于对照组（P<0.05）,对照组PFS为10（2.38,24.13）个月,观察组PFS为14（5.27~,5.27）个月,观察组高于对照组（χ²=4.536,P=0.041）;化疗后两组bFGF、VEGF,CA125、Cyfra21-1肿瘤标志物水平均比化疗前降低,且观察组[（17.85±3.32）ng/L、（310.51±88.37）ng/L、（51.62±13.66）U/mL、（10.26±3.37）ng/mL]低于对照组[（19.62±3.24）ng/L、（366.26±49.42）ng/L、（59.26±9.35）U/mL、（12.62±2.73）ng/mL],对比差异有统计学意义（t₁=2.413,P₁=0.018;t₂=3.482,P₂<0.001;t₃=2.919,P₃=0.005;t₄=3.442,P₄<0.001）;两组不良反应发生率对比差异无统计学意义（P>0.05）;化疗后两组世界卫生组织生存质量量表简表评分均升高,观察组[（98.62±8.24）、（101.53±12.62）、（95.28±11.15）、（97.79±10.47）分]高于对照组[（84.25±7.32）、（93.58±15.75）、（82.24±9.34）、（83.47±8.38）]分,对比差异有统计学意义（t₁=8.246,P₁<0.001;t₂=2.491,P₂=0.015;t₃=5.670,P₃<0.001;t₄=6.753,P₄<0.001）。结论对EGFR-TKIs耐药后晚期非小细胞肺癌患者采取二线化疗联合PD-1/L1免疫检查点抑制剂可提升其临床疗效及生存期,改善血清相关肿瘤标志物表达水平,提升患者生存质量。

Objective To explore the therapeutic effect of second-line chemotherapy combined with PD-1/L1 immune checkpoint inhibitor regimen on advanced non-small cell lung cancer（NSCLC） after epidermal growth factor receptor-tyrosine kinase inhibitors（EGFR-TKIs）resistance in first-line chemotherapy．Methods Retrospectively selected 80 patients with advanced NSCLC EGFR TKIs resistance,who were admitted to the Affiliated Cancer Hospital of Nantong University from June 2018 to October 2022．Patients were divided into an observation group and a control group according to different treatment methods,with 40 cases in each group．The control group received second-line chemotherapy after first-line EGFR-TKIs therapy resistance,while the observation group received second-line chemotherapy and PD-1/L1 inhibitor after first-line EGFR-TKIs therapy reactions and quality of live．Clinical efficacy and PFS,changes in serum levels of human Cyfra21-1,CA125,bFGF,VEGF,incidence of adverse chemotherapy of two groups were compared．Results The ORR and DCR of the observation group were significantly higher than those of the control group（P<0.05）．The mean PFS of the control group was 10（2.38-24.13）months,while the mean PFS of the observation group was 14（5.27-35.27）months．The observation group was higher than the control group（χ²=4.536,P=0.041）．After chemotherapy,levels of bFGF,VEGF,CA125 and Cyfra21-1 tumor markers decreased in both groups,and the observation group [（17.85±3.32）ng/L,（310.51±88.37）ng/L,（51.62±13.66）U/mL,（10.26±3.37）ng/mL] was lower than the control group [（19.62±3.24）ng/L,（366.26±49.42）ng/L,（59.26±9.35）U/mL,（12.62±2.73）ng/mL],which showed statistically significant difference in the comparison（t₁=2.413,P₁=0.018;t₂=3.482,P₂<0.001;t₃=2.919,P₃=0.005;t₄=3.442,P₄<0.001）．There was no significant difference in the incidence of adverse reactions between the two groups（P>0.05）．After treatment,the WHO QOL-BREF scores increased in both patient groups and the observation group scores[（98.62±8.24）,（101.53±12.62）,（95.28±11.15）,（97.79±10.47）] were higher than the control group scores[（84.25±7.32）,（93.58±15.75）,（82.24±9.34）,（83.47±8.38）],which showed statistically significant difference．（t₁=8.246,P₁<0.001;t₂=2.491,P₂=0.015;t₃=5.670,P₃<0.001;t₄=6.753,P₄<0.001）．Conclusions The combination of second-line chemotherapy with PD-1/L1 immune checkpoint inhibitors can improve the clinical efficacy and survival of advanced NSCLC patients who are resistant to EGFR-TKIs,improve the expression levels of serum related tumor markers,and enhance the quality of life of patients．

1、邹琴,龙玲,叶容,等.PD-1抑制剂免疫治疗NSCLC所致反应性毛细血管增生症的研究进展[J].中华肺部疾病杂志(电子版),2023,16(2):278-280.

2、李敏婕,刘淑红,陈洪云,等.非小细胞肺癌患者血清miR-374b-5p、VEGF-C的表达及与预后的关系[J].中国医药导报,2023,20(26):22-26.

3、权小英,陈小艳,雷蕾,等.免疫检查点抑制剂联合全身化疗及腹腔热灌注化疗治疗恶性腹膜间皮瘤1例[J].中国癌症防治杂志,2023,15(1):104-106.

4、冷家骅,林子义,宣建伟.PD-1抑制剂免疫治疗对中国食管鳞癌患者的潜在健康产出探索[J].世界临床药物,2023,44(1):51-58,100.

5、尹瑞华,王庆华,郑红娟,等.晚期食管鳞状细胞癌一线多种PD-1抑制剂免疫治疗策略的成本-效用分析[J].中国肿瘤生物治疗杂志,2023,30(2):150-155.

6、孙彦顺,王陵,姜诗瑶,等.基于真实世界的肿瘤免疫治疗药物PD-1/PD-L1抑制剂使用情况分析[J].中国医科大学学报,2023,52(9):769-774.

7、孙小虎,王璐,白静慧,等.晚期肝癌免疫微环境CD38表达水平与PD-1抑制剂疗效相关性分析[J].肝脏,2023,28(1):75-78,94.

8、郑杨,帕提古力·阿尔西丁.CTLA-4和PD-1/PD-L1免疫检查点抑制剂在广泛期小细胞肺癌中的研究进展[J].中国临床研究,2023,36(6):805-809.

9、顾晓凌,吴冠楠,王栋,等.免疫检查点抑制剂相关甲状腺不良事件对PD-1单抗治疗非小细胞肺癌的预测价值[J].东南国防医药,2023,25(1):7-12.

10、许雨柔,邹宜丰,蔡宁,等.晚期食管癌PD-1/PD-L1免疫检查点抑制剂疗法的Cochrane Meta分析[J].复旦学报(医学版),2023,50(5):660-669,682.

11、尹岳松,吴玉佩,王倩,等.PD-1/PD-L1抑制剂致免疫检查点抑制剂相关性肺炎的临床特点分析[J].临床药物治疗杂志,2023,21(9):62-66.

12、刘世一,陈中,张素欣.程序性死亡受体/配体免疫治疗策略在人乳头瘤病毒阳性头颈部鳞状细胞癌中的研究进展[J].国际口腔医学杂志,2024,51(1):21-27.

13、冉方兰,张孝彬,卢安静,等.特瑞普利单抗注射液联合长春瑞滨+顺铂化疗一线治疗晚期NSCLC的效果及对外周血淋巴细胞PD-1变化的影响[J].实用药物与临床,2022,25(11):981-985.

14、 KORDE R,VELUSWAMY R,ALLAIRE J C,et al.Small cell lung cancer patients treated with immune checkpoint inhibitor:a systematic literature review of treatment efficacy,safety and quality of life[J].Curr Med Res Opin,2022,38(8):1361-1368.

15、 SICILIANO MA,CARIDà G,CILIBERTO D,et al.Efficacy and safety of first-line checkpoint inhibitors-based treatments for non-oncogene-addicted non-small-cell lung cancer:a systematic review and meta-analysis[J].ESMO Open,2022,7(3):100465.

16、 ZHANG M,FAN Y,NIE L,et al.Clinical outcomes of immune checkpoint inhibitor therapy in patients with advanced non-small cell lung cancer and preexisting interstitial lung diseases:A systematic review and meta-analysis[J].Chest,2022,161(6):1675-1686.

17、 GENG Y,ZHANG Q,FENG S,et al.Safety and Efficacy of PD-1/PD-L1 inhibitors combined with radiotherapy in patients with non-small-cell lung cancer:a systematic review and meta-analysis[J].Cancer Med,2021,10(4):1222-1239.

18、 CHEN J,WANG J,XU H.Comparison of atezolizumab,durvalumab,pembrolizumab,and nivolumab as first-line treatment in patients with extensive-stage small cell lung cancer:A systematic review and network meta-analysis[J].Medicine(Baltimore),2021,100(15):e25180.

19、 ZHOU T,ZHANG Z,LUO F,et al.Comparison of first-line treatments for patients with extensive-stage small cell lung cancer:A systematic review and network meta-analysis[J].JAMA Netw Open,2020,3(10):e2015748.

20、冯浩洁,姚颐,耿庆.美国国家综合癌症网络临床实践指南:非小细胞肺癌(2021V1)更新解读[J].临床外科杂志,2021,29(1):25-28.

21、韦坤辰,包淑钧,陈杨,等.PD-1/L1免疫检查点抑制剂用于EGFR-TKIs耐药后晚期非小细胞肺癌的疗效分析[J].临床肺科杂志,2023,28(6):817-821.

22、王皓,曾晨欣,李俐,等.奥希替尼和吉非替尼/厄洛替尼一线治疗EGFR突变阳性非小细胞肺癌的成本-效果分析[J].医药导报,2020,39(12):1689-1696.

23、季刚,朱晓丽,张玲,等.BEAMing ddPCR与Super ARMS检测EGFR酪氨酸激酶抑制剂治疗后非小细胞肺癌患者循环肿瘤DNA EGFR基因突变的比较研究[J].中国癌症杂志,2020,30(5):335-339.

24、凌丰宇,李明,陈青娟,等.贝伐珠单抗联合第一代表皮生长因子受体-酪氨酸激酶抑制剂一线治疗EGFR基因突变阳性晚期非小细胞肺癌的Meta分析[J].肿瘤,2020,40(5):339-347,354.

25、 QIN K,HOU H,LIANG Y,et al.Prognostic value of TP53 concurrent mutations for EGFR-TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer:A meta-analysis[J].BMC Cancer,2020,20(1):1-9.

1、姚朝聪.PD-1抑制剂联合化疗比较单独化疗治疗复发或转移胸腺癌的临床疗效及安全性Meta分析[D].桂林医科大学,2025.DOI:10.27806/d.cnki.gglyx.2025.000279.

2、范丽丽,常金.非小细胞肺癌干细胞靶点筛选及NDC80临床意义分析[J/OL].广州医药,1-13[2026-01-08].https://link.cnki.net/urlid/44.1199.R.20250721.1651.002.