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免疫卡控点抑制剂联合化疗一线治疗晚期非小细胞肺癌的疗效与安全性Meta分析

Efficacy and Safety of Immune Checkpoint Inhibitors Plus Chemotherapy as a First line Treatment for Advanced Non small Cell Lung Cancer: a Meta analysis

DOI：

中文关键词: 非小细胞肺癌免疫卡控点抑制剂有效性安全性 Meta分析随机对照试验

英文关键词:Non small cell lung cancer Immune checkpoint inhibitors Efficacy Safety Meta analysis Randomized controlled trial

基金项目:国家自然科学基金项目（编号：81601153），江苏省自然科学基金项目（编号：BK20150104），南京市医学科技发展项目（编号:YKK16083）

作者	单位
丁芸兰1,2 周海辉1 周玉皆3	1.南京大学医学院附属鼓楼医院药学部，南京 210008；2. 中国药科大学基础医学与临床药学学院；3.南京大学医学院附属鼓楼医院呼吸内科

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中文摘要:

摘要目的：评价免疫卡控点抑制剂程序性细胞死亡蛋白1（programmed cell death 1，PD 1）/程序性细胞死亡蛋白1配体（programmed cell death protein ligand 1，PD L1）单抗联合化疗对比单纯化疗方案，一线治疗晚期非小细胞肺癌（non small cell lung cancer，NSCLC）的疗效和安全性。 方法：计算机检索PubMed、The Cochrane Library、Scopus、ScienceDirect数据库，纳入PD 1/PD L1单抗联合化疗对比单纯化疗一线治疗晚期NSCLC的随机对照试验（randomized controlled trials, RCTs），检索时限为建库至2019年1月。由两位研究者独立筛选文献、提取资料和评价纳入研究的偏倚风险后，采用RevMan 5.3软件进行Meta分析。 结果：共纳入7项RCTs，3 722例患者。Meta分析结果显示，联合组的无进展生存期（progression free survival，PFS）[HR=0.62，95%CI（0.57，0.67）， P<0.000 01]、总生存期（overall survival，OS）[HR=0.71，95%CI（0.58，0.87），P=0.000 7]和客观缓解率（objective response rate，ORR）[RR=1.56，95%CI（1.35， 1.79），P＜0.000 01]等指标的生存获益均显著高于化疗组。亚组分析显示，年龄＜65岁[HR=0.47，95%CI（0.36，0.61），P＜0.000 01]、非鳞癌[HR=0.66，95%CI（0.51，0.85），P=0.001]、女性[HR=0.32，95%CI(0.23，0.46），P＜0.000 01]及使用PD 1单抗[HR=0.56，95%CI（0.47，0.67），P＜0.000 01]的患者免疫治疗更能延长OS；PD L1表达水平≥50%的患者PFS显著延长[HR=0.39，95%CI（0.32，0.48），P＜0.000 01]。联合组≥3级药品不良事件（adverse drug event，ADE）[RR=1.17，95%CI（1.06，1.30），P=0.002]、任何级别的免疫相关性不良事件（immune related adverse event，IRAE）[RR=2.32，95%CI（1.92，2.81），P＜0.000 01]显著高于化疗组。 结论：现有证据表明，PD 1/PD L1单抗联合化疗一线治疗晚期NSCLC患者较单纯化疗表现出较好疗效，但需警惕≥3级ADE及IRAE。受纳入研究数量和质量的限制，上述结论尚待开展更多高质量研究予以验证。

英文摘要:

ABSTRACT Objective:To assess the efficacy and safety of PD 1/PD L1 inhibitor combined with standard chemotherapy in the first line treatment of non small cell lung cancer (NSCLC). Methods:PubMed, The Cochrane Library, Scopus and ScienceDirect were electronically searched to collect randomized controlled trials (RCTs) of PD 1/PD L1 inhibitor combined with chemotherapy versus chemotherapy as first line treatment for advanced NSCLC from inception to January 2019. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies, then, Meta analysis was performed using RevMan 5.3 software. Results: In all, 3 722 patients with advanced NSCLC were enrolled in 7 RCTs. The results of Meta analysis showed that PFS (HR=0.62, 95%CI 0.57 to 0.67, P<0.000 01), OS (HR=0.71, 95%CI 0.58 to 0.87, P=0.000 7) and ORR (RR=1.56, 95%CI 1.35 to 1.79, P<0.000 01) of patients in PD 1/PD L1 inhibitor combination group achieved a better survival benefit than those in chemotherapy group. Subgroup analysis showed that patients with age < 65 years (HR=0.47, 95%CI 0.36 to 0.61, P<0.000 01), non squamous cell carcinoma (HR=0.66, 95%CI 0.51 to 0.85, P=0.001), female (HR=0.32, 95%CI 0.23 to 0.46, P<0.000 01) and using PD 1 drugs (HR=0.56, 95%CI 0.47 to 0.67, P<0.000 01) achieved better OS; Patients with PD L1 expression level ≥ 50% (HR=0.39, 95%CI 0.32 to 0.48, P<0.000 01) significantly prolonged PFS. The rate of grade ≥ 3 ADE (RR=1.17, 95%CI 1.06 to 1.30, P=0.002), any grade of IRAE (RR=2.32, 95%CI 1.92 to 2.81, P<0.000 01) in combination group was significantly higher than chemotherapy group. Conclusion:Available evidence shows that, PD 1/PD L1 inhibitor combined with chemotherapy as first line treatment of patients with advanced NSCLC is more effective than chemotherapy alone, but ADE with grade 3 or IRAE should be alerted. Due to limited quantity and quality of the included studies, more high quality studies are needed to verify the above conclusions.

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