Association of Survival and Immune-Related Biomarkers With Immunotherapy in Patients With Non-Small Cell Lung Cancer A Meta-analysis and Individual Patient-Level Analysis
Association of Survival and Immune-Related Biomarkers With Immunotherapy in Patients With Non-Small Cell Lung Cancer A Meta-analysis and Individual Patient-Level Analysis
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DOI：
10.1001/jamanetworkopen.2019.6879
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发表时间：
2019-07-01
影响因子：
13.8
通讯作者：
Yao, Herui
中科院分区：
文献类型：
--
作者：
Yu, Yunfang;Zeng, Dongqiang;Yao, Herui
免疫治疗的有益作用和当前生物标志物在非小细胞肺癌（NSCLC）中的临床相关性仍不确定;因此，适当的策略和可靠的预测因子需要进一步定义。结论为了评估晚期NSCLC患者的临床结果与免疫检查点抑制剂、肿瘤疫苗和细胞免疫治疗的相关性，并探索适当的策略、候选物，数据来源PubMed、EMBASE和科克伦对照试验中心注册数据库从开始到2018年6月进行检索，使用相关检索关键词和医学主题词（MeSH）术语，包括肿瘤疫苗、细胞免疫疗法、免疫检查点抑制剂、细胞毒性T淋巴细胞相关蛋白4、程序性死亡配体1、程序性死亡受体1和非小细胞肺癌。系统评价、荟萃分析、参考文献和会议记录手动检索。研究选择纳入英文随机临床试验，并比较免疫检查点抑制剂、肿瘤疫苗或细胞免疫疗法与常规疗法治疗晚期或转移性NSCLC患者的总生存期（OS）、无进展生存期（PFS）或客观缓解率。纳入31项免疫治疗随机临床试验，多队列数据包括来自晚期NCSLC.DATA提取和综合的患者的下一代测序数据，合并风险比和95%CI以估计OS和PFS的生存增加。使用风险比分析二分数据，例如对象应答率数据。采用Mantel-Haenszel随机效应模型。I-2用于评估试验间的异质性; I-2值超过50%表明存在实质性异质性。分析时间为2018年2月1日至2018年8月31日。主要结局和指标主要结局为OS和PFS。荟萃分析中纳入了9500例[66.0%]男性患者，个体患者水平研究中纳入了1833例患者（平均[SD]，65.2 [9.9]岁; 1063例[58.0%]男性患者）。与常规治疗相比，免疫治疗与OS（风险比，0.76; 95%CI，0.71-0.82; P < .001）和PFS（风险比，0.76; 95%CI，0.70-0.83; P < .001）显著延长相关。最好的检查点阻断策略是一线pembrolizumab联合铂类化疗。程序性细胞死亡配体1（PD-L1）表达和肿瘤突变负荷（TMB）的联合预测效用与预测预后相关（全外显子组测序：1年PFS受试者工作特征曲线下面积[AUC]，0.829; 3年PFS AUC，0.839;靶向下一代测序：1年PFS AUC，0.826; 3年PFS AUC，0.948）。此外，加入CD 8 + T细胞肿瘤浸润淋巴细胞与改善的OS预后预测相关（3年OS AUC，0.659; 5年OS AUC，0.665）。RYRI或MGAM突变与伴随增加的持久临床获益显著相关（RYRI：持久临床获益[DCB]，51例患者中有12例[24%];无持久获益[NDB]，55例患者中有2例[4%]; P < .001; MGAM：DCB，51例患者中有12例[24%]; NDB，0例患者; P < .001），较高的TMB（RYRI：高TMB，12/53例[23%];低TMB，2/53例[38%]; P
IMPORTANCE The beneficial role of immunotherapy and the clinical relevance of current biomarkers in non-small cell lung cancer (NSCLC) remain inconclusive; thus, appropriate strategies and reliable predictors need further definition.OBJECTIVES To evaluate the association of clinical outcomes with immune checkpoint inhibitors, tumor vaccines, and cellular immunotherapy in patients with advanced NSCLC and to explore appropriate strategies, candidates, and predictors.DATA SOURCES The PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception to June 2018, using relevant search keywords and Medical Subject Headings (MeSH) terms, including tumor vaccine, cellular immunotherapy, immune checkpoint inhibitor, cytotoxic T-lymphocyte-associated protein 4, programmed death-ligand 1, programmed death receptorl, and non-small cell lung carcinoma. Systematic reviews, meta-analyses, references, and conference proceedings were manually searched.STUDY SELECTION English-language random zed clinical trials with available data that measured overall survival (OS), progression-free survival (PFS), or objective response rate comparing immune checkpoint inhibitors, tumor vaccines, or cellular immunotherapy with conventional therapy for patients with advanced or metastatic NSCLC were included. Thirty-one immunotherapy randomized clinical trials were included, and multicohort data included next-generation sequencing data from patients with advanced NCSLC.DATA EXTRACTION AND SYNTHESIS Hazard ratios and 95% CIs were pooled to estimate the survival increases in OS and PFS. Dichotomous data, such as object response rate data, were analyzed using the risk ratio. Mantel-Haenszel random-effects model was used. I-2 was used to assess the heterogeneity between trials; an I-2 value exceeding 50% indicated the existence of substantial heterogeneity. Analyses took place from February 1, 2018, to August 31, 2018.MAIN OUTCOMES AND MEASURES Primary outcomes were OS and PFS.RESULTS In total, 14 395 patients (9500 [66.0%] men) were included in the meta-analysis, and 1833 patients (mean [SD], 65.2 [9.9] years; 1063 [58.0%] men) were included in the individual patient-level study. Compared with conventional therapy, immunotherapy was associated with significantly longer OS (hazard ratio, 0.76; 95% CI, 0.71-0.82; P < .001) and PFS (hazard ratio, 0.76; 95% CI, 0.70-0.83; P < .001). The best checkpoint blockade strategy was first-line pembrolizumab with platinum-based chemotherapy. The combined predictive utility of programmed cell death ligand 1(PD-L1) expression and tumor mutation burden (TMB) was associated with predictive prognosis (whole-exome sequencing: 1-year PFS area under the receiver operating characteristic curve [AUC], 0.829; 3-year PFS AUC, 0.839; targeted next-generation sequencing: 1-year PFS AUC, 0.826; 3-year PFS AUC, 0.948). Moreover, the addition of CD8' T-cell tumor-infiltrating lymphocytes was associated with improved prognosis predictions for OS (3-year OS AUC, 0.659; 5-year OS AUC, 0.665). RYRI or MGAM mutations were significantly associated with concomitantly increased durable clinical benefits (RYRI: durable clinical benefit [DCB], 12 of 51 patients [24%]; no durable benefit [NDB], 2 of 55 patients [4%]; P < .001; MGAM: DCB, 12 of 51 patients [24%]; NDB, 0 patients; P < .001), a higher TMB (RYRI: high TMB, 12 of 53 patients [23%]; low TMB, 2 of 53 patients [38%]; P