RTI Health Solutions, The Pavilion, Towers Business Park, Wilmslow Road, Didsbury, Manchester, M20 2LS, UK.
Eli Lilly and Company Limited, Indianapolis, IN, USA.
BMC Cancer. 2019 Apr 15;19(1):353. doi: 10.1186/s12885-019-5569-5.
Locally advanced or metastatic non-small cell lung cancer (NSCLC) that has progressed after first-line treatment has a poor prognosis. Recent randomized clinical trials (RCTs) have demonstrated survival benefits of alternative treatments to docetaxel. However, information is lacking on which patients benefit the most and what drug or regimen is optimal. We report a systematic review and network meta-analysis (NMA) of second-line treatments in all subgroup combinations determined by histology, programmed death ligand 1 (PD-L1) expression, and epidermal growth factor receptor (EGFR) mutation.
MEDLINE, PubMed, EMBASE, Biosciences Information Service (using the Dialog Platform), Cochrane Library, and abstracts from scientific meetings were searched for RCTs published up to September 2015. Key outcomes were overall survival (OS) and progression-free survival (PFS). Bayesian hierarchical exchangeable NMAs were conducted to calculate mean survival times and relative differences for eight subgroups, using docetaxel as the reference comparator. For OS, the NMA was based on hazard ratios applied to a first-order fractional polynomial model fitted to the reference treatment. For PFS, a second-order fractional polynomial model was fitted to reconstructed patient-level data for the entire network of evidence.
The search identified 30 studies containing 17 different treatment regimens. Docetaxel plus ramucirumab was associated with a significant improvement in OS and PFS, relative to docetaxel, regardless of patient type. Docetaxel plus nintedanib showed similar efficacy to docetaxel plus ramucirumab in the nonsquamous populations. EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib showed superior levels of efficacy in EGFR mutation-positive populations and the one PD-1 immunotherapy (nivolumab) studied showed superior efficacy in the populations exhibiting high PD-L1 expression.
In the absence of head-to-head comparisons, we performed a mixed-treatment analysis to synthesize evidence of the efficacy of each treatment. Benefits are optimized by targeting specific treatments to individual patients guided by histology, PD-L1 expression, and EGFR mutation status.
This review is registered in PROSPERO (registration number: CRD42014013780 available at www.crd.york.ac.uk/PROSPERO ).
一线治疗后进展的局部晚期或转移性非小细胞肺癌（NSCLC）预后较差。最近的随机临床试验（RCT）已经证明了替代多西他赛治疗的生存获益。然而，关于哪些患者获益最大以及哪种药物或方案最优化的信息仍然缺乏。我们报告了一项系统评价和网络荟萃分析（NMA），评估了根据组织学、程序性死亡配体 1（PD-L1）表达和表皮生长因子受体（EGFR）突变确定的所有亚组组合的二线治疗。
MEDLINE、PubMed、EMBASE、Biosciences Information Service（使用 Dialog Platform）、Cochrane Library 以及科学会议摘要进行了检索，检索了截至 2015 年 9 月发表的 RCTs。主要终点是总生存（OS）和无进展生存（PFS）。采用贝叶斯分层可交换网络荟萃分析（NMA），以多西他赛为参照比较，计算 8 个亚组的平均生存时间和相对差异。对于 OS，NMA 基于适用于参照治疗的一阶分数多项式模型的风险比。对于 PFS，对整个证据网络的重建患者水平数据进行二阶分数多项式模型拟合。
检索共确定了 30 项研究，包含 17 种不同的治疗方案。与多西他赛相比，多西他赛联合雷莫芦单抗无论患者类型如何，均显著改善 OS 和 PFS。在非鳞状人群中，多西他赛联合尼达尼布的疗效与多西他赛联合雷莫芦单抗相似。表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）厄洛替尼和吉非替尼在 EGFR 突变阳性人群中显示出更高的疗效，研究中的一种 PD-1 免疫疗法（纳武单抗）在高 PD-L1 表达人群中显示出更高的疗效。
由于缺乏头对头比较，我们进行了混合治疗分析，以综合评估每种治疗的疗效证据。通过针对特定患者的组织学、PD-L1 表达和 EGFR 突变状态，靶向特定治疗，可优化获益。
本综述在 PROSPERO（注册号：CRD42014013780，可在 www.crd.york.ac.uk/PROSPERO 获得）中注册。
