In the absence of head-to-head trials of first-line treatments for metastatic
non-small cell lung cancer (NSCLC), synthesis of available evidence is needed. We conducted a systematic literature review and network meta-analysis of randomized controlled trials in patients with stage IV NSCLC and high
programmed death-ligand 1 (PD-L1) expression. Patients with other-stage NSCLC or without PD-L1 expression and populations with < 80% stage IV NSCLC were excluded. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events. English records from MEDLINE and Embase published through October 2020 were eligible, supplemented by hand searches of other sources. Three evidence networks were constructed based on histology (mixed, squamous, non-squamous). OS and PFS results were analyzed applying Bayesian fractional polynomial random-effects models. Hazard ratios over time with 95% credible intervals (CrIs) and expected differences in OS and PFS between each
cancer immunotherapy regimen and the
chemotherapy common comparator were generated. Seventeen clinical trials were included after screening 32,527 records. Heterogeneity and risk of bias were generally low across trials. In the mixed-histology network of PD-L1-high patients, expected OS was significantly longer with
atezolizumab (estimated difference: 10.4 months [95% CrI: 1.9, 18.2]),
pembrolizumab (7.2 [2.2, 12.3]), and
cemiplimab (13.0 [4.2, 21.0]) versus
chemotherapy but not with
nivolumab (3.5 [-2.5, 10.6]) or
nivolumab plus
ipilimumab (6.7 [-0.5, 14.2]) versus
chemotherapy. OS improvements were not significant compared with
chemotherapy for any regimen in the squamous and non-squamous networks, except
pembrolizumab plus
chemotherapy in the non-squamous network. All regimens showed significantly longer expected PFS versus
chemotherapy in the non-squamous network, whereas the increases were not significant in the mixed or squamous networks. ORR was significantly higher with
pembrolizumab and
cemiplimab versus
chemotherapy in the mixed-histology network, with
sintilimab in the non-squamous network, and with combination regimens, including
pembrolizumab or
atezolizumab, in the squamous and non-squamous networks, except with
atezolizumab plus
carboplatin,
paclitaxel, and
bevacizumab. Survival and safety versus
chemotherapy were generally similar across
cancer immunotherapies and histology networks. These findings may support treatment decisions for patients with high PD-L1 status receiving first-line treatment for NSCLC.