Efficacy of first-line immune checkpoint inhibitors in advanced non-small-cell lung cancer with or without brain metastases: a systematic review and network meta-analysis

Background Immune checkpoint inhibitors (ICIs) are the standard first-line care for advanced non-small cell lung cancer (NSCLC). However, optimal therapeutic choices for patients with brain metastases remain unclear due to a lack of direct comparisons. We conducted a systematic review and Bayesian network meta-analysis to evaluate the comparative efficacy of first-line ICI regimens stratified by brain metastasis status. Methods We searched PubMed, Cochrane Library, Embase, and Web of Science for randomized controlled trials (RCTs) of first-line ICI regimens in advanced NSCLC. We performed a Bayesian network meta-analysis to estimate hazard ratios (HRs) and 95% credible intervals (CrIs) for overall survival (OS) and progression-free survival (PFS). Models were stratified by brain metastasis status to rank treatment efficacy using the CINeMA system for quality assessment. The protocol is registered with PROSPERO (CRD420251236228). Results We synthesized data from 12 RCTs (n=7, 122) evaluating 14 ICI regimens. In patients with brain metastases, ICI plus chemotherapy significantly improved OS versus chemotherapy alone (HR = 0.57; 95% CrI: 0.45–0.72), while both monotherapy (HR = 0.50; 95% CrI: 0.30–0.85) and combination therapy (HR = 0.42; 95% CrI: 0.31–0.55) prolonged PFS. For patients without brain metastases, both strategies yielded superior OS and PFS. Bayesian ranking indicated that for brain metastases, cemiplimab plus chemotherapy conferred the greatest OS benefit (HR = 0.29; 95% CrI: 0.11–0.76; rank 1 probability: 41.66%). Regarding PFS in this subgroup, sugemalimab plus chemotherapy showed the strongest relative effect (HR = 0.30; 95% CrI: 0.15–0.59), whereas camrelizumab plus chemotherapy achieved the highest probability of ranking first (35.85%). In the non-brain metastasis cohort, pembrolizumab plus chemotherapy (HR = 0.58; 95% CrI: 0.46–0.73) and sintilimab plus chemotherapy (HR = 0.49; 95% CrI: 0.37–0.64) were the leading regimens for OS and PFS, respectively. Conclusions ICI plus chemotherapy provides a survival advantage over chemotherapy alone in advanced NSCLC, irrespective of brain metastasis status. Bayesian rankings favor cemiplimab, sugemalimab, or camrelizumab plus chemotherapy for patients with brain metastases, and pembrolizumab or sintilimab plus chemotherapy for those without. These findings, currently limited by low-certainty indirect evidence, warrant validation in adequately powered, head-to-head trials. Systematic review registration https://www.crd.york.ac.uk/prospero/ , identifier CRD420251236228.