Objective This meta-analysis aimed to assess the prognostic value of circulating tumor DNA (ctDNA) in predicting progression-free survival (PFS) and overall survival (OS) of advanced non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs), thereby providing evidence-based support for clinical decision-making. Methods Six major English and Chinese databases (PubMed, Embase, Cochrane Library, etc.) were scanned from inception to August 2025. Studies evaluating the association between ctDNA and survival outcomes in advanced NSCLC patients receiving ICIs were included. Thirty-one eligible studies (2,107 patients) were selected following predefined criteria. Study quality was evaluated using Cochrane RoB-2 and the Newcastle-Ottawa Scale (NOS). Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were pooled using random/fixed-effects models. Heterogeneity was assessed via Cochran’s Q test and I 2 statistics. Subgroup analyses, sensitivity tests, and funnel plots were conducted to evaluate robustness and publication bias. Results Patients with undetectable ctDNA at baseline showed significantly prolonged PFS (HR = 0.49, 95% CI: 0.34–0.70, P 0.01) and OS (HR = 0.45, 95% CI: 0.32–0.65, P 0.01). Patients achieving ctDNA reduction or response during treatment exhibited substantial PFS (HR = 0.27, 95% CI: 0.21–0.35, P 0.01) and OS (HR = 0.23, 95% CI: 0.17–0.31, P 0.01) benefits, with complete molecular response (100% reduction in variant allele frequency, VAF) demonstrating the strongest predictive power, characterized by the lowest heterogeneity and favorable HRs for PFS (HR = 0.27, 95% CI: 0.18–0.41, P 0.01) and OS (HR = 0.19, 95% CI: 0.12–0.29, P 0.01). Subgroup analyses revealed three key patterns: superior predictive value in combination therapy versus monotherapy; higher sensitivity of next-generation sequencing (NGS) over digital polymerase chain reaction (PCR); and enhanced predictive power in later-line therapy compared to first-line therapy. Sensitivity analyses confirmed the stability of the results. Conclusion Baseline ctDNA status and early dynamic changes are reliable prognostic indicators in advanced NSCLC patients receiving ICI therapy, particularly in combination regimens and cases achieving complete molecular clearance. These findings support ctDNA as a biomarker for personalized treatment strategies. Clinical Trial Registration https://www.crd.york.ac.uk/PROSPERO , CRD420251025308.
Wang et al. (Tue,) studied this question.