The Predictive Role of ctDNA and CTCs in Patients with Advanced Non-Small Cell Lung Cancer Receiving Immunotherapy: A Systematic Review and Meta-Analysis

Circulating tumour DNA (ctDNA) and circulating tumour cells (CTCs) have emerged as promising non-invasive biomarkers for the immunotherapy response in advanced non-small cell lung cancer (NSCLC). However, their clinical utility remains uncertain due to variability in findings across studies. We conducted a systematic review and meta-analysis of studies from 2014 to 2024, assessing the predictive value of ctDNA and CTCs in advanced NSCLC patients receiving immunotherapy. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Forty-four studies were included (28 ctDNA, 16 CTC cohorts). High baseline ctDNA was associated with worse OS (pooled HR = 1.38, 95% CIs: 1.17–1.63), while baseline CTC detection predicted worse PFS (pooled HR of 3.65 (95% CIs: 1.58–8.41) and OS (pooled HR = 2.30, 95% CIs: 1.54–3.44). An on-treatment ctDNA decrease or clearance was associated with improved PFS (pooled HR = 0.34, 95% CIs: 0.25–0.47) and OS (pooled HR = 0.33, 95% CIs: 0.24–0.44). Evidence for other ctDNA- and CTC-derived biomarkers (blood tumour mutational burden, genomic alterations, dynamic CTC changes, and CTC PD-L1 expression) was limited or inconsistent. The interpretation of these findings is limited by heterogeneity in assay platforms, biomarker definitions, the analytical threshold, and sampling timepoints across studies. While ctDNA and CTCs show significant potential as predictive biomarkers in advanced NSCLC, further validation is needed in larger prospective studies using standardized assays. At present, ctDNA and CTC monitoring can complement but cannot replace radiological assessments in guiding immunotherapy decisions for NSCLC patients.