Biomarker testing is crucial for managing non-small cell lung cancer (NSCLC), with plasma-based next-generation sequencing (NGS) emerging as a non-invasive option. Investigators conducted a study to assess the value of using complementary circulating tumor DNA (ctDNA) NGS alongside tissue single-gene testing (SGT). The study included 91 patients with advanced NSCLC who underwent tumor genotyping with tissue SGT (3 genes) followed by ctDNA analysis (38 genes amplicon panel). Results showed ctDNA positivity in 47% (43 patients) and identified treatable biomarkers in 21% (19 patients). Higher ctDNA positivity was observed in those with extra-thoracic disease (59%) or no ongoing treatment (59%). Compared with SGT, ctDNA offered extra insights in 41% cases but missed a known alteration in 8%. CtDNA-guided targeted therapy changes were seen in 5% (5 patients), while 7 patients with EGFR mutations or ALK fusions were missed. CtDNA had a median turnaround time of 10 days (range 6–25), quicker (P=0.002) than cumulative delays for tissue testing (13 days; range 7–1737). Overall, the study highlights ctDNA’s potential and limitations as a complementary approach to tissue testing, with some biomarkers not covered comprehensively.