AbstractBackgroundCell‐free tumor DNA (ctDNA) obtained through liquid biopsy is useful for the molecular analysis of advanced non‐small‐cell lung cancer (NSCLC). Few studies have directly compared analysis platforms in terms of their diagnostic performance in analyzing ctDNA obtained from the cerebrospinal fluid (CSF) of patients with leptomeningeal metastasis (LM).MethodsWe prospectively analyzed patients with epidermal growth factor receptor (EGFR)‐mutant NSCLC who were subjected to CSF analysis for suspected LM. To detectEGFRmutations, CSF ctDNA was analyzed using the cobas EGFR Mutation Test and droplet digital polymerase chain reaction (ddPCR). CSF samples from osimertinib‐refractory patients with LM were also subjected to next‐generation sequencing (NGS).ResultsSignificantly higher rates of valid results (95.1% vs. 78%, respectively,p= 0.04) andEGFRcommon mutation detection (94.3% vs. 77.1%, respectively,p= 0.047) were obtained through ddPCR than through the cobas EGFR Mutation Test. The sensitivities of ddPCR and cobas were 94.3% and 75.6%, respectively. The concordance rate forEGFRmutation detection through ddPCR and the cobas EGFR Mutation Test was 75.6% and that forEGFRmutation detection in CSF and plasma ctDNA was 28.1%. In osimertinib‐resistant CSF samples, all originalEGFRmutations were detected through NGS.METamplification andCCDC6‐RETfusion were demonstrated in one patient each (9.1%).ConclusionsThe cobas EGFR Mutation Test, ddPCR, and NGS appear to be feasible methods for analyzing CSF ctDNA in patients with NSCLC and LM. In addition, NGS may provide comprehensive information regarding the mechanisms underlying osimertinib resistance.