Here, we report a novel <i>EGFR</i> L858R/A859S/Y891D triple mutation in plasma-derived circulating tumor DNA (ctDNA) was identified in a 53-year-old male patient with NSCLC resistant to osimertinib treatment, using an ultra-deep (20,000×) 160-gene panel through the NGS platform. This evidence concerns the gene EGFR and neoplasm.