In summary, this is the first report to reveal that osimertinib has EGFR-independent inhibitory effects on cell cycle progression mediated by the interaction between EphB4 and the p53-p21-Cyclin D1 pathways and that EphB4 is a significantly poor prognostic factor, especially in EGFR mutation-positive lung adenocarcinoma. This evidence concerns the gene CDKN1A and lung adenocarcinoma.