EPHA5 mutation predicts the durable clinical benefit of immune checkpoint inhibitors in patients with lung adenocarcinoma.

Immune checkpoint inhibitor (ICI) therapy has shown remarkable clinical benefit in lung adenocarcinoma (LUAD) patients. Genomic mutations may be applicable to predict the response to ICIs. Eph receptor A5 (EPHA5) is frequently mutated in breast cancer, lung cancer, and other tumors; however, its association with outcome in patients who receive immunotherapy remains unknown. In this study, we report that EPHA5 mutations were associated with increased tumor mutation burden (TMB), neoantigen load, levels of immune-related gene expression signatures, and enhanced tumor-infiltrating lymphocytes (TILs) in LUAD. LUAD patients with EPHA5 mutations in the immunotherapy cohort achieved a longer progression-free survival (PFS) time than patients with wild-type EPHA5. Immune response pathways were among the top enriched pathways in samples with EPHA5 mutations. In addition, patients with EPHA5 mutations tended to be more sensitive to certain targeted molecular inhibitors, including serdemetan, lox2, and PF1-1. Collectively, our results suggest that identifying mutations in the EPHA5 gene may provide insight into the genome-wide mutational burden and may serve as a biomarker to predict the immune response of patients with LUAD.