EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma

Background Ephrin type-A receptors (EPHA) are members of family of receptor tyrosine kinases and are related to tumor immunogenicity and immune microenvironment, however, the association between EPHA mutation (EPHA(mut)) and efficacy of immune checkpoint inhibitors (ICIs) has not been investigated in non-small cell lung cancer (NSCLC). Methods Multiple cohorts were used to assess the immunotherapeutic predictive performance of EPHA(mut), including one discovery cohort (n=79) and two public validation cohort (cohort 1: NSCLC, n=165; cohort 2: pan-cancer, n=1662). The Cancer Genome Atlas cohort was used for prognostic analysis and mechanism exploration. Results In the discovery cohort, patients with EPHA(mut) had superior disease control rate (72.2% vs 36.1%, p=0.01) and progression-free survival (PFS) (HR 0.38; 95% CI 0.21 to 0.68; p<0.001) compared with those with wide-type EPHA (EPHA(wt)) in NSCLC. The association between EPHA(mut) and immunotherapy outcomes in NSCLC was consistently observed in the validation cohorts by multivariable models (cohort 1, PFS HR 0.59; 95% CI 0.37 to 0.96; p=0.03; cohort 2, overall survival (OS) HR 0.63; 95% CI 0.41 to 0.98; p=0.04). Further pooled estimates of the discovery and validation cohorts showed that patients with EPHA(mut) exhibited a significantly longer PFS and OS in lung adenocarcinoma (LUAD) while not squamous cell lung cancer (LUSC). Consistently, mechanism analysis revealed that patients with EPHA(mut) was associated with increased T cell signatures and downregulated transforming growth factor-beta signaling compared with patients with EPHA(wt) in LUAD while not LUSC. Conclusions Our results demonstrated that EPHA(mut) is an independent classifier that could stratify patients with LUAD for ICIs therapy. Further prospective studies are warranted.