Association of EPHA3 mutations with tumor mutational burden and efficacy of immune checkpoint inhibitors in cancer patients

Background: The erythropoietin-producing human hepatocellular receptor A3 (EPHA3 ), which was identified as a tumor antigen targeted by a lytic T-cell response in melanoma patients, is relatively tumor specific. Moreover, EPHA3 is frequently mutated in human cancers, and the association of EPHA3 mutations with immunotherapy efficacy in cancer patients has not been reported to date. Methods: We conducted a retrospective analysis of 1756 patients with 11 cancer types after immune checkpoint inhibitor (ICI) monotherapy identified from The Cancer Genome Atlas (TCGA) data portal in April 2021. The associations between EPHA3 mutations and tumor mutational burden (TMB), durable clinical benefit (DCB), and overall survival (OS) was assessed. Results: Among all 1756 patients, the mutational frequency of EPHA3 was 6.7%. The TMB of patients with EPHA3 mutations was substantially higher than that in patients without the mutations (odds ratio [OR], 5.35, 95% confidence interval [CI], 3.58–8.04; P < .001). EPHA3 mutations were significantly associated with better DCB (median: 52.3% vs 32.8%; OR, 2.24; 95%CI, 1.15–4.41; P = .011) and OS (median: 40.0 vs 16.0 months; hazard ratio, 0.57; 95% CI, 0.42–0.77; P < .001) compared with EPHA3 wild-type. Multivariable and subgroup analyses showed that these associations were independent of all known covariates, including TMB. Conclusions: These findings indicate that EPHA3 mutations may be associated with higher TMB, better immune response, and better survival than EPHA3 wild-type. Despite the need for validation, cancer patients with EPHA3 mutations might be appropriate candidates for ICI monotherapy.