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 mutation ( ) 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 , 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 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 ( ) in NSCLC. The association between 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 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 was associated with increased T cell signatures and downregulated signaling compared with patients with in LUAD while not LUSC.

CONCLUSIONS

Our results demonstrated that is an independent classifier that could stratify patients with LUAD for ICIs therapy. Further prospective studies are warranted.

TRIAL REGISTRATION NUMBER

NCC2016JZ-03, NCC2018-092.