In:
Journal for ImmunoTherapy of Cancer, BMJ, Vol. 8, No. 2 ( 2020-12), p. e001315-
Abstract:
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-β 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. Trial registration number NCC2016JZ-03, NCC2018-092.
Type of Medium:
Online Resource
ISSN:
2051-1426
DOI:
10.1136/jitc-2020-001315
Language:
English
Publisher:
BMJ
Publication Date:
2020
detail.hit.zdb_id:
2719863-7
