Biomarker analyses to predict benefit of immune checkpoint inhibitors for EGFR-mutated non-small cell lung cancer

• Patients with NSCLC and EGFR mutations are less likely to benefit from ICIs treatment. • There are no biomarkers predicting the response to ICIs in EGFR mutations positive NSCLC. • Gene enrichment analysis of the CR and PR group showed that platinum drug resistance was the most frequently enriched KEGG pathway. • TME defined by CD8 and TP53 mutational status may be a predictive outcome for ICI treatment of patients with EGFR-mutated NSCLC. Immune checkpoint inhibitors (ICIs) are effective for NSCLC, but patients with NSCLC and EGFR mutations are less likely to benefit from ICI treatment. A small subset of patients harboring EGFR mutations is reported to respond to the treatment, although no biomarkers have been identified. In this study, we retrospectively explored predictive biomarkers based on tumor mutational status and tumor microenvironment (TME) to identify patients with NSCLC and EGFR mutations who could respond to ICI. Patients with NSCLC and EGFR-sensitizing mutations who were treated with EGFR-TKIs followed by ICIs monotherapy were enrolled. Next-generation sequencing (NGS) was performed using DNA extracted from tissue samples at diagnosis to evaluate genetic mutations and tumor mutational burden (TMB). We also evaluated PD-L1, CD8 and FoxP3 expression in tumor tissues by immunohistochemical staining. Gene enrichment analysis using KOBAS-i with the KEGG pathway database was also carried out. Patients in the study cohort who had an immune-related adverse event had significantly longer progression-free survival (PFS) than those who did not. A high density of CD8-positive tumor-infiltrating lymphocytes was associated with significantly longer PFS and overall survival. The likelihood of complete response (CR) and partial response (PR) was significantly lower for patients who had TP53 mutations compared to those who did not. Response to ICI treatment was not correlated with TMB or PD-L1 expression, but gene enrichment analysis of patients in the CR and PR groups showed enrichment of platinum drug resistance pathways in the KEGG database. TME as defined by CD8 and TP53 mutational status may have predictive value for success of ICI therapy for patients with NSCLC with EGFR mutations.