Abstract C009: Biomarker analyses for predicting the benefit from immune checkpoint inhibitors in EGFR-mutated non-small cell lung cancer
Authors: Osuga Mitsuo , Azuma Koichi , Itoh Shoichi , Kawa Yoshitaka , Harada Daijiro , Toi Yukihiro , Murotani Kenta , Hata Akito , Kozuki Toshiyuki , Sugawara Shunichi , Satouchi Miyako , Yamamoto Nobuyuki , Koh Yasuhiro 
Published: December 2023

Abstract
Background: Although immune checkpoint inhibitors (ICIs) are effective for non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR)-mutated NSCLC patients are unlikely to benefit from ICIs treatment. It has been reported, however, a small subset of patients harboring EGFR-mutations respond to the treatment, although no biomarkers have been identified. In this study, we retrospectively explored predictive biomarkers to identify the responders by addressing tumor mutational status and tumor microenvironment (TME).
Methods: NSCLC patients harboring EGFR-sensitizing mutations who were treated with EGFR-TKIs followed by ICIs alone or ICIs combined with chemotherapy between October 1, 2014 and September 31, 2019 were enrolled into the study. Next-generation sequencing (NGS) was performed on Ion S5 system using DNAs extracted from tissue samples at diagnosis for evaluating genetic mutations and tumor mutational burden (TMB) using Oncomine Tumor Mutation Load Assay. We also evaluated the expression of PD-L1, CD8 and FoxP3 on tumor tissues by immunohistochemical staining. Gene enrichment analysis was performed using gene symbol of somatic mutations by KOBAS in database of KEGG pathway. Mutational signature was identified by SigProfilerAssignment with reference mutational signatures of COSMIC v3.3 using exported vcf file from Ion torrent FileExporter plugin. Fisher's exact test was performed by using EZR software version 1.61.
Results: Thirty-four patients were enrolled and the tissue DNA for NGS was successfully collected from 27 patients. Patient demographics were as follows: male/female, 17/17; nonsmoker/smoker, 17/17; 32/2 adenocarcinoma/non-adenocarcinoma, 32/2; EGFR mutation in exon19del/L858R/other, 21/11/2; overall response (ORR) to the past EGFR-TKI treatment CR-PR/SD/PD, 27/2/5; type of ICI pembrolizumab/nivolumab/atezolizumab/other, 17/11/5/1; response to ICI treatment CR-PR/SD/PD, 10/1/22. There was no correlation between the duration of initial EGFR-TKI treatment and the duration of ICI therapy. Patients who had immune-related adverse event (irAE) had significantly longer progression free survival (PFS) with ICIs than those without irAE (p = 0.049). Significantly more CR and PR were observed in patients who do not harbor TP53 mutations (p = 0.033). No correlation was found between TMB and the response to ICI treatment. With regard to PD-L1 expression, tissue tumor proportion score or combined positive score did not correlate with the response to ICI treatment. Patients with high expression level of CD8 showed significantly longer PFS and overall survival (p = 0.039 and p = 0.006). Gene enrichment analysis in CR and PR group indicated that most enriched KEGG pathway was platinum drug resistance and one CR case had a mutational signature of SBS31, relevant to platinum drug treatment, suggesting the involvement of platinum drug treatment in the response to ICI treatment.
Conclusions: TME defined by CD8 and TP53 mutational status may have predictive impact on ICIs treatment in EGFR-mutated NSCLC.
Citation Format: Mitsuo Osuga, Koichi Azuma, Shoichi Itoh, Yoshitaka Kawa, Daijiro Harada, Yukihiro Toi, Kenta Murotani, Akito Hata, Toshiyuki Kozuki, Shunichi Sugawara, Miyako Satouchi, Nobuyuki Yamamoto, Yasuhiro Koh. Biomarker analyses for predicting the benefit from immune checkpoint inhibitors in EGFR-mutated non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C009.