Abstract 375: High tumor mutation burden predicts unfavorable clinical outcome in EGFR-mutated lung adenocarcinoma treated with targeted therapy

Abstract

Abstract Purpose: Although high tumor mutation burden (TMB) has shown association with benefit from immune checkpoint blockade therapies, its implications in lung cancer patients with driving mutations are still unclear. The objective of this study is to determine the association between TMB and treatment outcome in epidermal growth factor receptor (EGFR)-mutated lung cancer treated with tyrosine kinase inhibitors (TKIs). Methods: We evaluated TMB in EGFR-mutant, lung adenocarcinoma patients who received first-line EGFR-TKIs. TMB was estimated by next-generation sequencing with a cancer gene panel (Oncomine™ Tumor Mutation Load Assay). We compared the response rate (RR), progression-free survival (PFS), overall survival (OS), and frequency of secondary T790M mutation according to the different TMB groups. Results: Among the 131 patients who were treated with EGFR-TKIs, a total of 63 patients were eligible for the analysis. TMB was stratified by tertiles; low (≤2.13 mutations/Mb), intermediate (2.14-4.25 mutations/Mb), and high (>4.25 mutations/Mb). The TMB levels were not associated with any clinical parameters. The RR was significantly lower in the high TMB group than in the other groups (43.5% vs. 72.1% vs. 78.5%, all p = 0.01). In multivariate analysis, high TMB was independently associated with a shorter PFS in the overall population (hazard ratio [HR] = 2.64, p = 0.004), and associated with shorter OS in patients with exon 19 deletion (HR = 2.55, p = 0.041) compared with low TMB. The frequencies of secondary T790M mutation after TKI failure were not different among the different TMB groups. Conclusion: High TMB was associated with unfavorable clinical outcome in patients with lung adenocarcinoma treated with EGFR-TKIs. Although further large-scaled studies are required, our data suggest that high TMB may be a predictive biomarker for adverse treatment outcomes and may constitute a distinct subgroup warranting tailored therapeutic approach in this clinical setting. Citation Format: Seung Hyeun Lee, Ji-Youn Sung. High tumor mutation burden predicts unfavorable clinical outcome in EGFR-mutated lung adenocarcinoma treated with targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 375.