The clinical utility of tumor mutational burden in non-small cell lung cancer.

Abstract

Despite advances made during the last two decades, lung cancer remains the leading cause of cancer-related death worldwide. Recently, immune checkpoint inhibitors (ICIs) became available for the treatment of advanced non-small cell lung cancer (NSCLC) patients. Although ICIs showed a survival advantage in comparison with chemotherapy in the second and first-line setting, overall response rate is only around 20% and a large proportion of patients will undergo disease progression within the first weeks of treatment. For this reason, there is a need for biomarkers to predict the efficacy of ICIs in NSCLC and to identify patients who will benefit from ICIs. The first biomarker developed was programmed cell death ligand 1 (PD-L1) expression. However, the predictive role of PD-L1 expression varied from one clinical trial to another, due to the multiple assays used, with different antibodies, different platforms, and different thresholds. Moreover, PD-L1 expression is highly heterogeneous. For these reasons, PD-L1 expression alone is not a good biomarker to predict the efficacy of ICIs and there is a need for the identification of other biomarkers. Tumor mutational burden (TMB) is defined as the number of mutations per DNA megabases. It was first assessed as a biomarker for ICI based on the observation of successful immune checkpoint inhibition in solid tumors with high TMB such as NSCLC, melanoma or bladder cancer. Pre-clinical data suggested that the association between TMB and ICIs efficacy could be explained by the creation of neoantigens induced by mutations acquisition, increasing tumor immunogenicity and response to ICIs. Preliminary observations of TMB role as a predictive biomarker for the efficacy of ICIs in patients with advanced NSCLC led to the assessment of TMB clinical utility in phase III clinical trials. This review reports the clinical features and prognostic role of TMB in NSCLC. This review also focuses on TMB predictive role for the treatment of NSCLC patients with single-agent programmed cell death 1 (PD-1) and PD-L1 inhibitors such as pembrolizumab, nivolumab and atezolizumab or ICIs combination.