From Tumor Mutational Burden to Blood T Cell Receptor: Looking for the Best Predictive Biomarker in Lung Cancer Treated with Immunotherapy

Abstract

Despite therapeutic advances, lung cancer (LC) is one of the leading causes of cancer morbidity and mortality worldwide. Recently, the treatment of advanced LC has experienced important changes in survival benefit due to immune checkpoint inhibitors (ICIs). However, overall response rates (ORR) remain low in unselected patients and a large proportion of patients undergo disease progression in the first weeks of treatment. Therefore, there is a need of biomarkers to identify patients who will benefit from ICIs. The programmed cell death ligand 1 (PD-L1) expression has been the first biomarker developed. However, its use as a robust predictive biomarker has been limited due to the variability of techniques used, with different antibodies and thresholds. In this context, tumor mutational burden (TMB) has emerged as an additional powerful biomarker based on the observation of successful response to ICIs in solid tumors with high TMB. TMB can be defined as the total number of nonsynonymous mutations per DNA megabases being a mechanism generating neoantigens conditioning the tumor immunogenicity and response to ICIs. However, the latest data provide conflicting results regarding its role as a biomarker. Moreover, considering the results of the recent data, the use of peripheral blood T cell receptor (TCR) repertoire could be a new predictive biomarker. This review summarises recent findings describing the clinical utility of TMB and TCRβ (TCRB) and concludes that immune, neontigen, and checkpoint targeted variables are required in combination for accurately identifying patients who most likely will benefit of ICIs.

NCCN Guidelines Insights: Non–Small Cell Lung Cancer, Version 2.2021

“…44,47 Although PD-L1 expression level is widely used as an immune biomarker, it is not an ideal biomarker because some patients with low PD-L1 expression levels respond to immunotherapy and others with high levels do not respond to immunotherapy. 48,49 PD-L1 expression levels are useful for deciding whether to use single-agent immunotherapy or combination immunotherapy.…”

“…50 Theoretically, high TMB levels will correlate with high neoantigen levels that will activate an antitumor immune response. 48 TMB levels are typically high in patients with NSCLC who are smokers or former smokers. Low TMB is more commonly detected in never-smokers.…”

“…54 TMB does not identify patients who will respond to chemotherapy; therefore, it has limited value for assessing combination immunotherapy 1 chemotherapy regimens. 48 TMB is also not an ideal immune biomarker, because some patients with low levels experience a response to immunotherapy and others with high levels do not. 48 In addition to the lack of clinical data to support use of TMB as an immune biomarker, there are technical problems with measuring TMB, 50 including lack of agreement on the definition of a cutoff for designating high TMB levels and lack of standardization of TMB measurements across laboratories.…”

“…48 TMB is also not an ideal immune biomarker, because some patients with low levels experience a response to immunotherapy and others with high levels do not. 48 In addition to the lack of clinical data to support use of TMB as an immune biomarker, there are technical problems with measuring TMB, 50 including lack of agreement on the definition of a cutoff for designating high TMB levels and lack of standardization of TMB measurements across laboratories. 50 PD-L1 expression level is a more useful immune biomarker than TMB for deciding how to use immunotherapy, because test results are obtained more quickly, less tissue is needed for testing, and data demonstrate relative reproducibility across platforms and individuals.…”

Prognostic and Predictive Biomarkers in Non-Small Cell Lung Cancer Patients on Immunotherapy—The Role of Liquid Biopsy in Unraveling the Puzzle

“…Similar results were observed by Wang et al [ 39 ]. Another clinical trial (B-F1RST, NCT02848651, n = 152) also showed a correlation between a high bTMB and atezolizumab response in NSCLC patients, using the same cut-off for bTMB as in the POPLAR and OAK studies [ 41 ].…”