PD‐L1 versus tumor mutation burden: Which is the better immunotherapy biomarker in advanced non‐small cell lung cancer?

Abstract

PD‐L1 and tumor mutation burden (TMB) are the most widely used immunotherapy biomarkers to identify populations who would attain clinical benefit, with the higher values predicting better therapeutic efficacy. This review addresses the predictive values and unresolved challenges of these two biomarkers. PD‐1 and PD‐L1 inhibitors have induced durable and effective responses in patients with advanced non‐small cell lung cancer, confirmed by multiple clinical trials and real‐world studies. Different clinical trials, involving both PD‐1/PD‐L1 inhibitors alone and combination regimens, adopted either PD‐L1 or TMB to stratify the patients, although the predictive capabilities of these two biomarkers are different. In the first‐line setting, PD‐L1 of 50% or more as a cut‐off value can help select candidates for pembrolizumab or atezolizumab monotherapy; however, these two biomarkers poorly predict the efficacy of immunotherapy combination regimens as first‐line treatments. In the second‐line setting, although patients can benefit from nivolumab regardless of PD‐L1 expression, both PD‐L1 and blood TMB can be used as biomarkers to find patients suitable for atezolizumab. Except for inaccurate predictiveness, there are many unresolved problems with regard to the two biomarkers, such as the lack of standard detection methods, and their susceptibilities to other dynamic changes. The predictive values of TMB and PD‐L1 were low in most circumstances; however, PD‐L1 expression greater than ≥ 50% can help select appropriate patients for pembrolizumab and atezolizumab, respectively, as first‐line monotherapies. Higher PD‐L1 or TMB was associated with greater efficacy for atezolizumab as a second‐line monotherapy.

PD-(L)1 Inhibitors as Monotherapy for the First-Line Treatment of Non-Small-Cell Lung Cancer Patients with High PD-L1 Expression: A Network Meta-Analysis

“…Several TMB testing panels are currently available, and their variability needs to be fully understood. Additionally, optimal TMB cut-offs for treatment decisions may need to be specified across different cancer types [ 41 ]. In NSCLC, preliminary results support this potential predictive role for TMB [ 38 , 42 ], but more evidence is needed.…”

A novel lactate metabolism-related signature predicts prognosis and tumor immune microenvironment of breast cancer

“…The TMB represents the number of mutations per megabase (Mut/Mb) in specific cancer. TMB, as the most widely used immunotherapy biomarker to identify populations, predicts better immunotherapy efficacy with higher values ( Dong et al, 2021 ). In our study, the higher values of LMRG risk score are positively related to immune checkpoints and TMB, which shows that it is more sensitive to immunotherapy.…”

Decoding circulating tumor DNA to identify durable benefit from immunotherapy in lung cancer

“…Not only to validate our results, but also to counter the combinatorial explosion of mutation profiles that can be tracked using ctDNA. Confronting both the curse of dimensionality 3 (where measurements span ~ 10 5 nucleotides) and molecular sparsity (with a handful of variants per 100 kb) will be imperative to train the next generation of plasma-based anti-cancer efficacy predictors. Finally, this work exemplifies that the information content from ctDNA is far from exhausted and suggests that there is still unmet potential that can be further distilled by increasing the positional resolution (e.g., expanding the number of genes) with the help of larger datasets.…”

“…Currently, expression of the programmed death-ligand 1 (PD-L1) receptor in tumor tissue and tumor mutational burden emerged as tools to predict outcome in patients receiving ICI [1]. However, despite initial promising data, both are not strong predictive markers for response to ICI [2,3]. Efficacy of ICI is traditionally assessed using computed and/or positron emission tomography (CT/PET) imaging by measuring changes in tumor size and metabolic activity [4,5].…”