Tumor Mutational Burden and Efficacy of Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

Abstract

Tumor mutational burden (TMB) is a genomic biomarker that predicts favorable responses to immune checkpoint inhibitors (ICIs). Here, we set out to assess the predictive value of TMB on long-term survival outcomes in patients undergoing ICIs. We systematically searched PubMed, Embase, CENTRAL and clinicaltrials.gov from inception to 6 August 2019. We included retrospective studies or clinical trials of ICIs that reported hazard ratios (HRs) for overall survival (OS) and/or progression-free survival (PFS) according to TMB. Data on 5712 patients from 26 studies were included. Among patients who received ICIs, high TMB groups showed better OS (HR 0.53, 95% CI 0.42 to 0.67) and PFS (HR 0.52, 95% CI 0.40 to 0.67) compared to low TMB groups. In patients with high TMB, those who received ICIs had a better OS (HR 0.69, 95% CI 0.50 to 0.95) and PFS (HR = 0.66, 95% CI = 0.47 to 0.92) compared to those who received chemotherapy alone, while in patients with low TMB, such ICI benefits of OS or PFS were not statistically significant. In conclusion, TMB may be an effective biomarker to predict survival in patients undergoing ICI treatment. The role of TMB in identifying patient groups who may benefit from ICIs should be determined in future randomized controlled trials.

The landscape of tumor mutational burden and its clinical significance in patients with lung cancer: a Multi-omics study with a meta-analysis

“…The clinical evaluation of TMB using blood specimens from the same institution differs greatly from the results obtained using tumor tissues, and the results of blood specimens show some instability. The conclusion drawn from this blood specimen is also inconsistent with the mainstream view that the high TMB patients should have better survival bene ts in NSCLC patients treated with ICIs [17,18]. The study author Chae YK et al also previously found a low correlation in ctDNA TMB and tissue TMB in paired patient samples [41].…”

“…Currently, TMB is mainly studied as a predictive biomarker for ICIs treatment response [15,30]. Recent studies have concluded that in patients with higher TMB, the survival bene t of patients receiving ICIs is better than that of patients receiving chemotherapy alone, but in patients with low TMB, the survival bene t of ICIs is not statistically signi cant [17,18]. In this study, we did not group patients according to TMB value, but grouped according to lung cancer types, treatment methods, detection methods, test samples.…”

“…The hypothesis that tumors with more neoantigens may respond better to immunotherapy is based on the positive relationship between tumor-speci c neoantigens and increased immunogenicity [16]. Most current researches focus on the relationship between TMB and the e cacy of immunotherapy in various cancers [17][18][19]. However, the role of TMB in lung cancer patients without receiving immunotherapy has not been fully elucidated.…”

Future Challenges in Cancer Resistance to Immunotherapy

“…Unexpectedly, the expression of MHC-II molecules was also detected on tumor cells and shown to correlate with T cell infiltration and the therapeutic response to CPI, indicating the presence of alternative antigen presentation pathways [87,88]. Notably, a lack of appropriate levels of tumor-specific antigen forms another important intrinsic resistance pathway against CPI [89]. In another screen, for key components determining the susceptibility of tumor cells to adoptively transferred effector cells, the GTPase Cdc42 was identified as a key factor in preventing CTL-induced cell death via MAPK signaling and posttranscriptional Bcl-2 stabilization [90].…”

Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge

“…The relationship between TMB and response to immunotherapy is explained by the generation of neoepitopes typical of tumors with many mutations that become a target for antigen presentation and powered CTLs activity [15].…”