Therapeutic guidance of tumor mutation burden on immune checkpoint inhibitors in advanced non-small cell lung cancer: a systematic review and comprehensive meta-analysis

Abstract

Tumor mutation burden (TMB) remains a promising but ambiguous predictive biomarker for the efficacy of immune checkpoint inhibitors (ICIs). We investigated the predictive value of TMB in patients with advanced non-small cell lung cancer (NSCLC) treated by ICI-containing therapies under strictly matched clinical settings. PubMed, Embase, Cochrane Central, ClinicalTrials.gov, and bioRxiv databases were searched till October 16, 2021. All randomized controlled trials (RCTs) that compared patients with high TMB (TMB-H) and low TMB (TMB-L) and provided hazard ratio (HR) and corresponding 95% confidence interval (CI) in advanced NSCLC patients receiving ICIs were included, and mirror-based meta-analysis was performed (Part1). Bayesian network meta-analysis was conducted to investigate the efficacy of distinct first-line regimens in TMB-H and TMB-L groups (Part2). Public cohorts were used for validation and further exploration (Part3). Twelve RCTs (n=5527) and 5 public cohorts (n=573) were included. In Part1, TMB-H patients generally exhibited a more significant progression-free survival (PFS) benefit from ICI-containing therapies compared to TMB-L patients (HR=0.58, 95% CI: 0.49-0.67, P < 0.0001). In Part2, anti-PD-1 plus chemotherapy ranked best for PFS in both TMB-H and TMB-L groups. Anti-PD-L1 plus anti-CTLA-4 therapies indicated better PFS and overall survival (OS) benefit than single ICI and chemotherapy in the TMB-H group, but ranked worst in the TMB-L group. Finally, TMB was validated to be an independent predictive biomarker from programmed cell death-ligand 1 (PD-L1) expression in Part3, which could further distinguish beneficiaries of ICI-containing therapies with PD-L1 < 50%. TMB-H could be a predictive biomarker independent of PD-L1 expression to identify beneficiaries of ICI-containing therapy in advanced NSCLC patients.