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

Background: 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. Methods: 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). Results: 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%. Conclusion: TMB-H could be a predictive biomarker independent of PD-L1 expression to identify beneficiaries of ICI-containing therapy in advanced NSCLC patients.