The Predictive efficacy of tumor mutational burden for immune Checkpoint Inhibitors in non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials

Abstract Background: To date, immune checkpoint inhibitors (ICIs) have become the mainstay of treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC). However, a subset of patients derives poor benefits from ICIs, highlighting the need for reliable biomarkers to identify those who are more likely to respond to such therapies. This review aims to evaluate the role of tumor mutational burden (TMB) as a predictive biomarker in NSCLC patients treated with ICIs. Methods: PubMed, Embase, Web of Science, and the Cochrane Library were systematically searched from inception to April 2, 2024. The endpoints of interest included overall response rate (ORR), overall survival (OS), and progression-free survival (PFS). Results: A total of 13 randomized controlled trials were included. High TMB was associated with improved ORR relative ratio (RR) 1.63, 95% confidence interval (CI) 1.24–2.14, longer PFS hazard ratio (HR) 0.78, 95% CI 0.71–0.86 and longer OS (HR 0.86, 95% CI 0.76–0.98). Subgroup analysis revealed that high tissue TMB (tTMB) was significantly associated with better PFS and OS, whereas pooled results for both PFS and OS based on blood TMB (bTMB) did not reach statistical significance. Furthermore, in the high TMB group, first-line treatment with ICIs provided significant benefits for NSCLC, as demonstrated by improved ORR, PFS, and OS. Conclusions: These results suggest that tTMB could serve as a potential predictor of clinical benefit from ICIs, particularly in previously untreated NSCLC. However, the predictive value of bTMB requires further investigation and defining an optimal bTMB cutpoint remains a significant challenge.