Biomarkers predicting clinical outcomes in nasopharyngeal cancer patients receiving immune checkpoint inhibitors: A systematic review and meta-analysis

Background: Optimal biomarkers to select patients who will benefit most from immunotherapy remain lacking in nasopharyngeal cancer (NPC). This systematic review and meta-analysis aimed to evaluate the association between various biomarkers and clinical outcomes in NPC patients treated with immune checkpoint inhibitors (ICIs).Methods: Systematic searches of PubMed, Embase, Cochrane Library, and Web of Science databases were performed up to October 2022. Studies evaluating the association between biomarkers and intended outcomes of ICIs were included. The pooled odds ratio (OR) and hazard ratio (HR) with 95% confidence intervals (CIs) were calculated, respectively, for the objective response rate (ORR) and progression-free survival (PFS) under fixed or random-effect models.Results: A total of 15 studies involving 1,407 patients were included. The pooled analysis indicated that NPC patients with lower plasma Epstein-Barr virus (EBV) DNA level at baseline (OR = 2.14, 95% CI: 1.46-3.14, P < 0.001), decreased EBV DNA load during immunotherapy (OR = 4.57, 95% CI: 2.24-9.34, P = 0.002) and higher programmed cell death-ligand 1 (PD-L1) expression (OR = 2.35, 95% CI: 1.36-4.09, P = 0.002) had superior ORR than the counterparts. No significant differences of ORR were observed between positive PD-L1 expression and negative PD-L1 expression (OR = 1.50, 95% CI: 0.92-2.45, P = 0.104), as well as higher tumor mutation burden (TMB) and lower TMB (OR = 1.62, 95% CI: 0.41-6.44, P = 0.494). Patients with lower plasma EBV DNA level at baseline obtained a significant benefit on PFS than those with higher plasma EBV DNA level (HR = 0.52, 95% CI: 0.42-0.63, P < 0.001). There were no differences in PFS between decreased EBV DNA load and increased EBV DNA load during immunotherapy (HR = 0.51, 95% CI: 0.22-1.17, P = 0.109), higher PD-L1 expression and lower PD-L1 expression (HR = 0.65, 95% CI: 0.42-1.01, P = 0.054), positive PD-L1 expression and negative PD-L1 expression (HR = 0.90, 95% CI: 0.64-1.26, P = 0.531), lower TMB and higher TMB (HR = 0.84, 95% CI: 0.51-1.38, P = 0.684).Conclusion: Lower baseline plasma EBV DNA level, decreased plasma EBV DNA during immunotherapy, and higher PD-L1 expression are reliable biomarkers predicting better response to ICIs treatment. Lower baseline plasma EBV DNA level was also associated with longer PFS. It is warranted to further explore and better illuminate the utility of these biomarkers in future clinical trials and real-world practice.