Risk of Neurological Toxicities Following the Use of Different Immune Checkpoint Inhibitor Regimens in Solid Tumors A Systematic Review and Meta-analysis

Objectives: The objective of this study was to assess risk of neurological toxicities following the use of different immune checkpoint inhibitor (ICI) regimens in solid tumors. Methods: Pubmed, Embase, and ClinicalTrials. gov databases were searched for publications, and data were analyzed using Review Manager 5.3 software to compare the risk of immune-related and nonspecific neurological complications potentially triggered by ICIs to controls. Results: In total 23 randomized clinical trials comprising 11,687 patients were included in this meta-analysis. Patients with PD-L1 (OR, 0.29; 95% confidence interval [CI], 0.18-0.48; P< 0.01) or programmed cell-death protein 1 (PD-1) inhibitor (OR, 0.21; 95% CI, 0.14-0.31; P< 0.01) were less likely to develop any-grade peripheral neuropathy than chemotherapy, while the risk of grade 3-5 was also smaller for PD1 inhibitor (OR, 0.16; 95% CI, 0.05-0.54; P= 0.003). Combination therapy with CTLA4 and PD-1 inhibitor did not significantly increase the risk of any-grade (OR, 0.83; 95% CI, 0.21-3.32; P> 0.05) or grade 3-5 (OR, 1.4; 95% CI, 0.2-9.61; P> 0.05) peripheral neuropathy compared to monotherapy with CTLA4 or PD-1 inhibitor. However, difference in risk of immune-related adverse events (irAEs) involving central nervous system did not reach statistical significance in patients with different ICI regimens compared those under chemotherapy. Additionally, risk of experiencing paresthesia was in line with that of peripheral neuropathy (OR, 0.42; 95% CI, 0.28-0.62; P< 0.01). Conclusions: This meta-analysis shows that PD-L1/PD-1 and CTLA4 inhibitor have decreased risk of peripheral neuropathy compared to chemotherapy, while combination therapy with CTLA4 and PD-1 inhibitor have no difference in neurological toxicities compared to monotherapy with CTLA4 or PD-1 inhibitor.