Immune-Related Neurological Toxicities of PD-1/PD-L1 Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis

Background: Systematic assessment of PD-1/PD-L1 inhibitor-related neurological toxicities is important for guiding anti-PD-1 and anti-PD-L1 immunotherapy. Therefore, we conducted this meta-analysis to reveal the relationship between PD-1/PD-L1 inhibitors and neurological toxicities among cancer patients. Methods: Clinical trials investigating PD-1/PD-L1 inhibitors in cancer patients were identified by a systematic search of PubMed. The random-effect model was used to synthesize individual studies. Neurological toxicities, including all-grades and grades 3-5, were taken into account for the final comprehensive meta-analysis. The Newcastle Ottawa Scale (NOS) was used to assess the quality of included trials. Results Thirty-one clinical trials containing data of neurological toxicities were included. Compared with chemotherapy, the risk of all-grade neurological toxicities caused by PD-1/PD-L1 inhibitors was much lower in terms of peripheral neuropathy (OR=0.07, 95%CI:[0.04, 0.13]), peripheral sensory neuropathy (OR=0.07, 95%CI:[0.04, 0.12]), dysgeusia (OR=0.26, 95%CI:[0.19, 0.35]), paraesthesia (OR=0.23, 95%CI:[0.14, 0.36]), and polyneuropathy (OR=0.12, 95%CI:[0.01, 0.94]). However, for grades 3-5, the statistically significant results were only seen in peripheral neuropathy (OR=0.15, 95%CI:[0.07, 0.34]) and peripheral sensory neuropathy (OR=0.13, 95%CI:[0.04, 0.40]). No statistically significant difference regarding the risk of headache, dizziness, and Guillain-Barre syndrome was found between PD-1/PD-L1 inhibitors and chemotherapy. For PD-1/PD-L1 inhibitors plus chemotherapy, the risk trends of the above-mentioned neurological toxicities, especially grade 3-5 peripheral neuropathy (OR=1.76, 95%CI:[1.10, 2.82]) was increased compared to chemotherapy alone. Conclusion Our comprehensive analysis showed that PD-1/PD-L1 inhibitors alone exhibited lower neurological toxicities than chemotherapy. However, the risk of headache, dizziness, and Guillain-Barre syndrome was similar between PD-1/PD-L1 and chemotherapy. For PD-1/PD-L1 inhibitors plus chemotherapy, the incidence trend of neurological toxicities would be increased, especially for peripheral neuropathy of grades 3-5.