Neurotoxicity of immune checkpoint inhibitors: a retrospective pharmacovigilance study using FAERS database

Immune checkpoint inhibitors (ICIs), an antitumor therapeutic strategy, have shown great potential for cancer treatment. With the widespread use of ICIs, immune-related adverse events (irAEs) have increased gradually. Neurotoxicity, as an irAE, has a low incidence rate, but high disability and mortality rates, warranting clinical attention.

This study aimed to quantify the association between neurological adverse events and ICI treatment and describe the characteristics of ICI-related neurological complications in real-world practice. Data were sourced from the FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the first quarter of 2025. Data mining was performed using the reporting odds ratio (ROR) method. Classification and statistics were conducted using the system organ class (SOC), high-level group term (HLGT), and preferred term (PT) from the Medical Dictionary for Regulatory Activities (MedDRA) terminology set (version 28.0).

The entire FAERS database included 56,321,150 adverse event records, of which 26,629 records were identified as being related to neurological immune-related adverse events (n-irAEs) following ICI therapy. The main adverse events include encephalitis, encephalopathy, myasthenia gravis, paraneoplastic syndromes, and peripheral neuropathy. Among these reports, males (53.51%) outnumbered females (37.82%), and the median patient age was 67 years. The number of reports in 2024 was slightly higher than that in other years, but the difference was not significant. Physicians were the primary reporters (43.23%) and the United States had the highest number of reports (35.78%). The median time to the onset of adverse events was 30 days. Serious reports accounted for a high proportion of the patients (91.23%).

Pharmacovigilance analysis indicated that neurological immune-related adverse events associated with ICIs mainly involved central nervous system inflammation and neuromuscular junction dysfunction. Different ICI immunotherapies are associated with distinct neurological disease characteristics, and combination therapies may influence the reporting patterns of neurotoxicity. In clinical practice, the early recognition and management of ICI-related n-irAEs are critical.