Objective:

To evaluate the heterogeneity of inflammatory CNS immune-related adverse event (irAE) reporting signals across primary CNS tumors, brain metastases, and non-CNS solid tumors.

Approach:

• Pharmacovigilance Signal Discovery: Constructed an ICI-exposed cohort from the FDA Adverse Event Reporting System (FAERS) to analyze inflammatory CNS irAE reporting signals.
• External Comparison: Compared findings with the Japanese Adverse Drug Event Report database (JADER) for corroboration.
• Transcriptomic Analysis: Analyzed public single-cell RNA sequencing datasets and utilized spatial transcriptomics for visualization of brain metastasis tissue.

Key Findings:

• Inflammatory CNS irAE reporting signals showed tumor phenotype-associated heterogeneity.
• Adjusted odds ratios were 1.65 (95% CI, 1.02–2.65) for primary CNS tumors and 3.12 (95% CI, 2.45–3.98) for brain metastases versus non-CNS solid tumors.
• Stricter phenotype definitions were more specific than broader neuroinflammatory definitions.
• Baseline single-cell analyses localized strict inflammatory module activity mainly to myeloid and T/NK compartments.

Interpretation:

Pharmacovigilance findings indicate differences in inflammatory CNS irAE reporting signals based on tumor phenotype, particularly in brain metastases.

Limitations:

• Findings should be interpreted as hypothesis-generating associations, not evidence of incidence or causality.
• Primary CNS tumor estimates in JADER were sparse and exploratory.

Conclusion:

The study highlights the need for accurate characterization of ICI-related CNS toxicity in the context of distinct immune microenvironments in brain tumors.