Pharmacovigilance Insights Into Immune Checkpoint Inhibitor‐Induced Risk of Paraneoplastic Syndrome: A Large‐Scale Real World Study

ABSTRACT Background Immune checkpoint inhibitor (ICI)‐associated paraneoplastic syndromes (PS) represent a rare but potentially life‐threatening adverse event. Despite the widespread use of ICIs in cancer treatment, the clinical characteristics and risk profiles of PS across different treatment regimens remain incompletely characterized. Methods We analyzed FAERS data (Jan 2011–Jun 2024) to identify PS cases potentially related to ICI use. Reporting odds ratios (RORs) were calculated to evaluate safety signals. Clinical features, time‐to‐onset, and outcomes were analyzed across different ICI regimens. Results Among 162,493 ICI‐associated adverse event reports, 179 PS cases were identified. Disproportionate reporting of PS was observed with PD‐1 inhibitors (ROR 21.77, 95% CI 16.36–28.97), PD‐L1 inhibitors (ROR 23.33, 95% CI 14.13–38.41), nivolumab plus ipilimumab (ROR 24.21, 95% CI 18.07–32.42), and durvalumab plus tremelimumab (ROR 24.55, 95% CI 18.73–32.79). PS onset showed a bimodal distribution, with a median time to onset of 6 days, where 42.31% occurring within 30 days and 23.08% after 360 days of treatment initiation. Combination therapy, particularly durvalumab plus tremelimumab, was associated with higher rates of severe outcomes (27.8%). In patients with PS related to ICI therapy, those with lung malignancies are the most commonly represented group. Conclusions This analysis reveals distinct temporal patterns and safety signals of ICI‐associated PS, with higher reporting rates and severity in combination therapy. These findings provide important insights for clinical monitoring strategies and highlight the need for increased vigilance during specific risk windows, particularly in patients receiving combination therapy.