Comparative safety profiles of immune checkpoint inhibitor monotherapy and combination therapy: Insights from the FAERS 2023–2024 database.

442 Background: The increasing utilization of immune checkpoint inhibitors (ICIs) for several malignancies has brought growing concerns about adverse events (AEs), particularly with combination regimens. While combination therapies demonstrate improved efficacy, they are also often associated with increased toxicity. Understanding the distinct safety profiles of ICI monotherapy versus combination therapy is essential to guide clinical decision-making. This study utilized data from the U.S. FDA Adverse Event Reporting System (FAERS) to compare the burden and nature of AEs between ICI monotherapy and combination therapies. Methods: We conducted a retrospective pharmacovigilance analysis of ICI-related AEs reported in FAERS from January 2023 to December 2024. Cases were categorized as monotherapy or combination therapy (defined as ICIs plus other chemotherapeutic agents). AEs, including serious AEs (defined as death, hospitalization, disability, or life-threatening adverse events) were identified using MedDRA Preferred Terms. Descriptive statistics and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. All analyses were performed using R version 4.5.0. Results: A total of 12,508 ICI-related AE reports were analyzed. Of these, 68.6% involved monotherapy and 31.4% involved combination therapy. The mean number of AEs per case was higher in combination therapy (3.77 vs. 3.19; p < 0.0001). Similarly, the mean number of serious outcomes was also higher with combination therapy (0.75 vs. 0.66; p < 0.0001). Logistic regression revealed that monotherapy was associated with significantly lower odds of serious outcomes (OR 0.69; 95% CI: 0.64–0.75; p < 0.001). In contrast, immune-related AEs, including myocarditis, pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, arthritis, and rash, were more frequently reported with monotherapy (23.7% vs. 17.8%; mean per case 0.29 vs. 0.22; p < 0.0001), with higher odds compared to combination therapy (OR 1.44; 95% CI: 1.31–1.58; p < 0.0001). Conclusions: ICI combination therapy is associated with a greater overall and serious adverse events burden but monotherapy shows stronger association with immune-related adverse events. Our findings underscore the importance of individualized risk–benefit assessment in selecting ICI treatment regimens.