# Immunotherapy Safety in Thymic Epithelial Tumors: Disproportionality Analysis of the Food and Drug Administration Adverse Event Reporting System

## TL;DR

This study uses real-world data to show that immunotherapy for thymic tumors carries serious side effects like myositis and myocarditis, which require close monitoring.

## Contribution

The study provides the first comprehensive safety profile of immunotherapy in thymic epithelial tumors using pharmacovigilance data.

## Key findings

- Myositis, myocarditis, and myasthenia gravis showed the strongest associations with immunotherapy in TET patients.
- Fatal outcomes occurred in 23.7% of cases and were linked to gender and treatment strategies.
- PD-1 inhibitors were more commonly used in fatal cases compared to nonfatal ones.

## Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but their safety profile in patients with thymic epithelial tumors (TETs) remains poorly characterized due to the rarity of these malignancies.

This study aims to comprehensively analyze immune-related adverse events (irAEs) profiles in patients with TETs using real-world pharmacovigilance data.

We conducted a retrospective analysis of the US Food and Drug Administration Adverse Event Reporting System database from the first quarter of 2016 through the fourth quarter of 2024. Cases of TETs with ICI-related adverse events were identified and deduplicated following Food and Drug Administration recommendations. Disproportionality analysis was performed by calculating odds ratios, using the entire US Food and Drug Administration Adverse Event Reporting System database as the reference cohort. Signals were defined as significant with at least 3 cases and a lower 95% CI exceeded 1. Time-to-onset analysis and Weibull Shape Parameter testing were used to characterize the temporal pattern of irAEs. Clinical characteristics between fatal and nonfatal cases and cardiotoxicity specifics were analyzed descriptively.

Among 152 eligible TET cases with irAEs, males slightly predominated (80/152, 52.6%), with a median age of 58.5 years. Reports originated predominantly from the United States (51/152, 33.6%) and Japan (16/152, 10.5%). PD-1 inhibitors were implicated in 66.4% (101/152) of cases. Disproportionality analysis identified 14 significant irAE signals across 11 System Organ Classes. Myositis (reporting odds ratio [ROR] 113.15, 95% CI 26.65‐480.34), myocarditis (ROR 10.96, 95% CI 5.70‐21.07), myasthenia gravis (ROR 3.86, 95% CI 1.86‐7.85), and febrile neutropenia (ROR 18.33, 95% CI 4.57‐73.55) demonstrated the strongest associations. The median time to irAEs onset was 21.0 days, with 73.2% (41/56) occurring within 2 months of treatment initiation. Fatal outcomes were reported in 23.7% (36/152) of cases and were significantly associated with gender distribution (P=.04) and different treatment strategies (P=.01). The utilization of PD-1 inhibitors was higher in the fatal group (29/36, 80.06%) than in the nonfatal group (72/116, 62.1%). Myocarditis was the most frequent cardiotoxicity, accounting for 51.3% (20/39) of cardiac events.

This large-scale pharmacovigilance study delineates a distinct and severe irAEs profile for ICIs in patients with TETs, characterized by robust disproportionality signals for myositis, cardiotoxicity, and myasthenia gravis. As a hypothesis-generating analysis, these findings underscore the need for vigilant monitoring and early detection strategies to mitigate irAE risks, particularly in high-risk subgroups such as patients with thymoma. The results provide clinically relevant evidence to guide risk-benefit evaluation and inform tailored surveillance protocols during ICI therapy in this population.