COVID-19 mRNA vaccination and risk of immune-related adverse events in ICI-treated cancer patients.

2641 Background: Immune checkpoint inhibitors (ICIs) are now standard-of-care in cancer therapy; however, concerns persist regarding whether COVID-19 mRNA vaccination may enhance immune activation and exacerbate immune-related adverse events (irAEs). We evaluated the association between COVID-19 mRNA vaccination and irAE risk among patients initiating ICI therapy and assessed toxicity and survival outcomes. Methods: We conducted a retrospective cohort study using target trial emulation with 1:1 propensity score matching based on data from the TriNetX Research Database (January 2021–December 2025). Adult patients with metastatic cancer initiating their first ICI therapy were included. Patients with prior ICI therapy, active irAE within 30 days before ICI initiation or immunosuppressive conditions were excluded. Vaccinated patients who received COVID-19 mRNA vaccination within 100 days prior to ICI initiation were matched to unvaccinated controls. The primary outcome was composite irAE incidence over 36 months. Secondary outcomes included severe irAEs, organ-specific irAEs, all-cause mortality, pneumonia, and intensive care unit (ICU) admission. Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (CIs). E-values and quantitative bias analyses assessed robustness to unmeasured confounding. Results: The matched cohort included 7,218 patients (3,609 vaccinated; 3,609 unvaccinated). Vaccinated patients had a higher risk of overall irAEs (HR 1.22, 95% CI 1.17–1.28; E-value 1.74) and severe irAEs (HR 1.11, 95% CI 1.04–1.18; E-value 1.45). Organ-specific analyses demonstrated a significant increase in ocular irAEs (HR 1.48, 95% CI 1.17–1.87; E-value 2.33), with non-significant associations for dermatologic (HR 1.08, 95% CI 0.97–1.21) and rheumatologic irAEs (HR 1.12, 95% CI 0.96–1.32). No significant increases were observed for cardiac, endocrine, gastrointestinal, hematologic, or pulmonary irAEs. Despite higher irAE risk, vaccination was associated with lower all-cause mortality (HR 0.86, 95% CI 0.80–0.93) and fewer ICU admissions (HR 0.43, 95% CI 0.25–0.73). Subgroup analyses showed stronger overall irAE associations in females and patients aged ≥50 years. Quantitative bias analysis indicated moderate robustness, with a 74.8% probability that HR>1.0 persists despite plausible unmeasured confounding. All P<0.001. Conclusions: COVID-19 mRNA vaccination among patients receiving ICIs is associated with a modest increase in irAEs, particularly ocular toxicities, but may offer survival and critical illness benefits. These findings support continued vaccination in eligible ICI-treated patients, along with enhanced irAE monitoring, including ophthalmologic surveillance in higher-risk groups.