Stratification of cardiovascular complications with immunotherapy.

e24004 Background: Immune checkpoint inhibitors (ICIs) are used to treat various malignancies and have expanded the therapeutic landscape. However, their use is linked with adverse drug reactions (ADRs), including cardiovascular toxicities. Prior studies have examined the relationship between ICIs and cardiac ADRs, but risk stratification among individual agents and regimens is limited. A pharmacovigilance analysis using the FDA Adverse Event Reporting System (FAERS) was done to evaluate disproportionate reporting of cardiovascular ADRs across ICIs, ICI classes, and combination regimens. Methods: FAERS is a database used for post-marketing surveillance. PD-1 inhibitors (pembrolizumab, nivolumab, cemiplimab), PD-L1 inhibitors (atezolizumab, durvalumab, avelumab), CTLA-4 inhibitors (ipilimumab, tremelimumab), and combination regimens (nivolumab/ipilimumab, durvalumab/tremelimumab) were evaluated. Cardiovascular ADRs assessed were atrial fibrillation, atrial flutter, atrioventricular block, myocarditis, pericarditis, pericardial effusion, cardiac arrest, and congestive heart failure (CHF). The Reporting Odds Ratio (ROR) was used to determine if these reports represented a significant signal in the FAERS database. 95% confidence intervals (CI) and p-values were calculated to assess the significance between each drug/combination and a cardiac ADR. P-values were significant (≤ 0.05), unless stated otherwise. ROR=(positive reports with drug/negative reports with drug)/(positive reports without drug/negative reports without drug). An ROR >1 is considered a potential signal for an ADR. Results: (Table 1) Combination ICI therapy demonstrated overall elevated CHF signals (ROR 1.37, 95% CI 1.39-1.67)- durvalumab/tremelimumab had an ROR of 17.90 (95% CI 14.27–22.45) and nivolumab/ipilimumab had an ROR of 4.52 (95% CI 3.83–5.33). Durvalumab/tremelimumab demonstrated the highest overall cardiac signal with ROR 2.30 (95% CI 1.98–2.68). Combination therapy also had disproportionate atrial fibrillation reporting (ROR 1.37, 95% CI 1.19–1.57). All monotherapy classes showed significantly lower CHF reporting: PD-1 (ROR 0.65, 95% CI 0.57-0.74), PD-L1 (ROR 0.61, 95% CI 0.48-0.78, and CTLA-4 (ROR 0.52, 95% CI 0.39-0.70). Conclusions: ICI-associated cardiotoxicity is strongly regimen-dependent- with combination therapy, particularly durvalumab-tremelimumab, showing the highest cardiac signals. Heightened cardiovascular surveillance should be considered for patients receiving combination regimens. Combination ADR signals. Drug/Class Total ADRs ROR, CI (Afib) ROR, CI (myocarditis) ROR, CI (CHF) ROR, CI (total) Nivolumab/ipilimumab 28388 - 1.32 (1.19-1.46) 4.52 (3.83–5.33) - Durvalumab/tremelimumab 2710 - 3.3 (2.70-4.03) 17.90 (14.27–22.45) 2.30 (1.98–2.68) Combination (all) 31098 1.37 (1.19–1.57) 1.52 (1.39-1.67) 5.89 (5.14-6.75) 1.13 (1.06-1.21)