Thyroid Dland Disorders Associated with Combination of Antiangiogenic Agents and Immune Checkpoint Inhibitors: A Pharmacovigilance Study

Purpose: Immune checkpoint inhibitors (ICIs), including anti-PD-1/L1 therapy and anti-CTLA-4 therapy, were reported with thyroid gland disorders adverse events. Recently, the FDA announced a warning that the combination of navolumab and cabozantinib can cause adrenal insufficiency. We performed a pharmacovigilance study to analyze the association between thyroid gland disorders and the use of ICI, anti-angiogenic agents or the combination treatment by mining the FDA adverse events reporting system (FAERS) database. Methods: Data were searched and analyzed in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Thyroid gland disorders, including hypothyroidism, hyperthyroidism, autoimmune thyroiditis, were defined by the Medical Dictionary for Regulatory Activities (MedDRA). We conducted disproportionality analysis using reporting odds ratio (ROR). The result was defined as a signal if the lower limit of the 95% confidence interval for ROR is over 2, the number of cases ≥3. And additive and multiplicative models were applied to analyze drug interactions. Results: In the FAERS database, we identified 2862 cases of thyroid gland disorders, and the cases number for hyperthyroidism, hypothyroidism and thyroiditis were 767 and 1579 and 556. In the disproportionality analysis, for ICI drugs group, our study detected moderate to strong signals between ICIs and thyroid gland disorders. Among these subgroups, ICI-related thyroiditis was associated with the strongest signal (ROR 23.09 [95% CI 21.08-25.28]). As for anti-angiogenic drugs group, however, very weak signals were found between anti-angiogenic drugs and thyroid gland disorders, only hypothyroidism was found with a significant signal (ROR 4.87 [95% CI 4.60-5.16]). As for combined regimen groups, we didn't identify significantly increased signals of thyroid gland disorders than monotherapy treatment. And we didn't find interactions between ICI and anti-angiogenic drugs according to additive/multiplicative models. Conclusion: In our study, we confirmed the increased risk of thyroid gland disorders of ICIs and anti-angiogenic agents monotherapy, however, there were no increased signals when the combination therapy was used. In order to prevent serious outcomes, we should be aware of thyroid gland disorders' risk when using ICIs or anti-angiogenic agents.