Endocrine Adverse Reactions of Tyrosine Kinase Inhibitors in Combination With Immune Checkpoint Inhibitors

BACKGROUND: Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) were recognized to cause endocrine adverse reactions (EARs). However, combination therapy-associated EARs are still unclear. METHODS: This was a retrospective study based on the FDA Adverse Event Reporting System. We identified 938 464 cases of all adverse events related to 3 types of treatments. A total of 22 275 cases were EARs and divided into TKIs (n = 9181), ICIs (n = 11 363), and TKIs + ICIs group (n = 1731). RESULTS: The incidence of EARs was the highest in TKIs + ICIs followed by the ICIs and TKIs group. The TKIs + ICIs group had a higher risk of hypothyroidism than the ICIs group [odds ratio (OR) 1.47, 95% confidence interval (CI) 1.28-1.69] and a lower risk compared to the TKIs group (OR 0.68, 95% CI 0.58-0.79). The TKIs + ICIs group presented a higher risk of type 1 diabetes mellitus compared to the TKIs group (OR 26.61, 95% CI 18.60-38.07) but a lower risk compared to the ICIs group (OR 0.63, 95% CI 0.47-0.84). The risk of hypoglycemia was approximately 2.77 times greater in the TKIs + ICIs group than in the ICIs group (OR 2.77, 95% CI 1.95-3.95) and was also higher in the TKIs group compared to the ICIs group (OR 3.44, 95% CI 2.93-4.03). Compared to the ICIs group, the TKIs + ICIs group did not display a higher risk of pituitary dysfunction and primary adrenal insufficiency. The mortality risk of the TKIs + ICIs group was comparable to the ICIs group but was significantly lower than the TKIs group. CONCLUSION: EARs were more common in TKIs + ICIs therapy. The distribution of EARs in different glands varied among combination therapy and monotherapy. Combination therapy-associated EARs did not increase the risk of mortality.