Endocrine adverse reactions of tyrosine kinase inhibitors in combination with immune checkpoint inhibitors.

Abstract

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 FDA Adverse Event Reporting System. We identified 938,464 cases of all adverse events related to three types of treatments. A total of 22,275 cases were EARs and divided into TKIs (n=9,181), ICIs (n=11,363) and TKIs+ICIs group (n=1,731).

Results: The incidence of EARs was the highest in TKIs+ICIs followed by ICIs and TKIs group. TKIs+ICIs group had a higher risk of hypothyroidism than in ICIs group (OR 1.47, 95% CI [1.28-1.69]), while a lower risk compared to TKIs group (OR 0.68, 95% CI [0.58-0.79]). TKIs+ICIs group presented a higher risk of type 1 diabetes mellitus compared to TKIs group (OR 26.61, 95% CI [18.60-38.07]), but a lower risk compared to ICIs group (OR 0.63, 95% CI [0.47-0.84]). The risk of hypoglycaemia was approximately 2.77 times greater in TKIs+ICIs group than in ICIs group (OR 2.77, 95% CI [1.95-3.95]) and was also higher in TKIs group compared to ICIs group (OR 3.44, 95% CI [2.93-4.03]). Compared to ICIs group, TKIs+ICIs group did not display a higher risk of pituitary dysfunction and primary adrenal insufficiency. The mortality risk of TKIs+ICIs group was comparable to ICIs groups, but significantly lower than TKIs group.

Conclusions: 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.