Atezolizumab and Bevacizumab Induced Primary Adrenal Insufficiency

With the increasing use of immune checkpoint inhibitors (ICI) in the treatment of several malignancies, many immune related adverse effects (IRAEs) are emerging. Atezolizumab is a humanized monoclonal antibody ICI that binds to programmed death ligand 1 (PD-L1) to prevent the interaction between the programmed cell death-1 (PD-1) and B7.1 receptors. It has been associated with hypophysitis leading to secondary adrenal insufficiency and type 1 diabetes mellitus. Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF) and has been associated with thyroiditis. Neither of these therapies have been associated with primary adrenal insufficiency (PAI).

Case Description:

A 70-year-old man with a history of hepatocellular cancer (HCC) on treatment with Atezolizumab and Bevacizumab for the last 6 months was referred to the endocrinology clinic for evaluation of elevated adrenocorticotropic hormone (ACTH) levels. MRI abdomen performed a month prior to presentation showed a 2.7x3.7 cm non-enhancing right adrenal lesion, which was biopsied, with pathology consistent with metastatic HCC. The left adrenal gland on the MRI was normal. Patient reported fasting hypoglycemia, weight loss and dizziness which started a month after starting the adjunctive treatment with Atezolizumab and Bevacizumab. Workup revealed an elevated ACTH level of 102.5 pg/ml (Reference range 7.2-63.3 pg/ml) and a low random cortisol level of 6.9 mcg/dl. An ACTH stimulation test was done with a baseline cortisol level of 5.1 mcg/dl, a 30 min cortisol level was 4.8 mcg/dl, and a 60 min cortisol level was 4.9 mcg/dl. Absent cortisol response to ACTH stimulation indicated PAI. The dehydroepiandrosterone sulphate (DHEA-S) level was low at 5 mcg/dl (Reference range 28-175 mcg/dl), which further supports the diagnosis of PAI. Hydrocortisone 10 mg twice a day was started with improvement of symptoms within 48 hours and resolution of hypoglycemia.

Discussion:

This the first reported case of Atezolizumab-Bevacizumab induced PAI. The left adrenal gland was reported normal on the MRI which excludes the possibility of adrenal metastasis contributing to the PAI. The temporal correlation of symptom onset with initiation of therapy indicates a medication induced etiology. The response to ACTH stimulation test confirms the diagnosis of PAI. Although either of these medications could have caused PAI, we think it is more likely attributable to Atezolizumab because it is a relatively new medication on the market. It highlights the importance of being vigilant about distinct types of immune mediated endocrinopathies in patients on ICIs.