Endocrine Abstracts

JOINT2452

Introduction: Secondary adrenal insufficiency (AI) is a potentially life-threatening adverse event that has been also associated with the use of immune checkpoint inhibitors (ICIs) in oncologic patients. Accumulating evidence link pembrolizumab, a programmed cell death protein-1 (PD-1) inhibitor, with adrenocorticotropic hormone (ACTH) deficiency in a frequency probably significantly higher than initially considered. We report a case series of three patients receiving pembrolizumab for diverse type of malignancies, who developed secondary AI.

Case 1: A 68-year-old man with metastatic non-small-cell lung cancer was referred from his oncologist due to pembrolizumab-induced thyroiditis [TSH = 124.78 μIU/ml (0.35–4.78) and FT4 = 2.9 pmol/l (10.5-22.7)], developing 20 weeks after starting ICI. Though he reported only mild fatigue attributed to the underlying cancer and hypothyroid status, endocrinological workup before levothyroxine supplementation revealed concomitant secondary AI, as indicated by low morning cortisol = 2.8 μg/dl (6-20) and ACTH<5 pg/ml (9-52) levels. MRI of the pituitary gland revealed partial empty sella and hydrocortisone 30 mg/day was started. Interestingly, five months after AI diagnosis, recovery of adrenal axis was observed with morning cortisol levels up to 17.52 μg/dl and ACTH levels up to 33.2 pg/ml while he was still receiving pembrolizumab. Glucocorticoid replacement was discontinued and the patient remained eucortisolemic during follow-up.

Case 2: A 68-year-old man completing a 6-cycle treatment with pembrolizumab for metastatic renal disease was referred from his oncologist due to severe fatigue and progressively worsening muscle weakness. Laboratory investigation was compatible with secondary AI (low morning cortisol = 2.62 μg/dl and ACTH = 4 pg/ml levels), while thyroid function was normal. Pituitary MRI showed only gland heterogeneity and hydrocortisone (30 mg/day) was started with significant clinical improvement. Six months after completing immunotherapy and while on glucocorticoids, AI still did not resolve.

Case 3: A 48-year-old woman treated with pembrolizumab (6 cycles) for poorly differentiated breast cancer was referred from her oncologist due to secondary AI (low morning cortisol = 1.2 μg/dl and ACTH = 5.4 pg/ml levels) with coexisting central hypothyroidism [subnormal FT4 levels = 0.51 ng/dl (0.8-2) with inappropriately low serum TSH = 1.98 μIU/ml (0.3–4.5) levels]. Hydrocortisone (30 mg/day) and then levothyroxine (68μg/day) were started with no biochemical sign of pituitary-adrenal axis recovery in a 6-month follow-up period, after pembrolizumab last administration.

Discussion: Oncologic patients receiving pembrolizumab are at considerable risk for developing secondary AI. Therefore, close monitoring seems a reasonable approach to avoid delayed diagnosis and management.