Case Presentation: A 71 year old male with a history of COPD, Hypothyroidism and Stage IIIA Lung Cancer status post wedge resection and prior treatment with chemotherapy and radiation currently on Pembrolizumab who presented with a two week history of fatigue. He denied any recent steroid use. Physical exam revealed hypotension and blood pressures dropping from 88/52 lying to 61/35 standing. He was found to have reduced breath sounds bilaterally with the rest of the exam normal. Admission labs revealed Na 120 mmol/L and K 4.5 mmol/L with inappropriately low cortisol 2.1 ug/dl, elevated TSH 15.8 UIU/ml, normal T4 1ng/dl, low supine aldosterone level < 1 ng/dl and normal renin level. Urine studies showed urine osmolality 440 mosm/kg and urine sodium 54 mmol/l. Given concern for adrenal insufficiency (AI), an ACTH test was done which was low < 5 pg/ml, subsequently an ACTH stimulation test was consistent with an inappropriate response (< 1.0 mcg/dL baseline, 7.8mcg/dL 30 minute, 9.1mcg/dL 60 minute). Prolactin, FSH, LH, Testosterone and IGF levels were within normal limits.Investigation for possible Pembrolizumab-induced Hypophysitis with MRI pituitary showed a normal pituitary gland. CT abdomen/pelvis with normal adrenal glands. Intravenous hydrocortisone was initiated for a diagnosis of adrenal insufficiency and = he was tapered to oral physiologic doses of hydrocortisone with subsequent improvement in fatigue, and normalization of sodium levels and blood pressure values. He was safely discharged home on Hydrocortisone therapy

Discussion: Pembrolizumab, an immune checkpoint inhibitor (ICI), is a highly selective monoclonal antibody against the programmed cell death protein 1 (PD-1) receptor that aids in T-cell mobilization to effectively exert tumour cell death. The KEYNOTE–024 trial helped establish Pembrolizumab as an effective monotherapy for advanced Non-small cell lung cancer (NSCLC) with an overall reported survival of 30 months as compared to 14 months with chemotherapy, 40% reduction in risk of death (1). Immune related adverse effects (irAEs) are increasing in frequency with gaining popularity of ICI usage. One category of irAEs include poly- endocrinopathies such as hypothyroidism, type 1 diabetes, adrenal insufficiency and hypophysitis (3).Isolated ACTH deficiency has a rare incidence of 0.5 – 1.7% (3,4), and secondary AI has been described in males over the age of 60 with presenting non-specific symptoms such as fatigue, anorexia, weight loss, nausea, vomiting, headache and orthostasis. Median time from initiation of Pembrolizumab treatment to presentation of secondary AI is generally 7 – 20 weeks (5). The pathophysiology behind hypophysitis with resultant anterior pituitary dysfunction is not well understood though lymphocytic inflammation is a postulated mechanism. The constellation of signs and symptoms including hypotension, hyponatremia, fatigue, low cortisol and inadequate ACTH stimulation test supported the diagnosis of secondary adrenal insufficiency. MRI pituitary in our patient was not suggestive of active hypophysitis which typically is associated with diffuse, symmetric enlargement of the pituitary gland (6).

Conclusions: The increased use of immune checkpoint inhibitor therapy for advanced malignancies and resultant risk of adverse effects, including the rare entity of isolated ACTH deficiency underscores the importance that clinicians remain vigilant with frequent monitoring when prescribing and managing patients on this treatment.