Endocrine Abstracts

Background: Immune checkpoint inhibitors like monoclonal antibodies targeting programmed death 1 receptor (PD1) or its ligand (PD-L1) have shown antitumor activity in many malignancies by enhancing immune response against cancer cells resulting in significant long-lasting responses. However, this therapy can induce endocrine immune-related adverse events (EirAEs). Thyroid dysfunction is a common EirAE, while adrenal insufficiency (AI) is very uncommon.

Objective: To report our experience on anti-PD1/anti-PD-L1-induced impairment of the hypothalamic-pituitary-adrenal (HPA) axis in cancer patients.

Results: Four patients (two males; mean age 55.5 (±7.6) years) with advanced cancer (3 non-small cell lung cancer (2 locally advanced and 1 metastatic) and one metastatic head and neck squamous cell carcinoma) were included. Three patients received anti-PD1 treatment (one combined with chemotherapy) and the other one was treated with anti-PD-L1 therapy plus chemotherapy. No one was under steroid therapy. The clinical features of AI were: fatigue (all patients), nausea/vomiting (25%), low blood pressure (25%), hyperkalemia (25%), and hyponatremia (50%). All cases had low baseline serum cortisol levels at diagnosis [mean: 23.5(±34) nmol/l; range: 5–80; normal range (NR): 172–497)] with absence of response to cosyntropin stimulation test. Three out of 4 patients developed secondary AI due to isolated adrenocorticotropic hormone (ACTH) deficiency (ACTH <1.1 pmol/l; NR: 2–12), whereas 1 patient developed primary AI due to autoimmune adrenalitis (positive anti-adrenal antibodies, ACTH: 237 pmol/l). All patients had a normal pituitary MRI and abdominal CT scan. Baseline serum concentrations of the rest of pituitary hormones (TSH, LH, FSH, GH, and PRL) as well as fT4 and IGF-1 were within the normal range in all cases. Patients were treated with replacement doses of hydrocortisone. All patients had to stop immunotherapy temporarily, but in 3 of them, it was reintroduced after a median of 41(±13.5) days. After 7.5±6.4 months (range: 3–18) of follow up, all patients remained with steroid hormone replacement therapy. Interestingly, 2 patients had a complete tumor response despite the advanced stage of the disease; one remained with stable disease after 12 months of follow-up and only one patient progressed 8 months after starting immunotherapy.

Conclusion: Cancer patients treated with anti-PD1 or anti-PD-L1 therapy can develop a persistent immune-related primary or secondary adrenal insufficiency. Isolated ACTH deficiency is the most frequent alteration in our series. In the primary failure, an autoimmune mechanism is suggested. Interestingly, half of these patients achieved a complete response.