The Risk of Adrenal Insufficiency after Treatment with Relatlimab in Combination with Nivolumab is Higher than Expected

Abstract Context Adrenal insufficiency from hypophysitis is a complication of immune checkpoint inhibitor (ICI) therapy. However, the risk associated with relatlimab, a lymphocyte activation gene 3 inhibitor, is unknown. Relatlimab was approved in 2022 in combination with nivolumab for the treatment of unresectable or metastatic melanoma. Objective To determine the prevalence, identify risk factors, and characterize the clinical presentation of central adrenal insufficiency in patients receiving relatlimab-nivolumab compared to nivolumab alone. Methods Retrospective analysis of Mass General Brigham healthcare system patients who received relatlimab-nivolumab from 2015 to 2023 matched by age, sex and race to individuals receiving monotherapy with nivolumab, an ICI with a risk of hypophysitis of <1%. Results Adrenal insufficiency was diagnosed in 10 patients (7.6%) after relatlimab-nivolumab administration and in 1 patient (0.8%) after nivolumab monotherapy (p=0.00056). Within the relatlimab-nivolumab group, median age and sex were comparable in patients who developed adrenal insufficiency compared to those who did not. The median number of doses received by subjects who developed adrenal insufficiency was 7 (4-10) compared to 3 (2-6) in those who did not (p=0.03). The most common presenting symptoms were fatigue, anorexia, nausea, and vomiting. No patients were diagnosed with additional anterior pituitary hormone deficiencies or AVP deficiency, though not all patients were evaluated for these diagnoses. Conclusions This study is the first cohort analysis of hypophysitis in patients treated with relatlimab-nivolumab compared to nivolumab monotherapy. Combination treatment with relatlimab-nivolumab confers a significantly higher risk of developing adrenal insufficiency, likely secondary to hypophysitis, compared to nivolumab alone.