Hypophysitis and Secondary Adrenal Insufficiency From Immune Checkpoint Inhibitors: Diagnostic Challenges and Link With Survival

Background: Hypophysitis is a serious adverse event stemming from immune checkpoint inhibitor (ICI) therapy for malignancy. This study aimed to characterize ICI-induced hypophysitis, identify diag-nostic challenges, and evaluate an association with survival in a large cancer cohort. Methods: We performed a retrospective cohort study of adult patients with cancer who received ICIs between December 1, 2012, and December 31, 2019. We identified 839 patients who received CTLA-4, PD-1, or PD-L1 inhibitors or a com-bination thereof who were followed for a median of 19.4 months. Hypophysitis was defined as MRI evidence of pituitary gland and/or stalk enlargement or biochemical evidence of hypopituitarism if not explained by another etiology. Results: A total of 16 (1.9%) patients developed hypophysitis a median of 7 months after ICI initiation, with most patients having melanoma (9/16; 56.2%) or renal cell car-cinoma (4/16; 25%). Two patients also had exogenous glucocorticoid exposure but exhibited secondary hypothyroidism and secondary adrenal insufficiency (AI). Median age at the start of ICI was 61.3 years and 57% were men. Patients who developed hypophysitis were youn-ger compared with those who did not develop hypophysitis (median age, 57 vs 65 years; P5.011). Hypophysitis occurred most frequently after combination therapy (13.7%) compared with CTLA-4 monother-apy (1.9%), PD-1 monotherapy (1.2%), and PD-L1 monotherapy (0.8%) (P<.0001). Pituitary gland enlargement on MRI occurred more fre-quently after CTLA-4 inhibitor monotherapy or combination therapy (5/7; 71.4%) compared with PD-1/PD-L1 inhibitor monotherapy (1/6; 16.7%). The survival benefit of hypophysitis was not apparent after ad-dressing immortal time bias and adjusting for other variables affecting patient outcomes. Conclusions: Secondary AI occurred in all patients, and secondary hypothyroidism occurred in half. Classic pituitary gland enlargement is usually absent in PD-1/PD-L1 inhibitor-induced hypo-physitis. Further pituitary evaluation must be conducted to differentiate secondary AI resulting from exogenous glucocorticoids and hypophysi-tis in patients with cancer receiving ICIs. The link between hypophysitis and ICI efficacy needs further investigation.