Long-term outcomes of adrenal insufficiency (AI) due to anti–PD(L)-1 immune checkpoint inhibitors (ICI) among patients with cancer.
Authors: Nguyen Ben , Shah Neil J. , Knezevic Andrea , Newman Samantha , Fitzgerald Kelly N. , Kotecha Ritesh , Lee Chung-Han , Carlo Maria Isabel , Aggen David Henry , Feldman Darren R. , Shapnik Natalie , Motzer Robert J. , Voss Martin H , Girotra Monica 
Published: June 2022

12092

Background: Endocrine immune-related adverse events (irAEs) to anti-PD-(L)1 ICI, including hypophysitis, autoimmune insulin-dependent diabetes mellites (ICI-DM), and primary adrenal insufficiency (AI), are rare but often associated with long term co-morbidities. AI from anti-PD-(L)1 ICI without CTLA-4 blockade is not well characterized in the literature. Long term outcomes for AI including need for replacement steroids and cortisol levels are unknown. Methods: We performed a single center retrospective analysis of patients treated with ICI including anti-programmed cell death protein-1 (Anti-PD-1: nivolumab or pembrolizumab), anti-programmed death-ligand-1 (anti-PD-L1: atezolizumab or cemiplimab) and diagnosed with ICI induced AI by a board-certified endocrinologist from 1/1/2011 to 12/31/2021. Patients treated with anti-CTLA-4 based therapy were not included. Patient baseline characteristics, presenting symptoms at the time of AI diagnosis, and treatment with corticosteroids were obtained by chart review. Baseline labs were collected at the time of AI and during routine patient follow-up. Descriptive statistics are reported for the cohort. Results: Twenty-nine patients were identified, 27 diagnosed with secondary and 2 diagnosed with primary AI. The median age was 63 (range 39-84), 18 (62%) males and 11 (38%) females, 14 (48%) receiving anti-PD(L)-1 monotherapy and 22 receiving anti-PD(L)-1 combination therapy either with chemotherapy (7, 24%), targeted therapy (6, 21%) or other/investigational therapy (2, 7%). The common tumor types were 6 renal cell carcinoma, 4 urothelial carcinoma, 4 melanoma, 15 others. The common presenting symptoms were 26 (90%) with fatigue,16 (55%) weakness, 11 (38%) nausea/vomiting, 4 (14%) headaches and 2 (7%) arthralgias. The common concomitant irAEs were 16 (55%) hypothyroidism, 8 (28%) acute kidney injury, 7 (24%) colitis, 6 (21%) joint pain, 3 (10%) pneumonitis & dermatitis. Eleven (38%) patients were treated with high dose steroids. Median follow-up time for survivors in the cohort was 24 months (range 7-68). Median cortisol level at time of AI diagnosis was 1.1 (IQR 0.9, 2.7; n = 27) and 1.8 (IQR 0.6, 6.4; n = 10) at last follow-up (median lab follow-up 39 months, range 29-58); 7 of 10 patients with available data had cortisol < 5.0 at last follow-up. For secondary AI patients, median ACTH at time of diagnosis was 2.3 (IQR 2.0, 5.0; n = 21) and 2.0 (IQR 2.0, 7.2; n = 7) at last follow-up. Twenty-two of 23 patients with available data continued replacement steroids at last follow-up. Conclusions: AI associated with anti-PD(L)-1 ICI is primarily secondary. Cortisol and ACTH levels remain low even during long-term follow-up. Most patients need long-term replacement steroids. Systemic and comprehensive follow-up for patients who develop AI due to anti-PD(L)-1 ICI is needed to confirm these findings.