Immune-Related Adverse Event-Related Adrenal Insufficiency Mediates Immune Checkpoint Inhibitors Efficacy in Cancer Treatment

Purpose: Immune checkpoint inhibitors (ICIs) have significantly improved the outcomes of patients with cancer; however, these agents may initiate immune-related adverse events (irAEs). Previous studies have demonstrated a robust correlation between disease prognosis and the occurrence of irAEs, specifically skin or endocrine irAEs. Herein, we aimed to evaluate the correlation between irAE-related adrenal insufficiency (AI) and ICI treatment efficacy. Patients and methods: Patients diagnosed with gastrointestinal, respiratory, head and neck, urological, skin and gynecologic cancers treated with anti-programmed cell death 1 (PD-1)/anti-programmed cell death ligand 1 (PD-L1) antibody as monotherapy or combined therapy (combined with chemotherapy or targeted therapy) were divided into irAE-A (patients with irAE-related AI), irAE-B (patients with other irAEs) and non-irAE groups. Immunotherapy efficacy was assessed based on the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Survival probabilities were estimated using the Kaplan–Meier method with the log–rank test. Results: Of the 192 patients enrolled in our study, 17 developed irAE-related AI and 83 developed other irAEs. The DCR of the irAE-A and irAE-B groups were higher than that of the non-irAE group ( P < 0.05). Multiple extended Cox regression analyses showed that irAE status (irAE-A vs non-irAE, P =0.008; irAE-B vs non-irAE, P =0.020), Eastern Cooperative Oncology Group (ECOG) status ( P =0.045), tumor-node-metastasis (TNM) stage ( P =0.000), and treatment line ( P =0.002) were independent predictors of PFS. Contrarily, irAE status (irAE-A vs non-irAE, P =0.009; irAE-B vs non-irAE, P =0.013), ECOG status ( P =0.007), TNM stage ( P =0.035), treatment line ( P =0.001) and treatment modality ( P =0.008) were independent predictors for OS. Conclusion: IrAE-related AI was significantly associated with ICI treatment efficacy in patients with cancer, which could be a potentially predictable marker. Due to the destruction of adrenal tissue by T cells with enhanced activity, AI reflects enhanced T cell activity to some extent. Keywords: endocrine adverse event, malignancies, monoclonal antibody therapy, immune-related side effects, treatment efficacy