Risk factors of immune-related endocrine toxicities in non-small cell lung cancer patients treated with pembrolizumab and its impact on patient outcomes: a multicenter retrospective study

Abstract

Abstract Background Pembrolizumab has been approved as a first-line treatment for non-small cell lung cancer (NSCLC) patients. However, a percentage of patients discontinue immunotherapy due to immune-related adverse events (irAE). Among these events, immune-related endocrine toxicities (E-irAE) represents the most common form, though their etiology, risk factors, and impact on patient outcomes remain poorly understood. Materials and methods This retrospective cohort study was conducted across 5 multiple centers to investigate the outcomes of NSCLC patients who received pembrolizumab treatment between October 1, 2019, and September 30, 2023. E-irAE can occur on the thyroid, pituitary, adrenal glands, pancreas, and parathyroid. So thyroid function, adrenocorticotropic hormone, cortisol, sex hormone and glycaemia were measured at baseline and at regular intervals after the initiation of pembrolizumab treatment. Results Our study included a total of 380 NSCLC patients treated with pembrolizumab, 114 patients (30.00%) developed E-irAE. Among them, 107 patients (93.86%) developed immune-related thyroid dysfunction (irTD) (5 cases of combined immune-related hypophysitis (IH)), 4 patients (3.51%) only developed IH, and 3 patients (2.63%) developed type 1 diabetes mellitus. IrTD was found to be independently associated only with monocyte-to-lymphocyte ratio (MLR) (odds ratios (OR) = 0.060, 95% CI 0.000-0.375; p = 0.015) and anti-thyroglobulin antibody (TGAb) (OR = 31.898, 95% CI 1.516-671.367; p = 0.026). Kaplan-Meier Survival Analysis showed that the progression-free survival (PFS) was significant longer in stage IV NSCLC patients with irTD than in those who did not (44.72 weeks vs. 27.79 weeks; hazard ratio (HR) = 0.645, 95% CI 0.440–0.946; p = 0.025), particularly in the subgroup of subclinical hypothyroidism (HR = 0.567, 95% CI 0.324–0.994; p = 0.047). We also found that sex (HR = 0.493, 95% CI 0.291–0.834; p = 0.008) was identified as an independent factor associated with better PFS. Conclusion E-irAE are recognized as prevalent common irAE with various phenotypic manifestations. Low MLR and positive TGAb at baseline have been identified as risk factors that increase the likelihood of developing irTD. Sex and the occurrence of irTD were independently associated with improved PFS.

Keywords

• Non-small cell lung cancer
• Immunotherapy
• Immune-related endocrine toxicities
• Immune-related thyroid dysfunction
• Pembrolizumab