Risk factors for endocrinological immune-related adverse events in patients with renal cell carcinoma treated with immune checkpoint inhibitors

Purpose: First-line treatment for renal cell carcinoma (RCC) commonly includes immune checkpoint inhibitors (ICIs), either as monotherapy or in combination with anti-angiogenic agents. These therapies can lead to endocrine immune-related adverse events (irAEs). This study aimed to identify predictive risk factors for the development of endocrine irAEs associated with ICI-based therapies. Methods: We conducted an observational, retrospective, single-center study involving 72 patients with RCC who initiated first-line treatment with ICIs (either in combination with another ICI or an anti-angiogenic agent) between January 2018 and May 2023. All patients had at least 18 months of clinical and biochemical follow-up. Results: 51.39% of patients experienced endocrine irAEs, including thyroid dysfunction (89.2%), primary hypocortisolism (10.8%), and hypophysitis (8.1%). Patients who developed endocrine irAEs had a significantly lower International Metastatic RCC Database Consortium (IMDC) score (p = 0.033), and renal/adrenal metastases were significantly associated with a lower risk of developing endocrine irAEs (p = 0.045) and thyroid dysfunction (p = 0.026). TNM stage II and III at diagnosis were linked with higher rates of endocrine irAEs in males and thyroid dysfunction in the overall population, whereas TNM stage IV was associated with a lower incidence of both outcomes (p = 0.02 and p = 0.05, respectively). In logistic regression analysis of the interaction between stage and sex, TNM stage III was significantly associated with a higher risk of irAEs and thyroid dysfunction in men compared with women at the same stage (p = 0.0184 and p = 0.0301, respectively). Among treatment variables, the use of tyrosine kinase inhibitors (TKIs) emerged as a significant predictor of thyroid irAEs (p = 0.041). A neutrophil percentage below the cohorts' 50th percentile (61.45%) was associated with increased risk of endocrine irAEs (p = 0.048). In multivariate analysis, renal/adrenal metastases and TNM stage IV remained negative predictors of both endocrine irAEs and thyroid dysfunction, while TKI use was a significant positive predictor of thyroid dysfunction. Conclusions: This study highlights several significant associations between the occurrence of endocrine irAEs and oncological parameters (renal/adrenal metastases, TNM stage), therapeutic factors (use of TKIs), and laboratory markers (neutrophil percentage) in RCC patients. These predictors may be useful in identifying patients who are more likely to develop endocrine irAEs and therefore require more rigorous endocrine surveillance during treatment.