Epidemiology, Predictors, and Impact of Endocrine Immune-Related Adverse Events on Outcomes in Patients with Malignant Tumors

Immune checkpoint inhibitors (ICIs) are widely used in the treatment of malignant tumors, either as monotherapy or in combination with chemotherapy or tyrosine kinase inhibitors (TKIs). Endocrine immune-related adverse events (e-irAEs) are a promising marker of ICI efficacy and patient survival due to their high frequency, early onset, and clear diagnostic criteria.

Objective: To conduct an epidemiological analysis of the development of e-irAEs, identify their predictors, and evaluate their impact on cancer outcomes.

Materials and methods: This retrospective cohort study included adult patients with solid malignant tumors who received their first administration of ICIs (as monotherapy or in combination with chemotherapy or TKIs) at the SBIH Moscow Clinical Scientific and Practical Center named after A. S. Loginov of DHM from June 1, 2016, to December 31, 2022. Overall survival (OS) was followed up until February 1, 2024. Results were considered statistically significant at p < 0.05.

Results: The study included 214 participants with a mean age of 62.6 years (range: 32–91). e-irAEs were reported in 45.3 % of participants, with 6.5 % experiencing two types of e-irAEs. The most common events were primary hypothyroidism (25.7 %), thyrotoxicosis (7.9 %), thyroiditis (7.5 %), secondary adrenal insufficiency (7.5 %), and ICI-induced diabetes mellitus (1.4 %); one patient developed secondary hypothyroidism. 64.2 % of e-irAEs occurred within the first 26 weeks of ICI therapy.

The development of e-irAEs correlated with better 1-year OS (11.52 vs. 10.85 months, log-rank p = 0.027), especially among patients with thyroid-related complications (11.6 vs. 10.82 months, log-rank p = 0.009).

In the subgroup of participants not receiving TKIs, there was a 44 % higher chance of achieving immune stable disease (iSD, p = 0.04) and a 45 % higher chance of clinical benefit (CBR, p = 0.03). e-irAEs occurred more frequently with concomitant use of incretin-based drugs, calcium channel blockers and antihistamines, and less frequently in patients with a derived neutrophil-to-lymphocyte ratio (dNLR) ≥ 3 at baseline and before the second ICI infusion, and a dNLR > 2.2 before the second ICI infusion. e-irAEs grade ≥ 2 were 2.09 times more often recorded in patients ≥ 60 years old. The combination of ICIs and TKIs increased the risk of primary hypothyroidism 2.3-fold (p = 0.035).

Conclusion: The study results indicate a high incidence of e-irAEs. Potential risk factors for their development have been identified. Further validation in prospective studies is required.

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