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Prognostic Significance of Endocrine-Related Adverse Events in Patients with Melanoma, Non-Small Cell Lung Cancer and
Stylianos Kopanos1, Charalampos Filippatos2, Pantelis Rousakis3
1Academic Department of Endocrinology, Diabetes and Infectiology, Klinikum Bielefeld, Medical School and University Medical Centre East Westphalia-Lippe, Bielefeld University, 33615 Bielefeld, Germany .
Background/Objectives:
Immune checkpoint inhibitors (ICIs) have revolutionized the management of several malignancies, including melanoma, non-small cell lung cancer, and urothelial carcinoma. However, these therapies frequently cause endocrine immune-related adverse events (irAEs), such as thyroid dysfunction, hypophysitis, or autoimmune diabetes, and may carry important prognostic implications. This systematic review and meta-analysis aimed to determine the incidence, spectrum, and clinical significance of endocrine irAEs across major tumor types.
Methods:
Following PRISMA guidelines and PROSPERO registration (CRD42025646504), we systematically searched PubMed, Embase, Cochrane CENTRAL, Web of Science, and Scopus for studies reporting endocrine irAEs in ICI-treated patients. Random-effects meta-analyses estimated pooled hazard ratios (HRs) for overall (OS) and progression-free survival (PFS) and odds ratios (ORs) for adverse events. Subgroup and meta-regression analyses explored associations by cancer type, ICI class, and event severity.
Results:
Forty-three studies comprising 17,399 patients were included. Endocrine irAEs occurred in 11-30% of patients and were associated with improved OS (HR: 0.60, 95% CI: 0.54-0.67; p < 0.001) and PFS (HR: 0.61, 95% CI: 0.54-0.68; p < 0.001). Severe events were most frequent with pembrolizumab in melanoma and non-small cell lung cancer and with anti-programmed death-ligand 1 therapy in urothelial carcinoma. In exploratory meta-regression analyses accounting for cancer type, ICI subclass, and irAE severity, no statistically significant correlation was observed between the occurrence of endocrine irAEs (OR) and survival benefit (PFS HR: 0.20, 95% CI -0.10 to 0.51; p = 0.19; OS HR: 0.14, p > 0.05).
Conclusions:
The development of endocrine irAEs coincides with favorable long-term survival outcomes but may represent surrogate markers of immune activation rather than direct predictors of ICI efficacy. However, the lack of consistent ≥ 3-year follow-up across studies warrants cautious interpretation. Routine endocrine monitoring and interdisciplinary management are essential to optimize the safety and effectiveness of immunotherapy.
Insights
Immune checkpoint inhibitors (ICIs) can cause endocrine immune-related adverse events (irAEs), which are linked to better survival outcomes in cancer patients. However, these irAEs may be markers of immune response rather than direct predictors of treatment efficacy.
Area of Science:
- Oncology
- Immunology
- Endocrinology
Background:
- Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, but frequently induce endocrine immune-related adverse events (irAEs).
- These irAEs, including thyroid dysfunction and autoimmune diabetes, have potential prognostic implications.
- Understanding their incidence and clinical significance is crucial for optimizing immunotherapy.
Purpose of the Study:
- To systematically review and meta-analyze the incidence, spectrum, and clinical significance of endocrine irAEs in patients treated with ICIs.
- To determine the association between endocrine irAEs and survival outcomes (overall survival and progression-free survival).
Main Methods:
- Systematic literature search following PRISMA guidelines across major databases (PubMed, Embase, etc.).
- Random-effects meta-analyses to estimate pooled hazard ratios for survival and odds ratios for adverse events.
- Subgroup and meta-regression analyses to explore associations by cancer type, ICI class, and event severity.
Main Results:
- Forty-three studies including 17,399 patients were analyzed.
- Endocrine irAEs occurred in 11-30% of patients and were associated with improved overall survival (OS) and progression-free survival (PFS).
- Exploratory analyses did not find a statistically significant correlation between endocrine irAEs and survival benefit when accounting for other factors.
Conclusions:
- Endocrine irAEs coincide with favorable survival but may serve as surrogate markers of immune activation, not direct efficacy predictors.
- Consistent long-term follow-up data is limited, requiring cautious interpretation.
- Routine endocrine monitoring and interdisciplinary management are essential for safe and effective immunotherapy.
