Prognostic Significance of Endocrine-Related Adverse Events in Patients with Melanoma, Non-Small Cell Lung Cancer and Urothelial Cancer After Treatment with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis.

Abstract

<h4>Background/objectives</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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; <i>p</i> < 0.001) and PFS (HR: 0.61, 95% CI: 0.54-0.68; <i>p</i> < 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; <i>p</i> = 0.19; OS HR: 0.14, <i>p</i> > 0.05).<h4>Conclusions</h4>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.