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ARTICLE

The Real-World Endocrine Toxicity Profile of ICIs, VEGFR-TKIs, and Their Combination: Analysis of the FDA Adverse Event Reporting System (FAERS) Database

Nicola Marrano1,#, Mariangela Caporusso2,#, Cosimo Matino1,#, Irene Caruso3,#, Carlo Ganini4, Mimma Rizzo5, Ludovico Di Gioia2, Angelo Cignarelli1, Sebastio Perrini1,6, Luigi Laviola1, Camillo Porta4, Francesco Giorgino1,*, Annalisa Natalicchio1
1 Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Bari, Italy
2 Endocrinology Unit, Regional General Hospital “Francesco Miulli”, Acquaviva delle Fonti, Bari, Italy
3 Endocrinology Unit, University Hospital “Consorziale Policlinico” of Bari, Bari, Italy
4 Division of Medical Oncology, Interdisciplinary Department of Medicine, University of Bari Aldo Moro, Bari, Italy
5 Division of Medical Oncology, University Hospital “Consorziale Policlinico” of Bari, Bari, Italy
6 Section of Endocrinology, Department of Medicine and Surgery, LUM University, Casamassima, Bari, Italy
* Corresponding Author: Francesco Giorgino. Email: email
# These authors contributed equally to this work

Oncology Research https://doi.org/10.32604/or.2026.074672

Received 15 October 2025; Accepted 29 January 2026; Published online 19 February 2026

Abstract

Background: Immune checkpoint inhibitors (ICIs) are a cornerstone of systemic therapy for renal cell carcinoma (RCC), used both in the adjuvant and metastatic settings across various lines of treatment, often in combination with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs). These therapies are associated with endocrine immune-related adverse events (irAEs), which can be irreversible and life-threatening if not promptly managed. Using data from the Food and Drug Administration Adverse Reporting System (FAERS), this study aimed to evaluate the real-world occurrence of endocrine irAEs in all approved VEGFR-TKI + ICI combinations for RCC, and to compare these findings with the corresponding VEGFR-TKI or ICI monotherapies. The immune doublet ipilimumab + nivolumab was not considered in this analysis. Methods: FAERS database from 2019 Q1 to 2024 Q2 was queried using OpenVigil 2.1-MedDRA-v24 and AERSMine to identify endocrine irAEs reports. Reports were filtered by age, gender, and report severity. The frequency of reported endocrine irAEs associated with VEGFR-TKI + ICI combination therapies was compared to that reported for VEGFR-TKI or ICI monotherapy. Results: Compared with VEGFR-TKI monotherapies, VEGFR-TKI + ICI combinations showed a significant disproportionate reporting of endocrine irAEs, mostly associated with the combination regimens. In contrast, when compared with ICI monotherapy, VEGFR-TKI + ICI showed more heterogeneous disproportionality signals, with generally lower reporting of hypothalamus, pituitary, and hyperglycemic disorders, whereas hypoglycemia and thyroid irAEs were more frequently reported, except for autoimmune thyroid diseases. Conclusion: Combination therapy, compared with VEGFR-TKI monotherapy, was associated with a higher reporting frequency of specific endocrine irAEs, whereas comparisons with ICI monotherapy yielded mixed signals, highlighting regimen- and event-specific differences.

Keywords

Immune checkpoint inhibitor (ICI); vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI); endocrine immune-related adverse events (irAEs); food and drug administration adverse reporting system (FAERS); pharmacovigilance

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