Adrenal Insufficiency with Anticancer Tyrosine Kinase Inhibitors Targeting Vascular Endothelial Growth Factor Receptor: Analysis of the FDA Adverse Event Reporting System

Abstract

Background: We described clinical features of adrenal insufficiency (AI) reported with tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor receptor (VEGFR) in the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Reports of AI recorded in FAERS (January 2004–March 2022) were identified through the high-level term “adrenal cortical hypofunctions”. Demographic and clinical features were inspected, and disproportionality signals were detected through the Reporting Odds Ratio (ROR) and Information Component (IC) with relevant 95% confidence/credibility interval (CI), using different comparators and adjusting the ROR for co-reported corticosteroids and immune checkpoint inhibitors (ICIs). Results: Out of 147,153 reports with VEGFR-TKIs, 314 cases of AI were retained, mostly of which were serious (97.1%; hospitalization recorded in 44.9%). In a combination regimen with ICIs (43% of cases), VEGFR-TKIs were discontinued in 52.2% of the cases (26% as monotherapy). The median time to onset was 72 days (IQR = 14–201; calculated for 189 cases). A robust disproportionality signal emerged, also in comparison with other anticancer drugs (ROR = 2.71, 95%CI = 2.42–3.04; IC = 0.25, 95%CI = 0.07–0.39). Cabozantinib, sunitinib and axitinib generated robust disproportionality even after ROR adjustment. Conclusions: We call pharmacologists, internists, oncologists and endocrinologists to raise awareness of serious AI with VEGFR-TKIs, and to develop dedicated guidelines, especially for combination regimens with immunotherapy.

Tumor Lysis Syndrome Associated with Monoclonal Antibodies in Patients with Multiple Myeloma: A Pharmacovigilance Study Based on the FAERS Database

“…Moreover, our consolidated analysis (comparing the signals of TLS between mAbs and other anticancer drugs for MM) indicated that all mAbs presented an increased disproportionate signal for TLS. We adopted the adjusted Bradford Hill Criteria from previous publications 33 and then assessed the link between TLS and mAbs point‐by‐point. Although it is impossible to build up a causal relationship between a specific drug and an AE only by using disproportionality analysis from the FAERS database without a proper review of the individual case reports, our results do show that mAbs may increase the potential of TLS in patients with MM.…”

“…A causal relationship assessment was carried out on the entire body of evidence by using adapted Bradford Hill Criteria used in epidemiology that have been applied to pharmacovigilance data, 33 including biological plausibility, strength, consistency, specificity, coherence, and analogy. The rechallenge/de‐challenge item were not analyzed in this study due to missing data.…”

Pneumocystis jirovecii pneumonia associated with immune checkpoint inhibitors: A systematic literature review of published case reports and disproportionality analysis based on the FAERS database

“…This study adopted novelty of the drug event association, seriousness, and disproportionate reporting as criteria for the signal prioritization. Moreover, a causal relationship appraisal was carried out on the entire body of evidence by using adapted Bradford Hill criteria used in epidemiology that have been applied to pharmacovigilance data ( van Hunsel et al, 2018 ; Raschi et al, 2022 ), including biological plausibility, strength, consistency, specificity, coherence, and analogy. The rechallenge/de-challenge item were not analyzed in this study due to missing data.…”

Inflammatory and Infectious Disorders in Endocrine Pathology

“…Immune checkpoint inhibitors may be associated with endocrine abnormalities in 25–50% of individuals on these medications [ 8 ]. Tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor have also been associated with adrenal insufficiency [ 235 ].…”