Renal Safety Profile of EGFR Targeted Therapies: A Study from VigiBase® the WHO Global Database of Individual Case Safety Reports.

Alexandre Crosnier,Laurence Lagarce,Marina Babin,Morgane Cellier,Chadi Abbara,Delphine Bourneau-Martin,Marie Briet

doi:10.3390/cancers13235907

Alexandre Crosnier, Laurence Lagarce + Show 5 more

Open Access

https://doi.org/10.3390/cancers13235907

Copy DOI

Abstract

Simple SummaryDrugs targeting the epithelial growth factor receptor (EGFR) are used in pulmonary and digestive cancers and represent major medical progress. In addition to its localization in cancer cells, EGFR can also be found in the kidney. This observation raises the question of the renal toxicity of these drugs. This issue has been addressed in the present study conducted on safety data from the largest international pharmacovigilance database, VigiBase®. This study showed that the renal toxicity of these drugs is mainly represented by renal failure in the context of digestive toxicity. A new adverse effect called haemolytic and uremic syndrome or thrombotic microangiopathy has been found for erlotinib, which is the first anti-EGFR drug to obtain market authorisation. This signal has to be confirmed. No other renal toxicity has been found related to anti-EGFR drugs, in particular, neither glomerular nor tubular toxicity.Kidney EGFR expression together with reported cases of glomerular diseases in the context of anti-EGFR drug administration raise concerns about the renal safety profile of these drugs. This issue is addressed in a case/non-case study carried out on VigiBase®, the WHO global database of individual case safety reports (ICRS). Disproportionality analysis of renal adverse effects related to the selected anti-EGFR drugs, erlotinib, gefitinib, afatinib, osimertinib, cetuximab and panitumumab, was assessed using the reporting odds ratio (ROR). Nine hundred and eighty-nine ICRSs were included. A signal of disproportionate reporting (SDR) was found for afatinib (ROR = 2.70; 95% CI [2.22–3.29]) and erlotinib (ROR = 1.73; 95% CI [1.46–2.04]) with acute kidney injury, and for afatinib (ROR = 2.41; 95% CI [1.78–3.27]), cetuximab (ROR = 1.42; 95% CI [1.14–1.78]) and erlotinib (ROR = 2.23; 95% CI [1.80–2.77]) with renal failure. The preferred term “diarrhoea” was frequently reported in the included cases. An SDR was found for erlotinib with haemolytic and uremic syndrome (ROR = 4.01; 95% CI [1.80–8.94]) and thrombotic microangiopathy (ROR = 4.94; 95% CI [2.80–8.72]). No SDR was seen for glomerular or tubule-interstitial diseases. This study showed that the anti-EGFR drug renal toxicity is mainly related to renal failure in the context of digestive toxicity.

Highlights

Anti-epidermal growth factor receptor (EGFR) drugs were one of the first targeted therapies developed in the field of oncology [1], and include monoclonal antibodies and tyrosine kinase inhibitors (TKIs)
Phosphorylated tyrosine residues lead to the activation of several cell-signalling pathways, such as RAS/MAPK [8], PI3K/AKT/mTOR [9,10] and JAK/STAT [11] involved in cell survival, proliferation, metastasis and angiogenesis
This observation, together with the absence of a significant disproportionality signal for renal diseases, such as glomerulopathy or tubuleinterstitial diseases suggest that the most common mechanism of renal failure or acute kidney injury related to anti-EGFR therapies is functional, secondary to dehydration which can be due to a digestive toxicity of these drugs

Summary

Introduction

Anti-epidermal growth factor receptor (EGFR) drugs were one of the first targeted therapies developed in the field of oncology [1], and include monoclonal antibodies and tyrosine kinase inhibitors (TKIs). The monoclonal antibodies, cetuximab and panitumumab, are approved by European Medicines Agency (EMA) and Food and Drug Administration (FDA) for the treatment of wild-type metastatic colorectal cancer, advanced non-small cell lung cancer (NSCLC) and head and neck cancer [2,3]. Erlotinib and gefitinib were the first generation of anti-EGFR drugs to be developed. EGFR is a transmembrane cell receptor with tyrosine kinase activity. The binding of a ligand to the extracellular domain of EGFR induces its activation by homodimerisation or heterodimerisation with one of the other receptors of the ErbB family [7]. The development of anti-EGFR drugs considerably improved the prognosis of the patients. The main adverse effects reported are digestive, hepatic and cutaneous toxicity [12,13,14,15,16,17,18,19]

Objectives

Methods

Results

Discussion

Conclusion