Skin Adverse Events Linked to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: A Disproportionality Analysis Using FAERS and Drug–Gene Interaction Network Analyses

Background: While tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have improved outcomes for non-small cell lung cancer (NSCLC) patients, these inhibitors also cause skin adverse events (AEs). Moreover, real-world, data driven studies on EGFR-TKI-related AEs remain limited. In particular, the mechanisms underlying EGFR-TKI-induced skin AEs remain unclear. Methods: EGFR-TKI AE reports from the FDA Adverse Event Reporting System (FAERS) (Q1 2004 to Q3 2024) involving skin and subcutaneous tissue were analyzed using the reporting odds ratio (ROR) and multi-item gamma Poisson shrinker (MGPS) methods. The onset time was assessed using the Weibull Shape Parameter (WSP). Drug-gene network analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were conducted to explore the underlying mechanisms. Results: A total of 13,786 skin and subcutaneous tissue AE reports were identified as associated with EGFR-TKI use. Significant signals were detected using both ROR and MGPS. Disproportionality signals for severe skin AEs were observed for erlotinib, afatinib, and osimertinib. All EGFR-TKIs showed early failure patterns. Gene analysis revealed key nodes in the network associated with skin AEs, including PIK3CA, PIK3R1, and PIK3CB. KEGG-enriched pathways included the MAPK signaling pathway, the proteoglycans in cancer pathway, and the phosphoinositide 3-kinase (PI3K)–protein kinase B (Akt) signaling pathway. Conclusion: This study underscores significant associations between EGFR-TKIs and skin AEs, including Stevens–Johnson syndrome. This study also identifies potential mechanisms and provides valuable mechanistic insights, although further studies are needed to confirm the findings.