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Osimertinib-induced interstitial lung disease insights from faers signal detection and network toxicology analysis
Shi Zhang1, Jian Liu2, Xiaojie Feng1
1The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Abstract:
Osimertinib is a key treatment for EGFR-mutated non-small cell lung cancer, but interstitial lung disease (ILD) remains a rare yet potentially life-threatening pulmonary adverse event. Early recognition of osimertinib-associated ILD and clarification of its underlying mechanisms are important for improving clinical management. In this study, real-world pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS; 2015Q4-2025Q2) were extracted, deduplicated, and evaluated using four disproportionality algorithms. Potential molecular links between osimertinib and ILD were further explored by integrating drug- and disease-related targets from SwissTargetPrediction, CTD, GeneCards, and DisGeNET, followed by intersection analysis, protein-protein interaction (PPI) network construction, and functional enrichment analysis. A total of 24,676 osimertinib-related adverse event reports were identified, and ILD emerged as one of the strongest pulmonary safety signals. Among 484 ILD reports, cases were more commonly observed in older patients, women, and Asian patients, and were associated with high rates of hospitalization and serious clinical outcomes. Twenty-one overlapping targets between osimertinib and ILD were identified, and PPI network analysis highlighted CTNNB1, KRAS, STAT3, and TP53 as central nodes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated significant involvement of cancer-related pathways, EGFR tyrosine kinase inhibitor resistance, and multiple signaling and regulatory pathways, including PI3K-Akt, MAPK, and Wnt/β-catenin-related signaling, suggesting potential roles in inflammation, epithelial injury, and fibrotic remodeling. Together, these findings integrate pharmacovigilance evidence with network-based mechanistic prediction and provide a basis for risk-stratified monitoring and further experimental validation of osimertinib-associated ILD.
Insights
Interstitial lung disease (ILD) is a rare side effect of osimertinib treatment for EGFR-mutated non-small cell lung cancer. This study identified ILD as a significant safety signal, highlighting key molecular pathways involved in its development.
Area of Science:
- Pharmacovigilance and Network Pharmacology
- Oncology and Pulmonary Medicine
Background:
- Osimertinib is a crucial therapy for EGFR-mutated non-small cell lung cancer (NSCLC).
- Interstitial lung disease (ILD) is a rare but severe adverse event associated with osimertinib, necessitating early detection and mechanistic understanding.
Purpose of the Study:
- To identify interstitial lung disease (ILD) as a safety signal for osimertinib using real-world pharmacovigilance data.
- To explore the potential molecular mechanisms underlying osimertinib-associated ILD through integrated network analysis.
Main Methods:
- Utilized FDA Adverse Event Reporting System (FAERS) data (2015Q4-2025Q2) and disproportionality algorithms.
- Integrated drug-target and disease-target databases (SwissTargetPrediction, CTD, GeneCards, DisGeNET) for molecular link analysis.
- Constructed protein-protein interaction (PPI) networks and performed functional enrichment analyses (GO, KEGG).
Main Results:
- ILD emerged as a significant pulmonary safety signal among 24,676 osimertinib-related adverse events.
- 484 ILD cases showed higher incidence in older, female, and Asian patients, with frequent hospitalizations and serious outcomes.
- Identified 21 overlapping targets, with CTNNB1, KRAS, STAT3, and TP53 as key nodes in the PPI network.
- Enrichment analyses revealed involvement of cancer, EGFR inhibitor resistance, and inflammatory/fibrotic signaling pathways (PI3K-Akt, MAPK, Wnt/β-catenin).
Conclusions:
- Pharmacovigilance data confirm ILD as a critical safety concern for osimertinib.
- Network-based analysis provides mechanistic insights into ILD pathogenesis, involving inflammation and fibrosis.
- Findings support risk-stratified monitoring and further experimental investigation of osimertinib-associated ILD.
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