Lung cancer is the leading cause of cancer-related deaths, with a 5-year survival rate of only 5%, of which Non-Small Cell Lung Cancer (NSCLC) accounts for 85% (Sung et al., 2021). Despite significant therapeutic advances over the past decade, NSCLC remains incurable for many patients (He et al., 2021). The epidermal growth factor receptor (EGFR) is a common driver gene in NSCLC, and approximately 20% of patients harbor activating EGFR mutations, making them targets for EGFR Tyrosine Kinase Inhibitors (EGFR-TKIs) (John et al., 2022; Roskoski, 2019). Current guidelines recommend EGFR-TKIs as first-line therapy for these advanced patients.

First-generation EGFR-TKIs (gefitinib, erlotinib) have been widely used, with gefitinib approved by the FDA as first-line treatment for advanced NSCLC patients with activating EGFR mutations (Kazandjian et al., 2016). Multiple studies have shown that gefitinib significantly prolongs progression-free survival in patients with advanced NSCLC (Zhang et al., 2012; Rosell et al., 2012). However, approximately 30% of patients exhibit primary or acquired resistance (Ohashi et al., 2013). While second-generation agents (afatinib, dacomitinib) have extended PFS and overall survival (34.1 months vs. 27.0 months) (Mok et al., 2021), they are associated with higher rates of cutaneous and gastrointestinal toxicity (He et al., 2021). Third-generation drugs, represented by osimertinib, have demonstrated improved efficacy while reducing the risk of severe adverse events (Soria et al., 2018) and show significant efficacy against brain metastases (Popat et al., 2023).

Although EGFR-TKIs have proven efficacy, their associated adverse reactions require careful attention, particularly interstitial lung disease (ILD). This fatal condition accounts for 58% of EGFR-TKI treatment-related deaths (Ohmori et al., 2021). Studies have reported cases of ILD in patients treated with gefitinib, erlotinib, and afatinib (Kashiwabara et al., 2017). Identifying and managing the risk of ILD is a significant clinical challenge. Traditional clinical trials, limited by factors such as sample selection, often fail to reflect the true risk in the patient population. Therefore, large samples, real-world studies are necessary to evaluate the risk characteristics of ILD.

Currently, there has been some exploration into the risk factors for EGFR-TKI-associated ILD. A study including 89 NSCLC patients aged 75 and older showed that the incidence of ILD was significantly higher in elderly patients treated with osimertinib (Ishibashi et al., 2023). However, this association and the specific risk threshold lack validation from large-sample, real-world data. Regarding dyslipidemia, existing research suggests that lipid metabolism disorders may contribute to the process of pulmonary fibrosis by promoting chronic inflammation and oxidative stress in the lungs. Furthermore, a synergistic effect of dyslipidemia has been observed in ILD induced by other drugs (Wu et al., 2023). However, research on the interaction between EGFR-TKIs and dyslipidemia is limited, and whether a dose-effect relationship exists between the two remains unclear. Additionally, some studies have indicated that the risk of developing ILD increases in NSCLC patients who use EGFR-TKIs in combination with proton pump inhibitors (Wang et al., 2025). Nevertheless, research on the impact of concomitant use of EGFR-TKIs with other drugs on ILD is currently lacking.

This study conducted a retrospective pharmacovigilance analysis of EGFR-TKIs using the FDA Adverse Event Reporting System (FAERS) database, aiming to elucidate the risk and characteristics of ILD associated with EGFR-TKI use, thereby providing clinicians with more reliable risk management strategies that could improve treatment outcomes and reduce adverse events in patients.

ILD, characterized by alveolitis, interstitial inflammation, and pulmonary fibrosis, is an umbrella term for a range of diseases with similar symptoms (Wijsenbeek et al., 2022). Drug-induced ILD accounts for approximately 5% of all ILD cases, while ILD induced by targeted drug therapy is rarer and may be life-threatening when it occurs (Skeoch et al., 2018). In recent years, studies have reported cases of ILD associated with EGFR-TKIs (Huang et al., 2020; Shi et al., 2025; Oshima et al., 2018); however, research on EGFR-TKIs for NSCLC-induced ILD remains limited. Therefore, it is important to explore the characteristics and risks of NSCLC-associated ILD with EGFR-TKI therapy using large-scale real-world data.

EGFR-TKI has become the standard treatment for NSCLC. Our study found that most patients who developed ILD were in the elderly population, specifically those over 65 years of age. This is consistent with previous findings (Shi et al., 2025) that elderly patients suffer from comorbidities and are on polypharmacy, which increases EGFR-TKI-mediated pulmonary toxicity during long-term treatment (Decoster and Schallier, 2019). Notably, the results of the multivariate regression analysis suggest that weight gain may reduce the risk of developing ILD. However, this finding contradicts another study, which demonstrated that being overweight and obesity are associated with poorer pulmonary function (Schaeffer et al., 2022). It is important to note that our study was limited by a high rate of missing data, ranging from 22.7% to 55.9%, which to some extent compromises the reliability of the conclusion. Therefore, further research is warranted to validate the association between weight gain and the risk of ILD.

In this study, the association between EGFR-TKIs and ILD, along with its subtypes, was systematically characterized through real-world pharmacovigilance data analysis. Notably, all EGFR-TKIs showed a significant ILD signal (ROR = 24.61), a result that differs from the 0.6%–2.2% incidence reported in previous clinical trials (Takeda et al., 2015), suggesting that the occurrence of ILD may be grossly underestimated in real-world settings. In further investigation into the factors affecting EGFR-TKI-associated ILD revealed a significant correlation between ILD occurrence and concomitant dyslipidemia in patients treated with EGFR-TKI. This phenomenon may be due to the activation of lung macrophages by free fatty acids via the TLR4/NF-κB pathway, which in turn promotes their polarization towards the M1 phenotype (Suganami et al., 2007).

Furthermore, existing evidence indicates that patients receiving lansoprazole therapy have an increased risk of developing ILD (Wang et al., 2025). This trend has been corroborated by a study from Kambara et al., whose results demonstrated that patients treated with proton pump inhibitors, including lansoprazole, exhibited significantly higher rates and risks of acute exacerbation of ILD (Sato et al., 2022). Our study further reveals that the concomitant use of an EGFR-TKI with lansoprazole further elevates the risk of ILD. This phenomenon may be attributed to a drug-drug interaction involving metabolic pathways. Both EGFR-TKIs and lansoprazole are metabolized by the CYP3A4 enzyme. However, EGFR-TKIs can inhibit the activity of CYP3A4, which in turn potentiates the acid-suppressive effect of lansoprazole, thereby potentially increasing the risk of ILD (Wang et al., 2025). These findings underscore the critical need for clinicians to focus on these interactions in clinical practice, offering a valuable reference for optimizing therapeutic strategies and mitigating the risk of ILD.

Dacomitinib (ROR = 21.39) warrants attention for its high-risk profile, the extremely small sample size (n = 5) precludes definitive conclusions. Further large-scale studies are needed to validate this observation. In addition, our study revealed that osimertinib was associated with the highest number of reported ILD cases. Notably, 45.5% of these patients were aged 65 or older, suggesting that the elderly population may be at an increased risk of ILD due to the widespread use of this drug. This finding is consistent with the results of a previous study (Ishibashi et al., 2023). This indicates that when treating NSCLC with EGFR-TKIs, particular attention should be paid to the occurrence of this adverse effect, especially in elderly patients.

All five EGFR-TKIs induced ILD; however, side effect profiles differed between EGFR-TKIs. Subgroup analysis revealed a significant, drug-specific toxicity profile. The association of osimertinib with rare ILD subtypes, such as sarcoidosis, fine bronchiolitis, alveolar lung disease, and diffuse alveolar hemorrhage, may be related to its enhanced lung tissue penetration (Sato et al., 2022; Forte and Sangani, 2019). Similarly, gefitinib-specific signals of radiological lung injury suggest that the choice of treatment regimen should be made with extra caution in patients with a history of radiotherapy. Of note is the strong association between dacomitinib and restrictive lung disease. Some studies have shown a poor safety profile for dacomitinib (Li et al., 2024), but there is no evidence of a significant difference between dacomitinib and other EGFR-TKIs in terms of restrictive lung disease. Therefore, enhanced dynamic monitoring of lung function during treatment should still be emphasized.

The median time to onset of ILD varies among EGFR-TKIs. Erlotinib has a median latency of up to 36.5 days, which may be related to its lower lipid solubility. This results in slower deposition of the drug in the alveolar epithelium, prolonging the time it takes for the drug to reach the threshold of toxicity in lung tissue. In contrast, the early onset of toxicity with gefitinib is associated with its unique anilino quinazoline structure, which enhances the binding affinity to the EGFR receptor in alveolar type II epithelial cells, thereby accelerating the burst release of pro-inflammatory factors IL-6 and TNF-α (Scheffler et al., 2011; Ishigu et al., 2013). Notably, despite being a third-generation EGFR-TKI, the median duration of ILD episodes with osimertinib was significantly shorter than that of erlotinib. This may be related to persistent ERK signaling inhibition triggered by its irreversible binding properties (He et al., 2021).

Beyond EGFR-TKIs, ILD is a recognized complication of immune checkpoint inhibitors (ICIs), albeit with distinct mechanisms and clinical features. While EGFR-TKI-associated ILD primarily arises from direct epithelial injury and pro-fibrotic signaling in genetically susceptible hosts (Scheffler et al., 2011; Ishigu et al., 2013), ICI-related pneumonitis stems from T-cell-mediated inflammation and dysregulated immune responses (Spagnolo et al., 2022). Clinically, ICI-pneumonitis often presents earlier (median onset: 2.1–4.6 months) than EGFR-TKI-ILD and exhibits radiographic patterns such as cryptogenic organizing pneumonia more frequently (Spagnolo et al., 2022). Management also diverges, High-dose glucocorticoids are the first-line treatment for ICI-related pneumonia, while EGFR-TKI-related ILD requires immediate discontinuation of the drug, with glucocorticoids used in combination if necessary (Ohmori et al., 2021; Skeoch et al., 2018). These distinctions underscore the importance of drug-class-specific vigilance in monitoring and intervention.

This study also has several inherent limitations. First, it was not possible to assess the true incidence of ILDs associated with drug use because FAERS safety reports do not include a denominator for drug users. Second, reports in the FAERS database are submitted voluntarily, meaning that not all adverse drug events are reported, which results in missing reports, especially for rarer or milder adverse events. Finally, the contribution of EGFR-TKIs to ILD-related deaths cannot be determined with certainty, but it warrants confirmation in a large prospective study.

The risk of ILD is notably higher in EGFR-TKI-treated NSCLC patients and is strongly associated with patient age, comorbidities, and the concomitant use of lansoprazole. Clinicians should carefully consider these factors when selecting a treatment regimen to minimize the incidence of ILD. Follow-up studies are necessary to further investigate effective strategies for preventing and managing EGFR-TKI-associated ILD.