Receptor tyrosine kinases (RTKs) are transmembrane enzymes that specifically phosphorylate tyrosines, leading to downstream signaling cascades. As an RTK, epidermal growth factor receptor (EGFR) mediates cell cycling and initiates oncogenic pathways involved in cell proliferation, apoptosis inhibition, angiogenesis, tumor invasion, and metastasis [1], with which mutated or up-regulated EGFRs are observed in tumors including non-small-cell lung cancer (NSCLC), breast cancer, glioblastoma, and colorectal cancer [2]. Emerging as targeted therapies, EGFR inhibitors (EGFRi) have gained success as first-line treatments for cancers such as EGFR mutation-positive NSCLC and can be classified into four generations including first-generation agents (erlotinib, gefitinib, and icotinib), second-generation agents (afatinib and dacomitinib), third-generation agents (osimertinib and olmutinib), and fourth generation agents (tarloxitinib and lazertinib) that are still under development. In contrast to conventional chemotherapy, tyrosine kinase inhibitors (TKI)-based targeted therapies including EGFRi have been associated with better overall survival and complete remission [3,4].

Despite their promising efficacy, since the EGFR protein is widely expressed on cells of epithelial origin, dermatological and gastrointestinal adverse events of EGFRi including rash and diarrhea have been reported [5]. In addition, lethal adverse events following the use of EGFRi included cardiotoxicity resulting in heart failure, left ventricular systolic dysfunction, and QT interval prolongation [6]. Pulmonary toxicities, including interstitial lung disease (ILD), have been reported in 1.1%–2.2% of EGFRi-treated patients and proposed as the most frequent cause of EGFRi-related death [7]. A study based on the United States Food and Drug Administration Adverse Event Reporting System (FAERS) found that commonly reported adverse drug reactions to EGFRi included cutaneous and ocular adverse events such as pruritis, dermatitis, and dry eye [5].

As the corneal epithelium develops from the ectoderm, corneal toxicity of EGFRi may share similar pathogenesis with that of cutaneous adverse events of EGFRi [8]. A retrospective chart review of 69 patients revealed that the most common ocular adverse events for patients on EGFRi were dysfunctional tear syndrome (DTS), blepharitis, and trichomegaly or trichiasis [9]. Another retrospective chart review reported that 1.38% out of 6871 patients on EGFRi or fibroblast growth factor (FGFR) inhibitors had been referred to ophthalmology clinics due to treatment-related ocular complications [10]. Because EGFRs are abundantly expressed in the conjunctival and corneal epithelium [11], the anti-mitogenic effect of EGFRi delays the proliferation and differentiation of epithelial cells [[12], [13], [14]], and slows re-epithelialization of the cornea [8]. This delay is followed by sequelae including corneal thinning or erosion and keratitis [[15], [16], [17]].

Although introduced in a few case reports or in clinical trials [[15], [16], [17]], there has been a lack of real-world evidence providing the incidence of keratitis following treatment with EGFRi. As such, this cohort study was designed to determine the risk of new-onset keratitis in lung cancer patients treated with EGFRi, to compare the incidence of keratitis following each EGFRi agent, and to specify subtypes of EGFRi-associated keratitis.