Epidermal Growth Factor Receptor Inhibitors May Elevate New-Onset Keratitis Risk

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New research suggests patients with lung cancer treated with epidermal growth factor receptor (EGFR) inhibitor therapy may experience an increased risk of new-onset keratitis.¹

The analysis of the TriNetX database identified an increased risk of various keratitis subtypes, including corneal ulcer and superficial keratitis, as well as keratoconjunctivitis, suggesting a greater risk of dry eye disease.

“These results support the need for prompt diagnosis and management of EFRi-associated ocular issues to prevent serious complications or treatment disruptions,” wrote the investigative team, led by Kevin Sheng-Kai Ma, DDS, department of epidemiology at Harvard T.H. Chan School of Public Health.

Since approval by the US Food and Drug Administration (FDA), EGFR inhibitors have served as a treatment for EGFR variation-positive non-small cell lung cancer.² The therapy class has three generations of commonly prescribed EGFRis: first-generation gefitinib and erlotinib, second-generation afatinib, and third generation osimertinib. Adverse events, including cutaneous and ocular side effects, have been reported with EGFRi use, but there is a shortage of knowledge related to the association between EGFRi treatment and keratitis.

For this analysis, Ma and colleagues looked to fill in the gap in the risk of new-onset keratitis among patients with lung cancer with a comparison of incident keratitis and subtypes following treatment with EGFR inhibitors or none.¹ The US population–based cohort was extracted from the TriNetX database, using patient diagnostic records, procedures, prescriptions, laboratory data, and pharmacy genomic information between May 2003 and October 2023.

Patients ≥18 years exposed to first- to third-generation EGFR inhibitors were included for analysis. Index dates were based on the date of the first prescription of an EGFR inhibitor for the exposed group and the data of the first diagnosis of lung cancer for the non-exposed group. Study outcomes consisted of a diagnosis of new-onset keratitis, corneal ulcer, superficial keratitis, keratoconjunctivitis, interstitial and deep keratitis, and corneal neovascularization.

The investigative team identified 1,388,108 patients with lung cancer, including 22,225 who were treated with EGFR inhibitors (mean age, 69.7 years; 62.8% female). Patients in the treatment and non-treatment groups exhibited a similar baseline distribution of comorbidities, medication, and healthcare utilization.

During the follow-up period, of 21,890 EGFRi users, 246 (1.12%) developed incident keratitis, while 0.74% of nonusers developed incident keratitis. Upon analysis, the study team found individuals treated with EGFR inhibitors had a higher risk of keratitis compared with nonexposed patients (hazard ratio [HR], 1.520; 95% CI, 1.339 - 1.725).

Specifically, those taking EGFR inhibitors exhibited an increased risk of keratitis subtypes, including keratoconjunctivitis (HR, 1.367; 95% CI, 1.158 - 1.615), superficial keratitis (HR, 1.635; 95% CI, 1.306 - 2.047), and corneal ulcer (HR, 2.132; 95% CI, 1.515 - 3.002). Investigators identified the higher risk of keratitis during the initial follow-up period from 2003 to 2013 (HR, 1.390; 95% CI, 1.016 - 1.901), as well as the following 10-year period from 2014 to 2023 (HR, 1.293; 95% CI, 1.045 - 1.600).

The analysis revealed patients with lung cancer taking afatinib had a higher risk of keratitis (HR, 2.229; 2.229; 95% CI, 1.480 - 3.356), superficial keratitis (HR, 2.590; 95% CI, 1.294 - 5.185), and keratoconjunctivitis (HR, 2.432; 95% CI, 1.489 - 3.973). In their conclusion, Ma and colleagues suggested the higher risk of keratitis with EGFR inhibitor treatment could be a result of several potential mechanisms, including trichomegaly and improper repair of damaged corneal epithelial cells.

"Treatment with EGFRis has been linked to trichomegaly, a recognized ocular adverse effect that elevates the risk of corneal cell damage due to abnormal overgrowth and misaligned eyelashes,” investigators wrote. “Additionally, EGFR inhibitors inhibit the proliferation, stratification, and migration of limbal and corneal stem cells, impeding the proper repair of damaged corneal epithelial cells.”

References

1. _{Huang P, Lin C, Dana R, Ma KS. Epidermal Growth Factor Receptor Inhibitors for Lung Cancer and the Risk of Keratitis. JAMA Ophthalmol. Published online January 11, 2024. doi:10.1001/jamaophthalmol.2023.6089}
2. _{Zhang H. Three generations of epidermal growth factor receptor tyrosine kinase inhibitors developed to revolutionize the therapy of lung cancer. Drug Des Dev Ther. 2016;10:3867-3872. doi:10.2147/ DDDT.S119162}