New-onset keratitis associated with epidermal growth factor receptor-based targeted therapies in han Chinese patients with lung cancer: A multi-center cohort study

Purpose To determine the risk and incidence of keratitis following treatment with epidermal growth factor receptor inhibitors (EGFRi) and subtypes of EGFRi-associated keratitis. Methods This multi-center cohort study included EGFRi-treated patients and non-users with lung cancer between 2010 and 2023. EGFRi included first-generation agent gefitinib and erlotinib, second-generation agent afatinib, and third-generation agent osimertinib. The primary outcome was new-onset keratitis. Cox proportional hazard models with multivariable adjustment were applied to determine the effect of EGFRi on keratitis over time. Subgroup analyses were conducted, stratified by agents of EGFRi. Sub-outcome analyses were performed to reveal the subtypes of EGFRi-associated keratitis. Results A total of 1549 EGFRi-treated patients and 6146 non-users were included. 38 (2.5%) EGFRi-treated patients developed keratitis. The incidence of keratitis in EGFRi-treated patients was significantly higher than that in controls (incidence rate, IR, per 1000 person-years = 0.0594 vs 0.015, p < 0.0001). EGFRi-treated patients presented with an increased risk for keratitis (adjusted hazard ratio, aHR = 3.14, 95% CI = 1.85–5.35, p < 0.001). Erlotinib (aHR = 2.64, 95% CI = 1.35–5.15, p = 0.004), afatinib (aHR = 4.42, 95% CI = 2.17–9.02, p < 0.001), and osimertinib (aHR = 4.67, 95% CI = 1.60–13.64, p = 0.005), but not gefitinib (aHR = 2.30, 95% CI = 0.96–5.55, p = 0.063), significantly contributed to the risk of keratitis. Subtypes of EGFRi-associated keratitis included corneal ulcer (IR = 0.00516 vs 0.00130, p < 0.0001) and keratoconjunctivitis (IR = 0.0374 vs 0.00944, p < 0.0001). None of the EGFRi-treated patients developed perforated corneal ulcer, interstitial and deep keratitis, or corneal neovascularization. Conclusion Treatment with EGFRi was associated with an increased risk of keratitis. Ocular toxicity of EGFRi was the greatest for third-generation agents, followed by second-generation agents, then first-generation agents.