Sex differences in adverse events associated with epidermal growth factor receptor inhibitor therapy for lung cancer.

Abstract

e20744 Background: Epidermal growth factor receptor (EGFR) inhibitors (EGFRi) have revolutionized the treatment of lung cancer. While utilized as first-line therapy for EGFR-positive lung cancer, these therapeutics show significantly better survival outcomes in clinical trials for female patients when compared to males. Given the sex differences in survival outcomes and pharmacokinetic properties, this study aimed to assess how biological sex may impact the safety profile of EGFRi. Methods: This U.S. population-based cohort study included patients with lung cancer who initiated treatment with EGFRi between 2016 and 2025. Propensity score matching was employed to minimize baseline differences in demographics, clinical characteristics, and medication use between females and males. Cox proportional hazards regression was used to calculate the comparative risks of adverse events and all-cause mortality after initiation of EGFRi were compared between females and males. The outcomes were also evaluated among a group of patients who were diagnosed with lung cancer within the same study period but were never exposed to EGFRi. Interaction analyses were conducted to assess whether EGFRi amplified or mitigated the risk of adverse outcomes between females and males with lung cancer. Results: We included 7,578 propensity score-matched pairs of female and male patients with lung cancer who initiated EGFRi therapy. During the follow-up, female patients receiving EGFRi had significantly higher risks of stomatitis (HR 1.307, 95% CI 1.119-1.525), diarrhea (HR 1.305, 95% CI 1.203-1.415), headache (HR 1.399, 95% CI 1.253-1.562), and nausea (HR 1.393, 95% CI 1.264-1.536), as well as significantly lower risks of thrombocytopenia (HR 0.749, 95% CI 0.679-0.826), fever (HR 0.909, 95% CI 0.843-0.979), and all-cause mortality (HR 0.803, 95% CI 0.769-0.839) compared to male patients receiving EGFRi. Interaction analyses indicated a significant interaction between the introduction of EGFRi and sex on the risk of stomatitis (interaction p = 0.003), anorexia (interaction p = 0.003) and fever (interaction p = 0.035), with females suffering from a significantly greater increase in the risk of these outcomes than males. Conclusions: Significant sex differences in the safety profile of EGFRi for lung cancer were observed. These findings illustrated the importance of considering biological sex in optimizing outcomes of EGFRi therapy.