Health-Related Quality of Life and Cost-Effectiveness of First-Line Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor Monotherapy in Advanced EGFR-Mutated Non-small Cell Lung Cancer: A Systematic Review.

First-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have transformed the management of advanced EGFR-mutated non-small cell lung cancer (NSCLC). Although randomized trials have demonstrated improvements in clinical outcomes, treatment decisions increasingly require consideration of health-related quality of life (HRQoL) and economic value. This systematic review synthesized evidence on HRQoL and cost-effectiveness of first-line EGFR-TKI therapies in advanced EGFR-mutated NSCLC. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement and prospectively registered in PROSPERO (CRD42024553180). PubMed/MEDLINE, Embase, Scopus, and the Cochrane Library were searched from database inception to 31 March 2026. Eligible publications included randomized controlled trial reports assessing HRQoL using validated patient-reported outcome instruments and full trial-informed economic evaluations of first-line EGFR-TKI strategies. Risk of bias in HRQoL studies was assessed using the Cochrane Risk of Bias 2 tool, whereas the methodological quality of economic evaluations was assessed using the Drummond checklist. Owing to methodological heterogeneity, findings were synthesized narratively. A total of nine publications linked to six pivotal randomized controlled trials met the inclusion criteria, comprising four HRQoL reports and five trial-informed economic evaluations. Across the included studies, global health status and functional outcomes were generally maintained or improved from baseline, and no consistent clinically meaningful between-group differences were demonstrated; however, the limited evidence base does not establish equivalence between individual EGFR-TKIs. Economic findings varied across healthcare settings. Afatinib and aumolertinib were considered cost-effective within the settings examined, whereas osimertinib, dacomitinib, and lazertinib exceeded the willingness-to-pay thresholds used in the respective analyses. Cost-effectiveness was influenced by drug acquisition costs, model assumptions, analytical perspectives, and country-specific thresholds. Available randomized-trial evidence suggests that global HRQoL does not clearly differentiate the currently evaluated first-line EGFR-TKIs, as most treatments maintained overall health status and functioning despite differences in efficacy and toxicity. However, these findings should be interpreted cautiously given the limited number and heterogeneity of available HRQoL studies. In contrast, cost-effectiveness varied markedly across healthcare systems and appeared to be largely driven by drug acquisition costs and country-specific willingness-to-pay thresholds. The principal value distinction among first-line EGFR-TKIs may therefore lie less in global HRQoL and more in whether additional clinical benefit is considered affordable within the local healthcare setting.