Background and Objectives <p>In clinical trials, osimertinib combined with chemotherapy has demonstrated improved efficacy in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer. However, the projected long-term outcomes and the associated cost effectiveness compared to osimertinib monotherapy and first-generation EGFR-tyrosine kinase inhibitors remain uncertain.</p> Methods <p>A lifetime partitioned survival model was developed from the US healthcare sector perspective using clinical trial data from pivotal trials FLAURA and FLAURA2. Model inputs included drug costs, administration costs, and health utilities sourced from the published literature. Dynamic drug pricing and a 3% discount rate were incorporated. Outcomes included life-years, quality-adjusted life-years (QALYs), total costs, and incremental cost-effectiveness ratios. One-way and probabilistic sensitivity analyses were performed.</p> Results <p>Combination therapy yielded 2.96 QALYs at a cost of $692,796. The resultant incremental cost-effectiveness ratio was $265,601/QALY versus osimertinib monotherapy and $467,747/QALY versus first-generation EGFR-tyrosine kinase inhibitors. Findings were consistent across sensitivity analyses.</p> Conclusions <p>While clinically effective, based on commonly accepted cost-effectiveness thresholds in the USA, our study suggests that osimertinib plus chemotherapy was not cost effective compared to osimertinib alone or first-generation EGFR-tyrosine kinase inhibitors.</p>