Background <p>The advent of antibody-drug conjugates (ADCs) has significantly reshaped therapeutic strategies for lung cancer. However, given their exceptionally high treatment costs, evaluating whether their clinical benefits justify these expenses is crucial, highlighting the need for robust economic assessments. This study was designed to clarify the relative cost-effectiveness of datopotamab deruxtecan (Dato-DXd) for individuals who had undergone treatment for advanced or metastatic non-small cell lung cancer (NSCLC) from the American payers’ perspective.</p> Methods <p>Utilizing data from the phase III TROPION-Lung01 randomized trial, a Markov model with a three-state structure and horizon of 20 years was implemented to simulate economic and clinical outcomes of Dato-DXd versus docetaxel. Outcomes were assessed using incremental cost-effectiveness ratios (ICERs), and incremental net health benefits (INHBs). All results were evaluated against a $150,000 per quality-adjusted life year (QALY) willingness-to-pay (WTP) threshold. To assess model robustness, probabilistic and one-way sensitivity analyses were performed.</p> Results <p>In the overall and nonsquamous populations, Dato-DXd incurred additional costs of $225,314 and $241,136, respectively, with corresponding QALY gains of 0.09 and 0.08. This yielded ICERs of $2,483,946/QALY and $3,025,602/QALY, far exceeding the WTP threshold. In contrast, among patients with squamous histology, Dato-DXd resulted in both higher costs ($118,390) and reduced effectiveness (−0.17 QALYs), rendering it a dominant strategy. Sensitivity analysis identified body weight and drug acquisition cost as key variables influencing cost-effectiveness outcomes.</p> Conclusions <p>Dato-DXd showed poor cost-effectiveness in individuals who had undergone treatment for advanced or metastatic NSCLC, particularly those with squamous cell carcinoma in the USA.</p>