Background <p>The IMforte trial had supported lurbinectedin as a recommended first-line maintenance therapy for patients with extensive-stage small-cell lung cancer (ES-SCLC), while its cost-effectiveness remains uncertain for patients and clinical decision-makers. This study aims to evaluate the cost-effectiveness of adding lurbinectedin to atezolizumab as maintenance therapy for ES-SCLC and to assess the impact of drug wastage and mitigation strategies from the perspective of the US healthcare system.</p> Methods <p>A partitioned survival model was developed to compare the cost-effectiveness of lurbinectedin plus atezolizumab versus atezolizumab alone. Key outcomes included total costs, effectiveness measured in quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER). Drug wastage was incorporated in the base-case analysis, and scenario analyses evaluated mitigation strategies through vial sharing and dose rounding. Model uncertainty was assessed using one-way sensitivity analysis and probabilistic sensitivity analysis.</p> Results <p>Over a 10-year time horizon, the lurbinectedin plus atezolizumab group accrued 0.3 more QALYs than the atezolizumab group. Under conditions of drug wastage, the addition of lurbinectedin resulted in an incremental cost of $230,000. When drug wastage was either excluded or mitigated through strategies such as vial sharing and dose rounding, the incremental cost was reduced to $180,000. The corresponding ICERs were $770,000 and $610,000/QALY, respectively. To achieve a greater than 50% probability of cost-effectiveness, an 85% price reduction in both high-cost drugs would be required. Sensitivity analyses indicated that the results were robust to variations in model parameters.</p> Conclusions <p>At current price, lurbinectedin plus atezolizumab is not cost-effective as ES-SCLC maintenance therapy. Mitigating drug wastage and implementing substantial price reductions are essential to improve its economic value.</p>