26 Background: The cost of lung cancer treatment and accessibility to the first-line oral targeted therapies is a growing concern worldwide. However, the cost-effectiveness of guideline-directed treatments is not well studied. The aim of this study was to evaluate cost-effectiveness of advanced epidermal growth factor receptor (EGFR) mutated and anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Methods: We calculated the cost of each targeted therapies based on the progress free survival and overall survival as shown in the major studies that led to the therapy approval. The cost-effectiveness of a treatment was measured by its incremental cost-effectiveness ratio (ICER). Lower ICER values indicate better cost-effectiveness, as they represent a lower cost per unit of health benefit. We evaluated the total costs, incremental ICERs and quality-adjusted life years (QALYs) associated with different treatment options. Results: The yearly-cost analysis revealed that Osimertinib, an oral agent targeting EGFR mutations, is the most expensive option. With a total cost of $222,044.10 per year, Osimertinib surpasses the cost of other oral agents, including erlotinib ($113,171.90) and Afatinib ($147,204.50). The ICERs indicate that Osimertinib has a higher ICER compared to other oral agents. Specifically, the ICER for Osimertinib versus erlotinib is calculated at $62,779.22. For each additional QALY gained, the cost of Osimertinib exceeds that of erlotinib by $62,779.22. Despite its higher cost, Osimertinib may offer a greater improvement in QALYs, making it a justifiable choice. In the context of ALK-positive NSCLC, Alectinib compared to Brigatinib, Lorlatinib and Crizotinib, as well as Brigatinib compared to Lorlatinib, and Lorlatinib compared to Crizotinib, are the drugs with lower ICER values, indicating better cost-effectiveness. Alectinib emerges as the most cost-effective oral agent, followed by Ceritinib. While Brigatinib and Lorlatinib are more expensive, they may provide a greater improvement in QALYs. Crizotinib is found to be the least cost-effective agent. Conclusions: The cost-effectiveness analysis presented in this study highlights the economic considerations associated with oral agents. The findings indicate the higher costs of Osimertinib and certain ALK inhibitors, which need to be weighed against the potential improvements in QALYs. By considering both costs and effectiveness, healthcare decision-makers can optimize treatment strategies, allocate resources efficiently and improve patient outcomes.