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Non-small-cell lung cancer (NSCLC) is the most common form of primary lung cancer. The discovery of several oncogenic driver mutations in patients with NSCLC has allowed the development of personalized treatments based on these specific molecular alterations, in particular in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (<i>EGFR)</i> gene. Gefitinib, erlotinib, afatinib, and osimertinib are TK inhibitors (TKIs) that specifically target <i>EGFR</i> and are currently approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as first line treatment for sensitive <i>EGFR</i>-mutant patients. However, these four drugs are associated with severe adverse events (AEs) that can significantly impact patient health-related quality of life and patient monitoring. EGFR-TKIs are commonly used together with other types of medication that can substantially interact. Here, we review approaches used for the management of TKI-AEs in patients with advanced NSCLC to promote the benefits of treatments and minimize the risk of TKI treatment discontinuation. We also consider potential TKI&#8722;drug interactions and discuss the usefulness of plasma concentration monitoring TKIs based on chromatographic and mass spectrometry approaches to guide clinical decision-making. Adjusting the most appropriate therapeutic strategies and drug doses may improve the performance therapy and prognosis of patients with advanced <i>EGFR</i>-mutated NSCLC.