Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide. While target therapies have changed the outcomes of patients harboring actionable mutations, resistance inevitably emerges. Circulating tumor DNA (ctDNA) offers a minimally invasive tool for capturing tumor evolution in real time. This approach enables the rapid detection of resistance mechanisms, complements or substitutes for tissue re-biopsy, and reduces the burden of invasive procedures for patients. In this review, we summarize the current evidence on the use of liquid biopsy to uncover resistance mechanisms in patients progressing on targeted therapies, with a focus on its role in dynamic tumor profiling and longitudinal disease monitoring.

Circulating tumour DNA (ctDNA) offers a minimally invasive approach for early detection of cancer, monitoring molecular residual disease, assessing molecular response and identifying treatment resistance in advanced stages. Additionally, ctDNA enhances clinical decision-making by enabling real-time tumour assessment. This review highlights the growing role of liquid biopsy as a predictive and prognostic tool in non-small cell lung cancer management.