Utilizing ctDNA to discover mechanisms of resistance to targeted therapies in patients with metastatic NSCLC: towards more informative trials

Advances in targeted therapies for patients with non-small-cell lung cancer have substantially improved the outcomes of those with actionable alterations in certain oncogenic driver genes. However, acquired resistance to these targeted therapies remains a major challenge. Understanding the mechanisms underlying acquired resistance will be crucial for the development of strategies that might either overcome this effect or delay the onset. Circulating tumour DNA, owing to the need for only minimally invasive sampling and a potential role as both a prognostic and predictive biomarker, is increasingly being used in both research and clinical practice. Several studies have explored the landscape of acquired resistance to targeted therapies using this approach. However, the methodologies of the published studies vary widely, and several major challenges remain in addressing the practical difficulties associated with these methods. These challenges currently limit the depth of research insight provided by the available data. In this Perspective, we review clinical reports describing the use of circulating tumour DNA to detect mechanisms of acquired resistance to targeted therapies, predominantly in patients with advanced-stage non-small-cell lung cancer, and highlight key unresolved questions with the aim of moving towards more-informative research studies. Acquired resistance is a common occurrence among patients with oncogene-driven non-small-cell lung cancer receiving targeted therapies. Monitoring of circulating tumour DNA in liquid biopsy samples provides an appealing, minimally invasive method of monitoring for acquired resistance in this setting. However, research into detecting mechanisms of acquired resistance in liquid biopsy samples has thus far been limited by various challenges. In this Perspective, the authors describe the available data on detecting mechanisms of acquired resistance to targeted therapies in patients with non-small-cell lung cancer, as well as the various challenges to progress, such as a lack of a consensus definition of acquired resistance, and other inconsistencies in the approach to detecting and investigating these alterations.