ABSTRACT
INTRODUCTION: Patients treated with third-generation EGFR TKIs will develop resistance to treatment at a certain point. Early detection of resistance occurrence could allow more options for treatment. AREAS COVERED: We discuss the development of third-generation EGFR TKIs, focusing on osimertinib and discuss the most common resistance mechanisms under evaluation. We also debate how this resistance can be detected; particularly we review the possible application of liquid biopsy in this scenario. Lastly we discuss available treatment options when resistance occurs, with an eye on ongoing trials and possible future developments. EXPERT OPINION: As resistance will ultimately develop, a strict instrumental follow-up as per international guidelines is required with the aim of detecting this resistance in an early phase. Detecting an oligoprogression could allow the integration of local ablative therapies while further delaying the need for a systemic therapy change. By exploiting the increasing potentiality of liquid biopsy, in the near future, physicians could be able to understand why a patient develops resistance and therefore can choose the best possible individualized treatment option.