Acquired Mechanisms of Resistance to Osimertinib—The Next Challenge

SIMPLE SUMMARY: Osimertinib has revolutionized the treatment of EGFR-mutated tumors. Its current applications include the first-line setting, second-line setting, as well as the adjuvant setting. Although it represents a milestone in the context of targeted therapy, inevitably all tumors develop an acquired resistance, some mechanisms involve EGFR, others do so through alternative pathways leading to a bypass in osimertinib inhibition. It is key to understand these acquired mechanisms of resistance, both in the clinical setting, as well as in preclinical models, in order to develop and contribute to the identification of possible therapeutic strategies to overcome this acquired resistance. ABSTRACT: EGFR-mutated tumors represent a significant percentage of non-small cell lung cancer. Despite the increasing use of osimertinib, a treatment that has demonstrated an outstanding clinical benefit with a tolerable toxicity profile, EGFR tumors eventually acquire mechanisms of resistance. In the last years, multiple mechanisms of resistance have been identified; however, after progressing on osimertinib, treatment options remain bleak. In this review, we cover the most frequent alterations and potential therapeutic strategies to overcome them.