Introduction: Lung cancer is the leading cause of cancer-related death worldwide. It is usually diagnosed at advanced stage for which platinum-based chemotherapy had been the standard approach, although with limited clinical benefits. Discovery of oncogenic EGFR mutations in lung cancer have shifted the treatment paradigm with molecularly targeted therapies.

Areas covered: EGFR tyrosine kinase inhibitors (TKIs) have become the first-line choice in patients with advanced NSCLC harboring EGFR activating mutations. However, resistance to targeted therapy develops inevitably during the course of treatment. Multiple mechanisms of acquired resistance have been discovered, most commonly the secondary mutation of T790M in exon 20. The second- and third-generation EGFR TKIs are holding promise to overcome T790M-associated acquired resistance and currently being tested in clinical trials. In this article, we focus on the emerging approaches to overcome the different mechanisms of resistance to targeted therapies in patients with EGFR-mutant advanced NSCLC.

Expert opinion: It is essential to uncover the complex mechanisms underlying the progression of lung cancer after upfront EGFR TKIs. Next generation, in particular, the third generations of EGFR TKIs have been developed against acquired T790M mutation with promising clinical activity and better toxicity profile. Combination of targeted therapies has also been explored. Further studies are needed to detect the real-time changes of the resistance mechanisms and to develop new therapeutic strategies for lung cancer patients with EGFR mutations.