Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer

Abstract

The tyrosine kinase inhibitors (TKI) against epidermal growth factor receptor (EGFR) are widely used in patients with non-small cell lung cancer (NSCLC). However, EGFR T790M mutation leads to resistance to most clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation have been in active clinical development. These agents include osimertinib, rociletinib, HM61713, ASP8273, EGF816, and PF-06747775. Osimertinib and rociletinib have shown clinical efficacy in phase I/II trials in patients who had acquired resistance to first- or second-generation TKIs. Osimertinib (AZD9291, TAGRISSO) was recently approved by FDA for metastatic EGFR T790M mutation-positive NSCLC. HM61713, ASP8237, EGF816, and PF-06747775 are still in early clinical development. This article reviews the emerging data regarding third-generation agents against EGFR T790M mutation in the treatment of patients with advanced NSCLC.

Fig. 1

Common mutations of the epidermal growth factor receptor (EGFR) that are targets for tyrosine kinase inhibitors. Exons 18 to 21 of EGFR gene are common sites for mutations. The most common mutations that are targets of EGFR TKIs are shown. As an example, three mutation-harboring lung cancer cell lines commonly used to characterize EGFR TKIs are also shown. Del19: exon 19 deletion