The safety and efficacy of osimertinib for the treatment of EGFR T790M mutation positive non-small-cell lung cancer

ABSTRACT

First- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the evidence-based first-line treatment for metastatic non-small-cell lung cancers (NSCLCs) that harbor sensitizing EGFR mutations (i.e. exon 19 deletions or L858R). However, acquired resistance to EGFR TKI monotherapy occurs invariably within a median time frame of one year. The most common form of biological resistance is through the selection of tumor clones harboring the EGFR T790M mutation, present in >50% of repeat biopsies. The presence of the EGFR T790M mutation negates the inhibitory activity of gefitinib, erlotinib, and afatinib. A novel class of third-generation EGFR TKIs has been identified by probing a series of covalent pyrimidine EGFR inhibitors that bind to amino-acid residue C797 of EGFR and preferentially inhibit mutant forms of EGFR versus the wild-type receptor. We review the rapid clinical development and approval of the third-generation EGFR TKI osimertinib for treatment of NSCLCs with EGFR-T790M.

KEYWORDS:

• mutation
• lung cancer
• adenocarcinoma
• EGFR
• kinase inhibitor
• TKI
• T790M
• osimertinib
• resistance

Financial and competing interests disclosure

This work was funded in part through an American Cancer Society grant RSG 11-186 (DBC), a Lung Cancer Foundation of America - International Association for the Study of Lung Cancer grant (DBC) and a National Cancer Institute grant P50CA090578 (DBC). DB Costa has received consulting fees from Pfizer Inc and Ariad pharmaceuticals, honoraria from Boehringer Ingelheim Inc, plus clinical research funding from AstraZeneca and Clovis Oncology. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.