Journal
EXPERT REVIEW OF ANTICANCER THERAPY
Volume 16, Issue 4, Pages 383-390Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1586/14737140.2016.1162103
Keywords
resistance; lung cancer; TKI; EGFR; adenocarcinoma; osimertinib; mutation; kinase inhibitor; T790M
Categories
Funding
- American Cancer Society [RSG 11-186]
- Lung Cancer Foundation of America - International Association for the Study of Lung Cancer grant
- National Cancer Institute [P50CA090578]
- Pfizer Inc
- Ariad pharmaceuticals
- AstraZeneca
- Clovis Oncology
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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.
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