Update on recent preclinical and clinical studies of T790M mutant-specific irreversible epidermal growth factor receptor tyrosine kinase inhibitors.

Bin-Chi Liao,Chia-Chi Lin,James Chih-Hsin Yang,Jih-Hsiang Lee

doi:10.1186/s12929-016-0305-9

Abstract

The first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors (1/2G EGFR-TKIs) gefitinib, erlotinib, and afatinib have all been approved as standard first-line treatments for advanced EGFR mutation-positive non-small cell lung cancer. The third-generation (3G) EGFR-TKIs have been developed to overcome the EGFR T790M mutation, which is the most common mechanism of acquired resistance to 1/2G EGFR-TKI treatment. This resistance mutation develops in half of the patients who respond to 1/2G EGFR-TKI therapy. The structures of the novel 3G EGFR-TKIs are different from those of 1/2G EGFR-TKIs. Particularly, 3G EGFR-TKIs have lower affinity to wild-type EGFR, and are therefore associated with lower rates of skin and gastrointestinal toxicities. However, many of the adverse events (AEs) that are observed in patients receiving 3G EGFR-TKIs have not been observed in patients receiving 1/2G EGFR-TKIs. Although preclinical studies have revealed many possible mechanisms for these AEs, the causes of some AEs remain unknown. Many mechanisms of resistance to 3G EGFR-TKI therapy have also been reported. Here, we have reviewed the recent clinical and preclinical developments related to novel 3G EGFR-TKIs, including osimertinib, rociletinib, olmutinib, EGF816, and ASP8273.

Highlights

BackgroundThe first-generation reversible epidermal growth factor receptor tyrosine kinase inhibitors (1G Epidermal growth factor receptor (EGFR)-TKIs) gefitinib and erlotinib are both quinazoline derivatives, as is the second-generation (2G) irreversible EGFR-TKI afatinib
Main text of the reviewOsimertinib Osimertinib (AZD9291) is a mono-anilino-pyrimidine compound that irreversibly targets tumors harboring EGFRL858R, EGFRdel19, and EGFRT790M, while having little effect on Wild-type Epidermal growth factor receptor (EGFR) (EGFRwt)
Three percent of the patients developed interstitial lung disease (ILD) and QT interval corrected for heart rate (QTc) prolongation while hyperglycemia developed in less than 1% of the patients [16]

Summary

Background

The first-generation reversible epidermal growth factor receptor tyrosine kinase inhibitors (1G EGFR-TKIs) gefitinib and erlotinib are both quinazoline derivatives, as is the second-generation (2G) irreversible EGFR-TKI afatinib These drugs are effective for treating advanced EGFR mutation-positive non-small cell lung cancer (NSCLC), especially in patients who harbor EGFR exon 21 L858R mutation (EGFRL858R) or exon 19 deletions (EGFRdel). These drugs are effective for treating advanced EGFR mutation-positive non-small cell lung cancer (NSCLC), especially in patients who harbor EGFR exon 21 L858R mutation (EGFRL858R) or exon 19 deletions (EGFRdel19) All of these drugs are currently standard first-line therapies for these patients [1,2,3,4,5,6]. A literature review of clinical studies published between January 2013 and June 2016 was conducted using PubMed and MEDLINE, with the entry keywords ‘non-small cell lung cancer,’ ‘epidermal growth factor receptor T790M mutation,’ ‘osimertinib,’ ‘rociletinib,’ ‘olmutinib,’ ‘EGF816,’ and ‘ASP8273.’ We performed a manual search of the abstracts presented at major oncology meetings

Main text of the review

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Findings

Discussion

Conclusions