Approximately 6,500 patients in the U.S. are diagnosed annually with EGFR and other HER-family Exon 20 insertion mutations in NSCLC1. Unfortunately, these patients exhibit poor responses to standard EGFR tyrosine kinase inhibitors (TKIs).
EGFR Exon 20 insertion mutations present a distinct challenge from the group of classical, sensitizing EGFR mutations in lung cancer that have been successfully addressed by various commercial EGFR inhibitors2. Classical EGFR mutations exhibit increased binding affinity to tyrosine kinase inhibitors and conventional EGFR inhibitors leverage this change, resulting in relatively less severe systemic toxicities.
However, EGFR Exon 20 insertion mutations lack this binding affinity for tyrosine kinase inhibitors and instead resemble wildtype EGFR. Patients with wildtype EGFR, or wildtype-like EGFR mutant tumors such as Exon 20 insertion mutations, present challenges in achieving meaningful drug concentrations at the site of the tumor while avoiding drug concentrations that are toxic in healthy tissues.
A novel solution to this problem would achieve tumor-selectivity with a potent tyrosine kinase inhibitor capable of inhibiting wildtype and mutant EGFR.
- American Cancer Society NSCLC incidence of 183,000 patients per year; Hirano et al., Oncotarget. 2015; 6(36): 38789–38803; Peters and Zimmerman, Transl Lung Cancer Res. 2014 Apr; 3(2): 84–88
- Yasuda et al., Sci Transl Med. 2013; 5(216): 216ra177