11P Preclinical evaluation of DS-2087b, a novel and selective inhibitor of EGFR/HER2 exon 20 insertions

Abstract

In-frame insertions in exon 20 of the epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) gene are oncogenic drivers in non-small cell lung cancer (NSCLC), breast cancer, and others. However, no pharmacologic treatments are available for EGFR/HER2 exon 20 insertions (ex20ins), and effective treatment should avoid the inhibition of wild-type (WT) EGFR, which causes dose-limiting toxicities, such as rash and diarrhea. Here we describe DS-2087b, a novel oral, potent, and selective inhibitor of EGFR/HER2 ex20ins. We evaluated the inhibitory effects of DS-2087b and poziotinib, an investigational tyrosine kinase inhibitor against Ba/F3 cells harboring WT EGFR and against EGFR/HER2 ex20ins mutations, including EGFR V769_D770 insertion ASV (EGFR ins.ASV); EGFR D770_N771 insertion SVD (EGFR ins.SVD); and HER2 A775_G776 insertion YVMA (HER2 ins.YVMA). Moreover, we measured the antitumor activity of DS-2087b in an NSCLC patient-derived xenograft (PDX) model with EGFR ins.ASV. DS-2087b inhibited the proliferation of Ba/F3 cells expressing EGFR ins.ASV, EGFR ins.SVD, and HER2 ins.YVMA with 50% maximal inhibition of cell proliferation (GI50) values of 23.5, 21.3, and 29.0 nM, respectively, but the GI50 value for Ba/F3 cells expressing EGFR WT was 368.9 nM. Poziotinib showed similar GI50 values between EGFR/HER2 ex20ins and WT EGFR. In Ba/F3 allograft models with EGFR ins.ASV, EGFR ins.SVD, and HER2 ins.YVMA and the PDX model with EGFR ins.ASV, DS-2087b showed remarkable antitumor effects in a dose-dependent manner without body weight loss. In in vitro and in vivo preclinical assays, DS-2087b is effective against EGFR/HER2 ex20ins and also showed selectivity over WT EGFR. DS-2087b may show clinical utility in patients who harbor EGFR/HER2 ex20ins mutations and reduced toxicities caused by WT EGFR inhibition.