Abstract 11P
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Yuki Abe.
Funding
Daiichi Sankyo Company, Limited.
Disclosure
Y. Nagamoto: Full/Part-time employment: Daiichi Sankyo Company, Limited. M. Miyamoto: Full/Part-time employment: Daiichi Sankyo Company, Limited. N. Togashi: Full/Part-time employment: Daiichi Sankyo Company, Limited. T. Taira: Full/Part-time employment: Daiichi Sankyo Company, Limited. T. Jimbo: Full/Part-time employment: Daiichi Sankyo Company, Limited. T. Isoyama: Full/Part-time employment: Daiichi Sankyo Company, Limited. M. Takahashi: Full/Part-time employment: Daiichi Sankyo Company, Limited. K. Takeuchi: Full/Part-time employment: Daiichi Sankyo Company, Limited. K-I. Yoshida: Full/Part-time employment: Daiichi Sankyo Company, Limited. S. Higuchi: Full/Part-time employment: Daiichi Sankyo Company, Limited. T. Seki: Full/Part-time employment: Daiichi Sankyo Company, Limited. Y. Abe: Full/Part-time employment: Daiichi Sankyo Company, Limited.