Abstract B002: Discovery of selective and potent EGFR kinase inhibitors for exon20 insertion mutations

Abstract The third generation EGFR tyrosine kinase inhibitors (TKIs), like Osimertinib, target classical activating EGFR mutations containing T790M resistance mutation. However, the exon 20 insertion (Ex20Ins), the third most common EGFR mutations in entire NSCLC, still lacks its therapeutic option. Recently, Robichaux JP et al., showed that Poziotinib, which had been developed as a second-generation EGFR TKI, had efficacy for the EGFR and Her2 Ex20Ins compared to EGFR T790M. Here, we developed inhibitors, structurally distinct from both Poziotinib and Osimertinib, targeting for the EGFR Ex20Ins mutations as well as EGFR T790M. According to kinase profiling, the inhibitors are highly selective to EGFR, ERBB2 and ERBB4 family. The candidate inhibitors demonstrated great activity (GI50 < 20 nM) in cell growth inhibition of Ba/F3 cells containing EGFR Ex20Ins (D770_N771insSVD, V769_D770insASV, D770_N771insNPG, A763_Y764insFQEA, and H773_V774insNPH), Her2 Ex20Ins (A775_G776insYVMA), or cancer cells containing activating EGFR mutations and T790M resistance mutation (L858R/T790M and Del19/T790M). Finally, in several Ex20Ins patient-derived xenograft models, the candidate inhibitors induced tumor regression as strong as Poziotinib and increased survival rates along with minimal weight loss. These novel small molecule compounds inhibiting EGFR exon 20 insertion mutations will provide future therapeutic options for patients with this molecular subtype of NSCLC. Citation Format: Sunghwan Kim, Younho Lee, Hwan Kim, Juhee Kang, Jiyoon Seok, Kyung-Ah Seo, Jaeyoung Ahn, Hee-Bum Kang, Sun-Hwa Lee, Jung Beom Son, Hwan Geun Choi, Nam Doo Kim. Discovery of selective and potent EGFR kinase inhibitors for exon20 insertion mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B002. doi:10.1158/1535-7163.TARG-19-B002