firmonertinib的发现与特征描述：一种对EGFR经典突变和exon 20插入突变均具有广泛活性的新型EGFR抑制剂

Background: Lung cancers harboring classical EGFR mutations are sensitive to approved EGFR tyrosine kinase inhibitors (TKIs) while those harboring EGFR exon 20 insertion mutations (ex20ins) show minimal sensitivity to approved EGFR TKIs and have limited treatment options. Firmonertinib is an investigational novel orally bioavailable and highly brain-penetrant irreversible EGFR TKI targeting classical and uncommon EGFR mutations including ex20ins. Firmonertinib received FDA Breakthrough Therapy Designation for first-line treatment of patients with advanced NSCLC with EGFR ex20ins mutations, and has now completed enrollment in a global phase 3 trial in these patients (NCT05607550). Here, we describe the structural and preclinical findings supporting the binding potency and anti-tumor activity of firmonertinib in EGFR ex20ins mutations. Methods & Results: Using high resolution crystal structures, we uncover a unique structural attribute that differentiates firmonertinib from other EGFR TKIs and that provides firmonertinib with superior binding to mutant EGFR proteins including those harboring ex20ins. Our biochemical and cellular assay findings are in line with the structural observations and demonstrate that firmonertinib is a potent and mutant selective EGFR inhibitor. In a large cell line panel evaluating EGFR ex20ins mutations within different regions of exon 20 (far and near loop, helical domain), all ex20ins mutations evaluated demonstrated a high sensitivity profile to firmonertinib compared to other EGFR TKIs. In addition, firmonertinib was equally highly potent against far and near loop insertion mutations which is a differentiating characteristic from some EGFR TKIs previously tested in the clinic (Elamin et al. 2022). In animal models, our findings demonstrate that firmonertinib is a highly potent inhibitor of cell proliferation in tumors harboring both near and far loop EGFR ex20ins mutations. Conclusions: Findings from this study support the structural mechanism of EGFR binding and inhibition by firmonertinib, eliciting strong anti-tumor activity in multiple in vitro and in vivo models harboring EGFR ex20ins mutations. These findings provide scientific support for the ongoing global Phase 3 study for first-line NSCLC patients with EGFR ex20ins mutations (NCT05607550).