2357P TRX-221, a 4th generation, mutant-selective, and CNS-active EGFR inhibitor with robust antitumor activity in osimertinib-resistant tumor models harboring C797S mutation

Patients with EGFR-mutant non-small cell lung cancer (NSCLC) can derive significant clinical benefit from EGFR tyrosine kinase inhibitor (TKI) therapy, including 3rd generation EGFR TKIs such as osimertinib. However, most patients will experience disease progression with osimertinib, mainly due to acquired mechanisms of resistance. Mutations in the C797 residue in exon 20 are the most frequent EGFR-dependent mechanism of resistance to osimertinib treatment. TRX-221 is an investigational, broad-spectrum, CNS-active, mutant-selective 4th-generation EGFR-TKI (AACR 2023 #4006). Here we report further preclinical data supporting the clinical development of TRX-221 for patients with EGFR-mutant NSCLC. Anti-proliferative activity and inhibitory potency of EGFR phosphorylation were determined in Ba/F3 cell lines using CellTiter-Glo® and EGFR AlphaLISA. In vivo antitumor efficacy of TRX-221 was evaluated in subcutaneous patient-derived cell line xenograft model and an intracranial tumor xenograft model. TRX-221 showed potent inhibitory activity of cell proliferation as well as EGFR phosphorylation in cellular assays driven by EGFR-mutants while sparing activity in EGFR wild-type. In osimertinib-resistant xenograft tumor models harboring EGFR C797S mutant cells, TRX-221 induced significant tumor regression without body weight loss. However, only moderate tumor growth inhibition was observed in an EGFR wild-type CDX model, demonstrating that in vivo efficacy was selective toward mutant EGFR. Furthermore, TRX-221 resulted in substantial intracranial antitumor activity with prolonged survival in an intracranial tumor model. Good correlation between plasma exposure levels and inhibitory effect on EGFR phosphorylation was observed with TRX-221 in a CDX tumor model PK/PD study. TRX-221 is a potent, broad spectrum, and selective 4th generation EGFR-TKI. TRX-221 demonstrates strong antitumor efficacy in osimertinib-resistant tumor models, and thus has potential to treat patients who have developed resistance to 3rd generation EGFR TKI treatment. Initiation of first-in human clinical trial is expected in Q4 2023.