Advancements in EGFR Inhibition: The Emergence of TQB3804 as a Fourth-Generation Inhibitor Targeting EGFR C797S Resistance

Osimertinib, a third-generation EGFR inhibitor, has been the standard treatment for NSCLC patients with the EGFRT790M mutation. However, the development of the EGFRC797S mutation has emerged as a significant resistance mechanism, hindering the drug's effectiveness. This mutation prevents the formation of a covalent bond with Osimertinib, leading to resistance. There is an urgent need for new EGFR inhibitors capable of targeting the EGFR triple mutants, d746-750/T790M/C797S and L858R/T790M/C797S.

Our research introduces TQB3804, a novel fourth-generation EGFR inhibitor with significant inhibitory effects on these triple mutants. The inhibitory activity of TQB3804 was assessed through kinase assays for various EGFR mutations and wild-type EGFR. Its anti-proliferative activity was evaluated in several cell lines, and its ability to inhibit EGFR phosphorylation was tested in one of the cell lines.

TQB3804 showed potent enzymatic inhibition across multiple EGFR mutations with low IC50 values and demonstrated expected anti-proliferative activity in the tested cell lines. Notably, it effectively inhibited EGFR phosphorylation in the Ba/F3 cell line. Furthermore, TQB3804 significantly reduced tumor growth in multiple EGFR triple mutant CDX models and one Osimertinib-resistant PDX model. Western blot analysis confirmed that TQB3804's tumor growth inhibition was due to the inhibition of the resistant triple mutant EGFR.

In conclusion, TQB3804 has been identified as a powerful orally active fourth-generation EGFR inhibitor. It has the potential to inhibit the activity of Osimertinib-resistant EGFR triple mutants and has exhibited strong antitumor activity in both in vitro and in vivo preclinical assays. These findings suggest that TQB3804 is a promising candidate for further clinical investigation.