Abstract 5613: TQB3002: A potent fourth-generation small molecule EGFR-TKI

Abstract Purpose: EGFR-TKIs have become important targeted therapies for patients with EGFR mutation-positive advanced NSCLC. However, EGFR-TKI resistance, particularly the C797S mutation resulted from the use of third-generation EGFR-TKI therapy, presents clear clinical and scientific concern. Therefore, novel EGFR-TKIs that can effectively inhibit triple mutations are urgently needed. Our clinical candidate, TQB3002, can effectively inhibit EGFR single/double/triple mutations. Method: The HTRF method was used to test the kinase inhibition activities of TQB3002 against EGFRWT, EGFRd746-750, EGFRL858R, EGFRd746-750/T790M, EGFRL858R/T790M, EGFRd746-750/T790M/C797S and EGFRL858R/T790M/C797S. The anti-proliferative activities of TQB3002 were measured in cell lines including PC-9 (EGFRd746-750), NCI-H3255 (EGFRL858R), NCI-H1975(EGFRL858R/T790M), 32D (EGFRd746-750/T790M/C797S, EGFRL858R/T790M/C797S), ect. The anti-tumor activities of TQB3002 were studied in animal models, including five CDX models of PC9(EGFRd746-750), 32D(EGFRd746-750/T790M), NCI-H1975(EGFR L858R /T790M) and triple mutations PC9(EGFRd746-750/T790M/C797S) and 32D (EGFRL858R/T790M/C797S), as well as in two Osimertinib-resistant PDX models. Results: TQB3002 potently inhibited the kinase activities of EGFR single and double mutations, with IC50 of 0.01 - 0.12 nM, which was 4 - 12 times better than that of Osimertinib. It had extremely potent inhibitory activities against the C797S mutant kinases which were resistant to Osimertinib, with IC50 of 0.01 - 0.093 nM. In EGFR triple mutant cell lines, TQB3002 had strong inhibitory activities with IC50 of 0.05 - 0.42 nM. In EGFR single/double mutant cell lines, it also showed superior or equivalent inhibitory activities compared with Osimertinib. In animal models of EGFR single/double/triple mutations, TQB3002 dose-dependently inhibited tumor growth with good animal tolerance. In the EGFR triple-mutation PDX model, TQB3002 could achieve tumor regression at a lower dose (15 mg/kg) compared with other fourth-generation EGFR-TKIs under development. Conclusion: With a clearly differentiated chemical structure, TQB3002 has shown strong activities both in-vitro and in-vivo against EGFR single/double/triple mutants, and is much more effective against the C797S mutation resistant to third-generation EGFR-TKIs. In addition, TQB3002 has good druggability and supports clinical oral QD dosing. It has good selectivity in EGFR single/double/triple mutant cells (36.5-fold selectivity over WT), and low risk of DDI and in-vitro cardiotoxicity are also observed in preclinical studies. In the GLP toxicological studies, the toxicity of TQB3002 is comparable to marketed third-generation EGFR-TKIs, with no significant toxicity concerns. IND of TQB3002 has been approved in China and the US, and phase I clinical trial has started in China (NCT06662760). Citation Format: Xun Chen, Lihua He, Xin Tian, Fei Liu, Hongjiang Xu, Ling Yang, Wei Zhao, Xiquan Zhang. TQB3002: A potent fourth-generation small molecule EGFR-TKI [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5613.