Abstract 837: A highly potent and selective small molecule TY-4028 for the targeted therapy of non-small cell lung cancer with EGFR exon 20 or HER2 exon20 insertion mutations

Abstract Introduction: Following EGFR exon 19del and EGFR L858R mutations, EGFR exon20 insertion mutations are the third most common type of EGFR mutations, representing up to 12% of all EGFR mutations. Approximately 2% of NSCLC patients bear hotspot mutations in HER2, and over 90% of these HER2 mutations are exon 20 insertion mutations. The FDA-approved 1st to 3rd targeted EGFR inhibitors failed to effectively treat NSCLC harboring constantly active EGFR exon20ins mutations in the clinic. To date, no small molecule targeted therapy has been approved by the FDA for the treatment of EGFR exon20ins in NSCLC. Furthermore, Antibody such as Amivantamab has difficulty penetrating the BBB, brain metastases presents a significant clinical challenge in lung cancer with EGFR exon20ins mutations. There is an urgent unmet medical need to develop targeted therapeutics against EGFR and Her2 exon20ins mutations. Results: TY-4028 is a novel, potent, and orally available inhibitor targeting EGFR and Her2 exon20ins mutations. It is a highly potent covalent inhibitor with rapid absorption and clearance, which contributes to the decreased toxicity of covalent drugs. Preclinical studies have shown a good PK profile and manageable toxicity with TY-4028. TY-4028 showed remarkable efficacy in in vitro and in vivo models of EGFR exon20ins and HER2 exon20 Ins. The data showed that the efficacy of TY-4028 was similar to that of Mobocertinib(TAK-788)and better than that of Sunvozertinib (DZD9008), whereas the tolerance of TY-4028 was better than that of Mobocertinib in CDX mouse models. The B/P ratio (brain tissue AUClast/plasma AUClast) of SD rats was 1.63 and 1.04, respectively, suggesting that TY-4028 has good potential to cross the BBB. Taken together, TY-4028 was fully developed by TYK Medicines, Inc., and the compound has great potential to meet the unmet medical needs of NSCLC patients with EGFR exon20ins mutation or HER2 exon20ins mutation. IND clearances of TY-4028 from the US FDA and CN NMPA has received. Citation Format: Chengshan Niu*, Shengli Dong*, Shaoqing Chen, Zhongwei Guo, Huan Wang, Apeng Liang, Kaige Ji, Meihua Li, Bailu Zheng, Yanchao Zhao, Ming Wu, Mingyu Jiang, Xiugui Chen, Jun Li*, Yusheng Wu. A highly potent and selective small molecule TY-4028 for the targeted therapy of non-small cell lung cancer with EGFR exon 20 or HER2 exon20 insertion mutations [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 837.