Abstract 4488: TY-4028: a novel, targeted therapy for non small-cell lung cancer with EGFR exon 20 or HER2 exon 20 insertion mutations
Authors: Li Jun , Niu Chengshan , Guo Zhongwei , Wang Huan , Zheng Bailu , Dou Yuge , Liang Apeng , Ji Kaige , Dong Shengli , Li Meihua , Zhao Yanchao , Zhang Yazhen , Gong Aishen , Liu Hao , Hu Xinmiao , Su Hui , Jiang Mingyu , Chen Shaoqing , Chen Xiugui , Wu Yusheng 
Published: April 2023

Abstract
Epidermal growth factor receptor (EGFR) activating mutations represent major drivers to the development of non-small cell lung cancer (NSCLC). Among the oncogenic EGFR mutations, a significant cohort, counting for approximately 4-10% of the EGFR mutation spectrum, bear EGFR exon 20ins mutations. Meanwhile, approximately 2% of NSCLC patients bear hotspot mutations in HER2. Strikingly, over 90% of the HER2 mutations occurred in NSCLC are identified as exon 20ins mutations. Despite the successful launch of 1st, 2nd, and 3rd generation of EGFR inhibitory agents in the clinic that inactivate oncogenic EGFR signaling through targeting specific EGFR mutations, de novo or acquired, none of these standard-of-care therapies is specific to EGFR exon 20ins or HER2 exon 20ins. In addition, trastuzumab and EGFR-TKIs have limited effectiveness for NSCLC patients with HER2 exon 20ins mutation. TAK-788 (mobocertinib) and JNJ6372 (amivantamab-vmjw) are the FDA approvals for NSCLC driven by EGFR exon 20ins mutations. Only T-Dxd is used as a second-line treatment for NSCLC patients with HER2 mutation. Considering the large population of lung cancer and the fact that many patients are missed in diagnosis due to the heterogeneous characteristics of EGFR and Her2 exon 20ins, there are probably more than ten thousand lung cancer patients suffering the EGFR or Her2 exon 20ins mutations. There are urgent unmet medical needs to develop target therapeutics for EGFR and Her2 exon 20ins mutations. We discovered and developed TY-4028, which is a novel, potent, and orally available inhibitor targeting EGFR and Her2 exon 20ins mutations and is currently in the IND enabling stage. In EGFR-related tumor cells and genetically engineered Ba/F3 cell lines, TY-4028 showed similar or better antitumor effects than TAK-788, and better antitumor effects than DZD9008. The B/P ratio (brain tissue AUC0-last/plasma AUC0-last) of SD rats was 1.63 and 1.04 respectively after oral administration of TY-4028 in male and female SD rats, which suggested that TY-4028 had good potential to cross Blood Brain Barrier (BBB). Preclinical studies showed a good PK profile and manageable toxicity with TY-4028. TY-4028 has remarkable efficacy in mouse models of EGFR exon 20ins and HER2 exon 20ins. The data showed that all doses of TY-4028 had significant effects, and the tumors nearly demonstrated complete regression in the PDX LU0387 model and PC9 CDX model. At the same dose, the efficacy of TY-4028 was similar to that of TAK-788, while the tolerance of TY-4028 was better than that of TAK-788. At the same dose, the efficacy of TY-4028 was better than that of DZD9008. Taken together, the data demonstrated TY-4028 has great potential to meet the unmet medical needs for NSCLC patients with EGFR exon 20ins mutation or HER2 exon 20ins mutation. #Jun Li and Chengshan Niu contributed equally to this work. *They are the correspondent authors.
Citation Format: Jun Li, Chengshan Niu, Zhongwei Guo, Huan Wang, Bailu Zheng, Yuge Dou, Apeng Liang, Kaige Ji, Shengli Dong, Meihua Li, Yanchao Zhao, Yazhen Zhang, Aishen Gong, Hao Liu, Xinmiao Hu, Hui Su, Mingyu Jiang, Shaoqing Chen, Xiugui Chen, Yusheng Wu. TY-4028: a novel, targeted therapy for non small-cell lung cancer with EGFR exon 20 or HER2 exon 20 insertion mutations. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4488.