Abstract B179: TAS0728, a HER2-selective covalent inhibitor, demonstrates potent antitumor effect as a single agent and in combination with anti-HER2 antibodies in HER2-overexpressed tumor models
Authors: Irie Hiroki , Oguchi Kei , Ito Kimihiro , Fujioka Yayoi , Kawai Yuichi , Shimamura Tadashi , Araki Hikari , Fujioka Akio , Nakagawa Fumio , Kawabata Rumi , Nagase Hideki , Sagara Takeshi , Uchida Junji , Matsuo Kenichi , Utsugi Teruhiro , Iwasawa Yoshikazu 
Published: August 2018

Abstract
Background: HER2 is a well-established therapeutic target in breast and gastric cancer. Although HER2-targeting therapies are available for HER2-overexpressed breast and gastric cancer, the combination with chemotherapy is still necessary. Recent preclinical and clinical studies suggest that combination therapies of HER2-targeting agents without chemotherapy may be effective. Therefore, the dual HER2-targeting approaches as well as a single-agent HER2-targeting therapy are desired. TAS0728 (former name TPC-107) is an orally available, HER2-selective covalent inhibitor that has a high kinase specificity excluding EGFR. In previous studies, TAS0728 showed potent inhibitory activities for both activated mutations of HER2 and overexpressed HER2, while sparing EGFR activity in cells. Here, we report that TAS0728 demonstrates potent antitumor activity for HER2-amplified tumor models both as a single agent and in combination with HER2-targeting antibodies. Materials and Methods: TAS0728 was administered for 14 days to nude mice and the plasma concentration profile and PK parameters of TAS0728 were determined. For pharmacodynamic (PD) evaluation, TAS0728 was administered to mice bearing N87 xenografts as a single dose and PD markers in tumor were examined by Western blot analysis. BT-474 or N87 xenograft models were used for in vivo antitumor evaluation of TAS0728 as a single agent. The 4-1ST xenograft model was used to investigate the combination of TAS0728 with trastuzumab or trastuzumab emtansine (T-DM1). In this model, TAS0728 (q.d., p.o.) was administered in combination with trastuzumab (q1w, i.v.) or T-DM1 (Day 1, i.v.). Tumor volumes and body weights were measured twice a week. Results: TAS0728 demonstrated favorable oral PK properties in mice, and exhibited a robust inhibition of PD markers including phosphorylation of HER2 and HER3 in tumor tissues of N87 xenografts. Consistent with the results of the PD study, TAS0728 showed significant antitumor effect in the N87 and BT474 xenograft models at PD effective doses (30 and 60 mg/kg/day) with minimum body weight changes. In the 4-1ST xenograft model, TAS0728 at 15 mg/kg/day strongly enhanced the antitumor effect of trastuzumab (20 mg/kg) or T-DM1 (7.5 mg/kg). Conclusion: TAS0728 was effective both as a single agent and in combination with HER2-targeting antibodies including trastuzumab and T-DM1. These studies provide a rationale for both a single-agent therapy of TAS0728 and a dual HER2 blockade with TAS0728 and HER2-targeting antibodies for the therapy of HER2-overexpressed tumors.
Citation Format: Hiroki Irie, Kei Oguchi, Kimihiro Ito, Yayoi Fujioka, Yuichi Kawai, Tadashi Shimamura, Hikari Araki, Akio Fujioka, Fumio Nakagawa, Rumi Kawabata, Hideki Nagase, Takeshi Sagara, Junji Uchida, Kenichi Matsuo, Teruhiro Utsugi, Yoshikazu Iwasawa. TAS0728, a HER2-selective covalent inhibitor, demonstrates potent antitumor effect as a single agent and in combination with anti-HER2 antibodies in HER2-overexpressed tumor models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B179.