Abstract Background: TAS0728 is a novel oral small-molecule inhibitor targeting HER2’s tyrosine kinase domain via covalent binding, showing significant antitumor activity in preclinical models. HER2 aberration including mutation and amplification drives progression of various solid tumors. Despite advances in HER2-targeted therapies, unmet needs remain, particularly for advanced-stage disease and post-standard therapy settings. In the first-in human phase I study of TAS0728 at escalating doses from 50 to 200 mg BID for 21-day cycles, dose-limiting toxicity of Grade 3 diarrhea was observed at the doses of 150 mg and 200 mg BID. And partial responses were observed in 2 of 14 evaluable patients. However, the maximum tolerated dose was not determined due to the occurrence of unacceptable toxicity at 150 mg BID. This study aims to assess the safety, tolerability, and pharmacokinetics, and to determine the recommended phase II dose (RP2D) of TAS0728 at escalating doses of 50, 75, and 100 mg BID for 21-day cycles. Methods: This multicenter phase I study includes dose escalation and expansion parts. The primary endpoint is to determine the RP2D in the dose escalation part and to evaluate safety at the RP2D in the expansion part. Pharmacokinetics and efficacy are also assessed. In the dose escalation part, the dose level is escalated according to a typical 3 + 3 design, and dose-limiting toxicities are assessed during the first cycle. A total of 30 patients will be enrolled. Inclusion criteria include ≥ 18 years old, unresectable tumors with confirmed HER2 aberration (protein overexpression, gene mutation or amplification), ECOG performance status 0-1, and adequate organ function. Exclusion criteria are significant cardiovascular conditions and active brain metastases. TAS0728 is a substrate for a transporter of breast cancer resistance protein (BCRP). Therefore, the genotypes for ABCG2, which encode a BCRP, are evaluated as a candidate factor for interpatient variability of pharmacokinetics. HER2 gene status is also analyzed from circulating tumor DNA in blood at baseline and disease progression. Citation Format: K. Nozawa, C. K. Imamura, S. Watanabe, T. Kogawa, M. Furuta, T. Toyama, H. Hayashi, J. Tsurutani. Phase I Study of TAS0728 in Patients with Advanced Solid Tumors with HER2 Aberration (TAIBRAKHER Study) abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-07-25.
Nozawa et al. (Tue,) studied this question.