LAUSR

Background: Patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC) who develop brain metastasis (BM) often have a poor prognosis. The treatment options for HER2+ BCBM is limited due to the presence of the blood–brain barrier (BBB). TL938 is an oral HER2 inhibitor capable of crossing the BBB, demonstrated by a brain-to-plasma partition coefficient (Kp, uu,brain) of over 400% in rat. This suggests TL938 has significant potential for the treatment of HER2+ BCBM. Methods: Cancer patients with advanced HER2+ solid tumors (overexpression, amplification, or mutation) confirmed by histology or cytology were treated with TL938. Seven dose levels of TL938 were investigated: 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, and 350 mg. TL938 was administered orally once daily. The study followed a 3 + 3 design. The primary endpoints were the maximum tolerated dose (MTD), recommended phase 2 dose (PR2D) and safety of TL938. Secondary endpoints included Investigator-assessed (RECIST v1.1) objective response rate (ORR), duration of response (DoR), disease control rate (DCR), progression free survival (PFS), and pharmacokinetics. Results: As of the cutoff date of May 17, 2024, TL938 has been administered to 44 patients. No dose-limiting toxicities (DLTs) were observed, and the MTD was not reached. The most common treatment related adverse events (TRAEs) (>20%) were diarrhea (75.0%), followed by increased blood creatine phosphokinase (38.6%), increased aspartate aminotransferase (36.4%), increased blood creatinine (31.8%), increased α-hydroxybutyrate dehydrogenase (27.3%), increased alanine aminotransferase (22.7%), proteinuria (22.7%), decreased lymphocyte count (22.7%), vomiting (22.7%), and increased blood creatine phosphokinase MB (20.5%). Grade 3 or higher TRAEs included diarrhea (18.2%), increased blood creatine phosphokinase (11.4%), and upper abdominal pain (2.3%). Three subjects (6.8%) experienced dose reduction due to TRAEs, including diarrhea (2.3%) and increased blood creatine phosphokinase (4.5%), and three subjects (6.8%) had dose interruption due to TRAEs, increased blood creatine phosphokinase (4.5%), vomiting (2.3%), gastritis (2.3%), upper abdominal pain (2.3%), and gastroesophageal reflux disease (2.3%). Among the 41 patients with tumor assessments, a total of 7 cancer types were represented, with the most common being BC (44%), lung cancer (22%), and salivary gland cancer (12%). Of the 18 BC patients who had tumor assessments at least once, a 50.0% overall response rate (ORR) and an 83.3% disease control rate (DCR) were observed. Notably, for the BC patients treated at a dose of 200 mg (N=10), an ORR of 70.0% and a DCR of 100.0% were achieved, including 1 patient who achieved a complete response. TL938 demonstrated intracranial disease control in five (including one with BC) patients with brain metastasis, who had previously undergone surgery, chemotherapy, and HER2-antibody-drug conjugate therapy. Among these patients, two achieved significant regressions in intracranial target lesions with reductions of 60% and 41%, respectively. After a single oral dose of TL938, the maximum plasma concentration (Cmax) was reached at a median time (Tmax) of 6-8 hours in most dosage groups. After 15 consecutive once-daily oral doses, minimal fluctuation of plasma concentrations around the average levels was observed across all dose cohorts, with fluctuation percentages below 30% for doses ranging from 100 to 250 mg. This indicates relatively stable exposure with repeated dosing. Conclusions: TL938 has demonstrated preliminary efficacy as a single agent therapy in HER2+ metastatic breast cancer patients with good tolerance. The most common TRAE observed was diarrhea, which is consistent with other similar tyrosine kinase inhibitors. Citation Format: Yuankai Shi, Lin Gui, Xinrui Chen, Hongming Pan, Wei Jin, Jiping Sun, Liqun Zou, Yongsheng Wang, Yuyao Yi, Chang Tan. A Phase 1 study Evaluating the Safety, Efficacy and Pharmacokinetics of TL938 in HER2-Positive Patients with Advance Solid Tumors [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS8-02.