Abstract B008: TFX06 demonstrated intracranial efficacy in patients with ER+/HER2- brain metastatic breast cancer in a phase 1/2 study

Abstract Background: Brain metastases remain a significant clinical challenge in ER+/HER2− breast cancer, with limited systemic therapies demonstrating meaningful intracranial efficacy. TFX06, a third-generation oral complete estrogen receptor antagonist and degrader (CERAN/SERD), is under investigation in a multicenter phase 1/2 study (NCT05927779) for patients with ER+/HER2- locally advanced or metastatic breast cancer (Zhang J, et al., 2024 SABCS Annual Meeting). The recommended phase 2 dose (RP2D) was established at 150 mg once daily (QD). The study cohort included 9 patients with brain metastases, and the preliminary findings are reported here. Patients and Methods: Eligible patients included those regardless of menopausal status who had received ≥1 prior lines of endocrine therapy (ET), prior treatment with CDK4/6 inhibitors and fulvestrant, and ≤2 prior lines of chemotherapy for metastatic disease. TFX06 was administered orally at 150 mg QD in 28-day cycles until disease progression or intolerable toxicity. As of the cutoff date (July 11, 2025), nine patients with brain metastases were enrolled (median age 59 years [range 41-69]; ECOG 0–1). The median number of prior ETs was 2 (range: 1–2), including fulvestrant (77.8%), CDK4/6 inhibitors (66.7%), and their combination (55.6%). The median number of chemotherapies was 2 (range 0-2). ESR1 mutations were detected in 55.6% (5/9) of patients. Intracranial responses were assessed every eight weeks by investigators by RECIST v1.1. Results: TFX06 was well tolerated in patients with brain metastases. The most common (≥20%) treatment-emergent adverse events (TEAEs) were grade 1–2 laboratory abnormalities, including anemia, lymphopenia, hypertriglyceridemia, leukopenia, constipation, and neutropenia. Among 8 evaluable patients, intracranial disease control was achieved in 7 patients (DCR 87.5%), with 3 intracranial complete or partial responses (ORR 37.5%) and a clinical benefit rate (CBR) of 75%. Notably, radiologic evaluation showed >70% reduction in the sum of target brain lesions in 2 patients and complete resolution of non-target lesions in 2 others. Median progression-free survival (mPFS) was 7.4 months in ESR1-mutation detectable and 8.3 months in ESR1-mutation undetectable subgroups, suggesting activity irrespective of ESR1 mutation status. In 4 patients pretreated with fulvestrant and CDK4/6 inhibitors, intracranial DCR was 75% (3/4). Conclusions: In this subgroup of patients with ER+/HER2− breast cancer and brain metastases, TFX06 demonstrated a favorable safety profile and compelling intracranial antitumor activity, including tumor regression and lesion resolution, irrespective of ESR1 mutational status. These findings highlight TFX06’s potential therapeutic advantage over fulvestrant in managing brain metastatic disease. Given the paucity of systemic therapies effective against CNS metastases in ER+ breast cancer, these results underscore the clinical relevance of developing CNS-penetrant SERDs such as TFX06. Citation Format: Wenxing Qin, Yang Chen, Jian Zhang, Zhiye Zhang, Tingjing Yao, Yongsheng Wang, Yuping Sun, Yehui Shi, Yefeng Lu, Jia Song, Panpan Li, Ningyi Ma, Douglas Fang, Wei Sha, Charles Z. Ding. TFX06 demonstrated intracranial efficacy in patients with ER+/HER2- brain metastatic breast cancer in a phase 1/2 study [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B008.