Abstract LB240: Preclinical evaluation of ABSK112, a selective and CNS-penetrant compound with strong HER2 inhibitory activity for treating HER2-driven solid tumors

Abstract Background: HER2+ cancers, driven by the overexpression or amplification of the HER2 oncogene, are prevalent in various malignancies, including breast, gastric, and lung cancers. These tumors are often associated with a heightened risk of brain metastases. Despite advancements in treatment options, such as the expanded use of tucatinib and HER2-targeting antibody-drug conjugates (ADCs), there remains a significant unmet need for therapies that are both more effective and better tolerated. Such therapies should aim for improved safety and more durable responses, particularly in HER2+ cancers with brain metastases. ABSK112 is a wild-type EGFR-sparing, brain-penetrant small molecule inhibitor currently under investigation in a first-in-human phase I clinical trial for NSCLC patients harboring EGFR exon20 insertion mutations (NCT06225804). Here, we present the preclinical activity profile of ABSK112 in HER2+ cancers. Method: The cellular target engagement and antiproliferative activity of ABSK112 were assessed in HER2- or EGFR-driven cancer cell lines and engineered Ba/F3 cells. In vivo antitumor efficacy was evaluated using both subcutaneous and intracranial xenograft models, either as monotherapy or in combination with trastuzumab deruxtecan (T-DXd). Results: ABSK112 exhibited potent antiproliferative activity in HER2-driven cancer cell lines (BT474 and NCI-N87) and the engineered Ba/F3-HER2 cell line, while exhibiting minimal effects on wild-type EGFR-dependent cell lines, including A431, NCI-H292, NCI-H358, and Ba/F3-EGFR. On-target potency of ABSK112 and its selectivity for wild-type EGFR were further validated through its effects on HER2 and EGFR phosphorylation. In vivo, oral administration of ABSK112 at well-tolerated doses led to significant tumor regression in BT474 and NCI-N87 subcutaneous xenograft models. Additionally, the combination of ABSK112 with T-DXd exhibited synergistic antitumor effects in both HER2+ and HER2-low subcutaneous xenograft models. Moreover, ABSK112 demonstrated strong antitumor efficacy in the NCI-N87 intracranial xenograft model, with further enhancement observed in combination with T-DXd. Conclusion: These findings establish ABSK112 as a potent, selective and CNS-penetrant HER2 inhibitor, warranting further clinical evaluation of it as a monotherapy or in combination with HER2-targeted ADCs for the treatment of HER2+ cancers with brain metastases. Citation Format: Bin Shen, Cheng Dai, Shenyan Liu, Cong Li, Jie Wang, Jie Zhang, Manqi Liu, Zhui Chen, Nannan Zhang. Preclinical evaluation of ABSK112, a selective and CNS-penetrant compound with strong HER2 inhibitory activity for treating HER2-driven solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB240.