Abstract LB284: VRN101099: A novel treatment option for HER2-driven cancer patients, overcoming T-DXd resistance and brain metastases

Abstract Many systemic therapeutic options for advanced metastatic HER2-positive breast cancer have been approved, including antibody-based therapies, chemotherapies, and tyrosine kinase inhibitors (TKIs). However, brain metastasis and acquired resistance are still major unmet medical needs for HER2-driven metastatic breast cancer and advanced solid cancers. VRN101099 is an orally available HER2 kinase inhibitor with excellent selectivity over other kinases, including EGFR. VRN101099 tightly occupies the ATP-binding pocket of HER2 forming a covalent bond with Cys805, resulting in high efficacy against various HER2 amplification and HER2 activating mutations. VRN101099 showed potent activity in HER2 antibody-resistant isoforms such as p95HER2 and exon16-deletion, lacking the binding epitope for HER2 antibodies including trastuzumab. It further demonstrated significant activity in T-DXd-acquired resistant cell lines (TR), including SK-BR-3 TR cell lines, which exhibits reduced HER2 expression and overexpression of BCRP (breast cancer resistance protein), suggesting that VRN101099 is not a substrate of BCRP. It also showed potency in N87-TR cell lines, which exhibits overexpression of AKR1C, an enzyme involved in the metabolism of chemical drugs, suggesting that VRN101099 can overcome the metabolism of chemical drugs such as DXd. VRN101099, a non-BCRP substrate, exhibits intracranial activity by efficiently crossing the blood-brain barrier(BBB). In intracranial xenograft models, VRN101099 demonstrated superior anti-tumor efficacy to tucatinib, neratinib, zongertinib, trastuzumab, and T-DXd. Key aspects including safety, intracranial activity, and potency against HER2 amplification, activating mutations, antibody-resistant isoforms, and T-DXd-acquired resistance in cancer cells will position VRN101099 as a valuable therapeutic option for various HER2-driven solid tumors, both as monotherapy and in combination with other treatments, including HER2 antibodies and antibody-drug conjugates (ADCs). The phase 1 dose-escalation study of VRN101099 in Korea and Australia has been approved and is evaluating its safety, tolerability, pharmacokinetics, and pharmacodynamics of VRN101099 to determine the recommended Phase 2 dose (RP2D). In conclusion, VRN101099 is a promising HER2-selective TKI with a favorable profile including potency, tolerability, and brain permeability. This identifies VRN101099 as a potential novel systemic treatment option for patients with HER2-driven cancers, particularly those with brain metastases or those who have progressed after or failed with T-DXd. Citation Format: Hong-Ryul Jung, Jihye Yoo, Yikyung Ko, Somi Lee, Yeonsil Kim, Byung-Woo Park, Donghyuk Seo, Hyerim Im, Ha Yeon Cho, Haelee Kim, DongGuk Shin, Hayeong Kim, Se-Hyuk Kim, Soochan Kim, Kyungah Seo, Daekwon Kim, Sunghwan Kim. VRN101099: A novel treatment option for HER2-driven cancer patients, overcoming T-DXd resistance and brain metastases [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 LB284.