ORIC-114, an orally bioavailable, irreversible kinase inhibitor, has superior brain penetrant properties and enhanced potency in preclinical studies of HER2-positive breast cancer

Amplification of human epidermal growth factor receptor 2 (HER2) is an oncogenic driver found in approximately 25% of breast cancer. Despite the arsenal of HER2-directed therapies available to patients, more than 50% of patients with HER2 amplification eventually develop central nervous system (CNS) metastases over the course of their disease indicating a clear medical need for brain penetrant therapies in this patient population. ORIC-114 is a brain penetrant, orally bioavailable, irreversible small molecule inhibitor that was designed to target exon20 insertions in epidermal growth factor receptor (EGFR) and HER2. ORIC-114 is highly selective for the EGFR/HER2 family of receptors, reducing the risk for off-target kinase liabilities. In biochemical assays, ORIC-114 displayed low nanomolar potency on HER2. To explore the application of ORIC-114 in the HER2-amplified tumor setting, a cell viability screen was performed against a panel of human breast cancer lines containing both HER2-amplified and non HER2-amplified cell lines. ORIC-114 demonstrated greater than 100-fold enhanced cellular potency on HER2-amplified cancer cell lines relative to non-amplified cancer cell lines. Notably, ORIC-114 cellular EC50s in HER2-amplified breast cancer cell lines were below 30 nM and more potent than both lapatinib and tucatinib, two FDA-approved tyrosine kinase inhibitors for the treatment of HER2-positive breast cancer. ORIC-114 was designed to incorporate physicochemical properties suitable to cross the blood-brain barrier and has exhibited good brain penetration across multiple preclinical species. To further investigate the brain penetrant attributes of ORIC-114 in the context of HER2-positive breast cancer with brain metastases, key features were assessed relative to tucatinib, which has demonstrated clinical efficacy in this setting. In contrast to tucatinib, ORIC-114 displayed minimal impact on efflux transporters as it was only a weak substrate for P-glycoprotein (P-gp) and was not a substrate for breast cancer associated protein (BCRP) in vitro. In addition, ORIC-114 demonstrated superior in vivo brain penetration relative to tucatinib as measured by free brain-to-plasma ratio in mouse. Consequently, ORIC-114 free brain concentrations in rodents were greater than tucatinib, even when the active metabolites of tucatinib were considered. Taken together, these data further establish ORIC-114 as a selective, irreversible, and brain penetrant EGFR/HER2 inhibitor, making it a promising therapeutic candidate for development in patients with HER2-positive tumors including those with CNS metastases. A Clinical Trial Application for ORIC-114 is anticipated in the second half of 2021. Citation Format: Melissa R. Junttila, Jason E. Long, Robert Warne, Sunghwan Kim, Younho Lee, Hwan Kim, Juhee Kang, Jiyoon Seok, Jihye Yoo, Youngyi Lee, Dong-Hyuk Seo Seo, Jung Beom Son, Daekwon Kim, Hwan Geun Choi, Nam Doo Kim, Tatiana Zavorotinskaya, Chelsea Chan, Matthew Panuwat, Jessica Sun, Jae H. Chang, Lori S. Friedman. ORIC-114, an orally bioavailable, irreversible kinase inhibitor, has superior brain penetrant properties and enhanced potency in preclinical studies of HER2-positive breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P234.