Abstract LB174: OKI-219 is an inhibitor of PI3Kα H1047R that has brain penetrance and anti-tumor activity in a preclinical intracranial model of metastatic breast cancer
Authors: Strait Alexander A. , Taylor Molly A. , Litwiler Kevin S. , Zhao Qian , Mareska David A. , Boys Mark L. , Izrayelit Yevgeniy , Woessner Richard , Winkler James D. 
Published: April 2024

Background: Dysregulation of PI3K signaling is a common driver of solid tumors, with the PI3KαH1047R activating mutation found in 4% of all cancers. Because many cancers, including breast and lung cancers, can metastasize to the CNS, brain penetration should be a key feature of new therapies. The FDA-approved PI3K inhibitor alpelisib lacks CNS activity, and brain-penetrant alternatives such as buparlisib and paxalasib were not approved due to toxicity associated with a lack of mutant selectivity. OKI-219 is a potent, highly selective PI3KαH1047R inhibitor that has shown preclinical anti-tumor activity in multiple cancer models, both as a monotherapy and in combination with HER2- and ER-mediated therapeutics. Here, we demonstrate its brain penetrance across multiple animal species and anti-tumor activity in an intracranial mouse model of PI3KαH1047R mutant breast cancer.

Materials and methods: Brain penetrance in mouse, rat, dog, and monkey was quantified by the ratio of unbound drug concentrations in brain to plasma (Kp,uu). Plasma, brain, and cerebrospinal fluid (CSF) concentrations of OKI-219 were measured by LC/MS, and protein binding in plasma, CSF, and brain homogenate were measured by rapid equilibrium dialysis. Additionally, free drug levels in the brain were directly measured by microdialysis in rats. Mice were implanted subcutaneously and intracranially with PI3KαH1047R xxT47D-luc tumors and tumor growth was measured by calipers (subcutaneous tumors) and luminescence (intracranial tumors).

Results: At the Cmax of a pharmacologically active 10 mg/kg PO dose, OKI-219 had a Kp,uu of 0.34, 0.61, and 0.58 in rat, dog, and monkey CSF, respectively. Additionally, OKI-219 had an average Kp,uu of 0.67 over 24h post-dose as measured by brain microdialysis in rats at 30 mg/kg, with a dose-proportionate increase in brain free drug levels at 300 mg/kg. After 21 days of treatment, OKI-219 induced a statistically significant dose-dependent anti-tumor effect on both flank and brain xxT47D-luc tumors.

Conclusion: Here we show that OKI-219 had consistently good brain penetrance across multiple species by multiple methods of measuring free drug levels in the brain. We further demonstrated that OKI-219 had anti-tumor activity against xxT47D-luc tumors in an intracranial mouse model that is similar to activity in the same tumor when implanted subcutaneously, demonstrating that the brain levels achieved were pharmacologically active. These data indicate the potential for activity of OKI-219 in CNS disease settings, including metastatic brain cancer, which are not currently addressed with existing PI3K pathway inhibitors. OnKure has initiated the PIKture Phase I clinical study (OKI-219-101) to evaluate OKI-219 in patients with PI3KαH1047R-mutated solid tumors.

Citation Format: Alexander A. Strait, Molly A. Taylor, Kevin S. Litwiler, Qian Zhao, David A. Mareska, Mark L. Boys, Yevgeniy Izrayelit, Richard Woessner, James D. Winkler. OKI-219 is an inhibitor of PI3Kα H1047R that has brain penetrance and anti-tumor activity in a preclinical intracranial model of metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB174.