Abstract PO3-25-09: OKI-219, a PI3KαH1047R-mutant-selective inhibitor demonstrates efficacy as a single agent and drives combination responses with standard of care therapies in pre-clinical PI3KαH1047R mutant breast cancer models
Authors: Taylor Molly A. , Zhao Qian , Mareska David , Hoh Maria , Izrayelit Yevgeniy , Litwiler Kevin , Boys Mark L , Woessner Rich , Walker Duncan , Winkler James D , Diamond Jennifer 
Published: May 2024

Mutations in PI3Kα lead to constitutive activation of the PI3K/AKT/mTOR pathway and are highly prevalent in cancer. PI3KαH1047R is the most common amino acid substitution mutation and represents approximately one-third of all PI3Ka mutations, with 15% of breast cancers having a PI3KαH1047R mutation. In breast cancer, PI3KαH1047R mutations are associated with resistance to targeted therapies, including HER2- and estrogen receptor (ER)- targeted agents. Although targeting PI3Kα in cancer is a therapeutically proven strategy, with the currently approved drug alpelisib showing clinical efficacy alone or in combination with other therapies, treatment with non-mutant selective PI3Kα inhibitors such as alpelisib is associated with significant toxicities such as hyperglycemia, due to on-target inhibition of the wild-type enzyme. This often leads to dose modification or discontinuation. Therefore, there is a significant need to develop new PI3Kα-targeted therapies that can avoid or minimize on-target toxicity and improve the safety and clinical benefit for patients.  OKI-219 is an orally bioavailable, PI3KαH1047R mutant-selective inhibitor, with ~100-fold cellular selectivity for the H1047R mutation over wild-type. OKI-219 demonstrates selectivity across a panel of 412 kinases, with no other kinases showing &gt;30% inhibition at 1 µM. In vitro, OKI-219 drives decreased phosphorylated AKT (pAKT) and decreased proliferation specifically in PI3KαH1047R mutant cell lines across several tumor types, including breast cancer. In vivo, as a monotherapy, OKI-219 demonstrates dose dependent antitumor activity in multiple human tumor xenograft models, including the H1047R mutant breast cancer CDX models T47D and HCC1954 and several PDX models, with regression rates up to 100% at doses that show no sign of the metabolic dysfunction (increased glucose or insulin) associated with wild-type protein inhibition. The in vivo antitumor activity correlates with pathway inhibition, measured by decreased pAKT in tumors. Moreover, OKI-219 dosed in combination with the selective estrogen receptor degraders (SERDs) fulvestrant, elacestrant or camizestrant showed significant combination benefit leading to tumor regressions of up to 100% in the ER+ H1047R mutant breast cancer model xxT47D, at doses where no regressions were observed with single agent treatment. Dosing OKI-219 in combination with HER2-inhibitors, such as tucatinib, led to tumor regressions in the ER-HER2+ and H1047R mutant breast cancer CDX model HCC1954, also at doses where no regressions were observed with single agent treatment. These data indicate that OKI-219 offers improved efficacy and a wider therapeutic window compared to non-mutant selective PI3Kα inhibitors. OKI-219 is advancing into clinical trials.

Citation Format: Molly A. Taylor, Qian Zhao, David Mareska, Maria Hoh, Yevgeniy Izrayelit, Kevin Litwiler, Mark L Boys, Rich Woessner, Duncan Walker, James D Winkler, Jennifer Diamond. OKI-219, a PI3KαH1047R-mutant-selective inhibitor demonstrates efficacy as a single agent and drives combination responses with standard of care therapies in pre-clinical PI3KαH1047R mutant breast cancer models [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-25-09.