OKI-219 + fulvestrant + atirmociclib

OKI-219 + fulvestrant + atirmociclib is an investigational combination therapy being studied in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) locally advanced, unresectable, or metastatic breast cancer harboring the PI3Kα H1047R mutation. **OKI-219** is a small molecule inhibitor selective for the PI3Kα (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) H1047R mutant, anticipated to block oncogenic PI3Kα signaling and inhibit tumor growth. **Fulvestrant** is a selective estrogen receptor degrader that antagonizes and degrades the estrogen receptor, impairing hormone-driven tumor proliferation. **Atirmociclib** is a CDK4/6 inhibitor, disrupting cell cycle progression in cancer cells. The combination aims to target complementary pathways driving breast cancer: PI3K pathway hyperactivation, estrogen receptor signaling, and cell cycle progression. The regimen is being tested in a Phase 1b dose-escalation clinical trial led by OnKure for safety, pharmacokinetics, and preliminary antitumor activity[2][3].