Phase 2 inavolisib PI3Kα inhibitor + ribociclib CDK4/6 inhibitor + letrozole in early HR+ breast cancer

This Phase 2, open-label, multicenter neoadjuvant study from Roche/Genentech tests inavolisib-based endocrine combinations in untreated Stage II–IIIC, ER-positive/HER2-negative breast cancer with a tumor PIK3CA mutation (a common alteration in HR+ disease, ~30–40%). Inavolisib is a selective PI3K-alpha (PIK3CA) inhibitor; ribociclib (Novartis) inhibits CDK4/6 to deepen cell-cycle arrest; and letrozole (generic) is an aromatase inhibitor that suppresses estrogen signaling.The three arms mainly vary the “lead-in” (starting with doublet vs triplet) before converging on the triplet, aiming to understand safety/tolerability and whether early pathway co-inhibition improves tumor shrinkage and pathologic responses prior to surgery. Today’s care for many Stage II–III ER+/HER2− cases is neoadjuvant chemotherapy for higher-risk disease or neoadjuvant endocrine therapy in selected patients, followed by surgery and adjuvant endocrine therapy ± CDK4/6 inhibition (e.g., abemaciclib) based on recurrence risk; this trial explores a genomically selected, chemo-sparing neoadjuvant strategy in PIK3CA-mutant tumors.