Abstract PS1-08-24: A phase 1/2 trial of LY4064809 (STX-478), a pan-mutant-selective PI3Kα inhibitor in HR+, HER2- advanced breast cancer (ABC): Updated results from PIKALO-1

Abstract Background: PI3Kα inhibitors (PI3Kαi) have demonstrated clinical benefit in the ∼40% of HR+, HER2- ABC with PIK3CA mutations (PIK3CAm). However, broad use is often constrained by: 1) toxicities mediated through wild-type PI3Kα inhibition, and 2) the exclusion of patients (pts) with diabetes (DM) or prediabetes (pDM). LY4064809 is an oral, allosteric, CNS-penetrant, pan-mutant-selective PI3Kαi with favorable safety, PK, and efficacy in pts with PIK3CAm HR+ HER2- ABC. Methods: In PIKALO-1 (NCT05768139), pts with PIK3CAm HR+ HER2- ABC received monotherapy (≥1 prior therapies, txs), LY4064809 plus fulvestrant (fulv, 1-2 prior txs), and LY4064809 plus fulv and CDK4/6 inhibitors (≤2 prior txs). Pts with pDM/DM were eligible; pts with uncontrolled DM (HbA1c ≥8% / FBG ≥140mg/dL) were excluded. Pts with prior PI3K/AKT/mTORi were excluded except for intolerance. Results: As of 7 Jul 2025, 121 pts with HR+, HER2- ABC were treated: 50 with LY4064809 (20-160 mg QD), 33 with LY4064809 (60-100 mg QD) + fulv, and 38 with LY4064809 (20-100 mg QD) + fulv + CDK4/6i (ribociclib, 9; palbociclib, 29). Median age was 62 (27-84) yrs, 49% had pDM/DM. Median prior txs was 2 (0-7) including: CDK4/6i (84%), SERD (51%), chemotherapy/ADC (31%/11%) and PI3Ka/AKT/mTORi (8%). Across all HR+, HER2- pts, all hyperglycemia events were low grade ([G]; 26% G1-G2, 37%/15% in pts with and without pDM/DM); no G≥3 events were reported. Other TEAEs ≥20% (any G/G≥3) were nausea (35%/