98 A Phase 1/2 Trial of LY4064809, A Pan-Mutant-Selective PI3Kα Inhibitor in HR+/HER2− Advanced Breast Cancer, Updated Results From PIKALO-1

Background

PI3Kα inhibitors (PI3Kαi) demonstrated clinical benefit in approximately 40% of patients with hormone receptor–positive/HER2-negative (HR+/HER2–) advanced breast cancer with PIK3CA mutations. However, broad use is often constrained by 1) toxicities mediated through wild-type PI3Kα inhibition, and 2) exclusion of patients with diabetes (DM)/prediabetes (pDM). LY4064809 (STX-478) is an oral, allosteric, central nervous system (CNS)-penetrant, pan-mutant-selective PI3Kα inhibitor with favorable safety, pharmacokinetics, and efficacy in patients with PIK3CAm HR+/HER2– advanced breast cancer.

Methods

In PIKALO-1, patients received monotherapy (≥ 1 prior therapies), LY4064809+fulvestrant (1-2 prior therapies), and LY4064809 plus endocrine therapy (ET) (fulvestrant/aromatase inhibitors) and CDK4/6 inhibitors (≤ 2 prior therapies). Patients with pDM/DM were eligible; patients with uncontrolled DM were excluded. Patients with prior PI3K/AKT/mTORi were excluded except for intolerance.

Results

As of July 8, 2025, 121 patients with HR+/HER2– advanced breast cancer were treated: 50 with LY4064809 (20-160 mg QD), 33 with LY4064809 (60-100 mg QD) plus fulvestrant, and 38 with LY4064809 (20-100 mg QD) plus fulvestrant plus CDK4/6i (ribociclib, 9; palbociclib, 29). Median age was 62 (27-84) years, 49% had pDM/DM. Median prior therapies was 2 (0-7) including CDK4/6i (84%), SERD (51%), chemotherapy/ADC (31%/11%), and PI3Ka/AKT/mTORi (8%). Across all patients with HR+/HER2– cancer, hyperglycemia events were low grade 1/2 (26% any grade, 37%/15% in patients with and without pDM/DM); no grade 3 or higher events were reported. Other treatment-emergent adverse effects (TEAEs) ≥ 20% (any grade/grade ≥ 3) were nausea (35%/< 1%), fatigue (33%/5%), diarrhea (26%/< 1%), neutropenia (25%/17%), and ALT/AST increased (24%/10%). Incidence of other common class-toxicities (rash [3%/0%] and stomatitis [5%/< 1%]) were low. TEAEs led to dose reduction in 10 patients (8%) [ALT/AST increased (n = 5 at 60, 80, and 160 mg), fatigue (n = 3 at 60 and 100 mg), hyperglycemia (n = 1 at 100 mg), dysesthesia (n = 1 at 60 mg); all related], and discontinuation in 2 patients (2%) [AST increased (n = 1 at 100 mg, related), intracranial hemorrhage (n = 1 at 80 mg, unrelated)]. Throughout the study, LY4064809 exposures reached the target coverage for in vitro pAKT IC₈₀ (from 20 mg) and in vivo efficacy (from 40 mg). No significant drug-drug interactions were noted with fulvestrant and palbociclib. PIK3CAm ctDNA was reduced at all dose levels across all therapies (Table). Updated safety, efficacy, biomarker, and PK data (data cutoff: October 2025) will be presented at the meeting.

Conclusion

LY4064809, alone or with ET with or withoutCDK4/6 inhibitors, was well-tolerated, with notably lower incidence of PI3K inhibitor–class toxicities and no grade 3 or higher hyperglycemia in HR+/HER2– patients with normal baseline glycemic control. Robust target coverage and promising antitumor activity were observed in heavily pre-treated patients with PIK3CAm HR+/HER2– advanced breast cancer, highlighting LY4064809’s potential as a best-in-class mutant selective PI3Kα inhibitor.