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

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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%/<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 pts (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 pts (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 txs. See table for efficacy. Updated safety, efficacy, biomarker, and PK data (data cutoff: Oct 2025) will be presented at the meeting. Conclusion: LY4064809, either alone or in combination with fulvestrant +/- CDK4/6 inhibitors, was well-tolerated, with notably lower incidence of PI3K inhibitor (PI3Ki)-class toxicities and no grade ≥3 hyperglycemia in HR+, HER2- pts with normal baseline glycemic control. Robust target coverage and promising antitumor activity were observed in heavily pre-treated pts with PIK3CAm HR+, HER2- ABC, highlighting LY4064809’s potential as a best-in-class mutant selective PI3Kα inhibitor. Citation Format: K. Jhaveri, D. Juric, A. Giordano, A. Italiano, G. Daniele, J. Rodon, A. Patnaik, J. Bartolomé, A. Elias, P. Munster, P. LoRusso, A. Soyano, M. de Miguel, J. O'Shaughnessy, R. Wesolowski, G. Curigliano, T. Hernández, A. Lombard, S. T. Estrem, L. Du, X. Xu, A. Montero. 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]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-08-24.

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