PI3Kα inhibitor / Eli Lilly - LARVOL DELTA

A phase 1/2 trial of LY4064809 (STX-478), a pan-mutant-selective PI3Kα inhibitor: Updated PIKALO-1 results (DKK 2026) - "In PIKALO-1, pts w/ PIK3CAm advanced solid tumors received LY alone (≥1 prior therapies, txs); pts w/ HR+, HER2- PIK3CAm ABC (≤2 prior txs) received LY + fulvestrant (fulv; 1-2 prior txs) or LY + fulv + CDK4/6i...LY alone or in combination was well-tolerated, w/ notably lower incidence of PI3Ki-class tox and no G≥3 hyperglycemia in pts with normal baseline glycemic control. Robust target coverage & promising antitumor activity were observed in heavily pre-treated pts w/ PIK3CAm tumors, demonstrating LY's potential as a best-in-class mutant selective PI3Kαi."

Late-breaking abstract • P1/2 data • Dental Disorders • Metabolic Disorders • Solid Tumor • Stomatitis • CDK4 • HER-2 • PIK3CA

A phase I/II trial of LY4064809 (STX-478), a pan-mutant-selective PI3Kα inhibitor: Updated PIKALO-1 results (ESMO 2025) - P1/2 | "Methods In PIKALO-1, pts w/ PIK3CA m advanced solid tumors received LY alone (≥1 prior therapies, txs); pts w/ HR+, HER2- PIK3CA m ABC (≤2 prior txs) received LY + fulvestrant (fulv; 1-2 prior txs) or LY + fulv + CDK4/6i...Results As of 7 Jul 2025, 204 pts were treated: 132 (49 ABC, 83 other solid tumors) w/ LY (20-160 mg QD), 34 w/ LY (60-100 mg QD) + fulv, & 38 w/ LY (20-100 mg QD) + fulv + CDK4/6i (ribociclib, 9; palbociclib, 29)...Conclusions LY alone or in combination was well-tolerated, w/ notably lower incidence of PI3Ki-class tox and no G≥3 hyperglycemia in pts with normal baseline glycemic control. Robust target coverage & promising antitumor activity were observed in heavily pre-treated pts w/ PIK3CA m tumors, demonstrating LY's potential as a best-in-class mutant selective PI3Kαi."

Late-breaking abstract • P1/2 data • Oncology • Solid Tumor • CDK4 • HER-2 • PIK3CA

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 (SABCS 2025) - P1/2 | "Pts with prior PI3K/AKT/mTORi were excluded except for intolerance. 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)... 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.Table"

Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

PIKALO-1: A phase I/II trial of LY4064809 (STX-478), a pan-mutant-selective PI3Kα inhibitor in PIK3CA-mutant (PIK3CAm) advanced breast cancer (ABC) and other solid tumors (Trial in Progress) (ESMO 2025) - P1/2 | "Table: 619TiP Parts Study Drug Key Eligibility Part A: Advanced solid tumors LY4064809 ≥1 prior therapy Part B: HR+, HER2- ABC LY4064809 + fulvestrant 1–2 prior therapies, ≥1 CDK4/6i and antiestrogen therapy; ≤1 prior chemotherapy *Part C/D/E: HR+, HER2- ABC LY4064809 + ET (aromatase inhibitor, fulvestrant, or imlunestrant) +CDK4/6i (ribocicblib, palbociclib, or abemaciclib) ≤2 prior regimens CDK4/6i-naive, -treatment-ongoing (up to 6 months), or –pretreated ≤1 prior chemotherapy ∗ Sub-cohorts C1, D1, and E1 will be randomized to various LY4064809 doses. 1 Martínez-Sáez, O. et al. Breast Cancer Res 2020, 22(1):45."

Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

PIKALO-1: First-in-Human Study of STX-478 as Monotherapy and in Combination With Other Antineoplastic Agents in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=720 | Recruiting | Sponsor: Eli Lilly and Company | Trial completion date: Feb 2029 ➔ Jul 2030 | Trial primary completion date: Feb 2027 ➔ Jul 2030

First-in-human • Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • PIK3CA

Epinephrine inhibits PI3Kα via the Hippo kinases. (PubMed, Cell Rep) - "These changes are abrogated when MST1/2 are genetically deleted or inhibited with small molecules or if the T1061 is mutated to alanine. Our study defines an inhibitory pathway of PI3K signaling and a link between epinephrine and insulin signaling."

Journal • Oncology • PIK3CA