LY4064809 / Eli Lilly - LARVOL DELTA

PIK3R1 (p85α) alterations define a targetable subset of breast cancer with broad sensitivity to PI3K and AKT inhibitors (SABCS 2025) - "Strikingly, PIK3R1 mutations conferred pan-sensitivity to active-site PI3Ki (alpelisib, inavolisib), AKTi (capivasertib), and mutant-selective PI3Ki (STX-478, RLY-2608) in vitro. This is the first comprehensive study of PIK3R1 alterations in breast cancer. Our findings establish PIK3R1 as a functional driver of oncogenic PI3K signaling and show that PIK3R1 alterations confer sensitivity to both established and investigational PI3K and AKT inhibitors. These findings nominate PIK3R1 alterations as an actionable genomic biomarker and support the inclusion of patients with PIK3R1-altered breast cancer in clinical trials testing PI3K and AKT inhibitors."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • AKT1 • ER • PIK3CA • PIK3R1 • PTEN

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

BBO-10203, a first-in-class breaker of the RAS:PI3Kα interaction, inhibits tumor growth alone and in combination with fulvestrant or ribociclib in breast cancer models without inducing hyperglycemia (SABCS 2025) - P1 | "In the EFM-19 CDX model, which harbors a kinase domain PIK3CA mutation, the combination of BBO-10203 and fulvestrant show the same activity as the combination of STX-478 and fulvestrant. In conclusion, BBO-10203 blocks RAS-mediated activation of PI3Kα, strongly inhibits pAKT signaling in tumor cells without affecting glucose metabolism, and shows robust tumor activity alone or in combination with standard of care therapies in mutant or wild-type PIK3CA breast cancer models. BBO-10203 has entered phase 1 clinical trials (NCT06625775) and may provide clinical benefit without the limiting toxicities that have restricted the use of PI3Kα inhibitors."

Combination therapy • Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ER • HRAS • KRAS • NRAS • PIK3CA

A Study of LY4064809 in Healthy Adult Chinese Participants (clinicaltrials.gov) - P1 | N=10 | Recruiting | Sponsor: Eli Lilly and Company

New P1 trial

Presentation Highlights:…LY4064809 / STX-478 (investigational pan-mutant-selective PI3Kα inhibitor) (PRNewswire) - "Lilly to highlight progress across key programs in early and advanced hormone receptor-positive breast cancer at the 2025 San Antonio Breast Cancer Symposium....In a poster presentation, Lilly will share findings from PIKALO-1, the ongoing Phase 1/2 study evaluating LY4064809 alone and in combination with endocrine therapy and CDK4/6 inhibitors in patients with PIK3CA-mutant HR+, HER2– advanced breast cancer, including updated data on safety, efficacy, biomarkers, and analyses across pre-diabetic, diabetic, and non-diabetic subgroups. LY4064809 is planned to advance into the Phase 3 PIKALO-2 study (NCT07174336), for which a dose optimization lead-in is ongoing."

P1/2 data • Trial status • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

PIKALO-2: A Study of LY4064809 With Other Anti-Cancer Treatments in Participants With Advanced Breast Cancer With a Genetic Change (PIK3CA) (clinicaltrials.gov) - P3 | N=920 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

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

The farnesyl transferase inhibitor KO-2806 constrains mTORC1 activity to enhance the antitumor efficacy of mutant-selective PI3Kα inhibitors (AACR-NCI-EORTC 2025) - "We have previously demonstrated farnesyl transferase inhibitors (FTIs) enhance the antitumor activity of multiple targeted therapies, including the α-selective PI3K inhibitor alpelisib, by blocking RHEB-mediated mTORC1 activation...In this study, we assessed the potential therapeutic utility of combining KO-2806 with mutant-selective PI3Kα inhibitors STX-478 or RLY-2608 in a panel of in vitro cell line and in vivo xenograft models spanning the breadth of solid tumor indications with the highest frequency of PIK3CA mutation...In the ER+ model MCF7, combination of KO-2806 and RLY-2608 was comparable to combination of fulvestrant and RLY-2608, resulting in tumor regressions, while the triplet further deepened tumor regression. These data suggest that, due to its ability to constrain mTORC1 signaling, KO-2806 holds promise as a combination agent for mutant-selective PI3Kα inhibitors across a broad range of PIK3CA-mutant solid tumor indications."

Clinical • Bladder Cancer • Colorectal Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AKT1S1 • PIK3CA • RHEB

Dual PI3K and RAS pathway inhibition overcomes therapeutic resistance in KRAS/PIK3CA co-mutant colorectal cancer patient-derived organoids (AACR-NCI-EORTC 2025) - "PDOs were stratified as wild-type, KRAS-mutant, or KRAS/PIK3CA double-mutant and treated with PI3Kα-selective inhibitors RLY-2608, STX-478, or alpelisib, either alone or in combination with the RAS inhibitor RM-042, a first-in-class oral agent targeting GTP-bound RAS. Together, our studies establish that KRAS/PIK3CA co-mutant CRC exhibits unique vulnerabilities to combined PI3K and RAS inhibition. This work provides a rationale for developing dual-pathway therapeutic strategies tailored to this aggressive molecular subtype in CRC."

Clinical • Late-breaking abstract • Colorectal Cancer • Oncology • Solid Tumor • KRAS • 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

LY4064809 (investigational pan-mutant-selective PI3Ka inhibitor) (PRNewswire) - "In a late-breaking oral presentation, Lilly will share updated results from the Phase 1/2 PIKALO-1 trial, a study of LY4064809 (STX-478), a pan-mutant-selective PI3Ka inhibitor, in PIK3CA-mutant advanced breast cancer and other solid tumors."

Late-breaking abstract • P1/2 data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Solid Tumor

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

A Study of Food Effect and Esomeprazole on LY4064809 in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=36 | Completed | Sponsor: Scorpion Therapeutics, a wholly owned subsidiary of Eli Lilly and Company | Recruiting ➔ Completed

Trial completion

A Study of LY4064809 With Other Anti-Cancer Treatments in Participants With Advanced Breast Cancer With a Genetic Change (PIK3CA) (clinicaltrials.gov) - P3 | N=920 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P3 trial • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

Structural Insights into the Development of Inhibitors Against Cancer-Specific Mutations of PI3Kα. (PubMed, Annu Rev Pharmacol Toxicol) - "While early pan- and isoform-selective PI3K inhibitors (alpelisib) show clinical utility, their intrinsic toxicity and resistance to treatment persist. Recent breakthroughs include the emergence of allosteric inhibitors (RLY-2608 and STX-478) that exploit mutation-induced cryptic pockets to achieve mutant selectivity as well as covalent inhibitors and degraders (inavolisib) that enhance specificity, aiming at decoupling antitumor activity from metabolic dysfunction. This review synthesizes current progress in PI3Kα inhibitor development, emphasizing structural characteristics, clinical challenges, and emerging strategies. Addressing challenges to increase mutant selectivity, exploring conformational modulation, uncovering new mechanisms of action, and implementing personalized therapies are key future directions for PI3Kα-targeted drug discovery."

Journal • Review • Metabolic Disorders • Oncology • PIK3CA

ETX-636, a novel allosteric pan-mutant-selective PI3Kα dual inhibitor and degrader with best-in-class potential (AACR 2025) - "Orthosteric ATP-competitive inhibitors, alpelisib and inavolisib, which inhibit both Wild-type (WT) and mutant PI3Kα, are approved in combination regimens for treating PIK3CA-mutant, HR+/HER2-, advanced or metastatic BrCA...In addition to greater biochemical selectivity for mutant PI3Kα over WT PI3Kα, ETX-636 has stronger target binding affinity, better on-target potency in biochemical and cellular pharmacodynamic assays, and demonstrates superior anti-tumor activity in vivo when compared to other allosteric, pan-mutant-selective PI3Kα inhibitors (i.e. RLY-2608 and STX-478)...In an ER-positive, HER2-negative, PI3Kα-mutant BrCA xenograft, ETX-636 is efficacious as a single agent and shows synergistic activity with fulvestrant, inducing tumor regression while being well-tolerated...In addition, based on pharmacokinetic, pharmacodynamic, efficacy, and toxicology studies, predicted human efficacious doses of ETX-636 are not projected to cause hyperglycemia. The preclinical..."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRCA • ER • HER-2 • PIK3CA

STX-478-101: 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: Scorpion Therapeutics, Inc. | N=400 ➔ 720

Enrollment change • Monotherapy • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • PIK3CA

A Study of LY4064809 [14C]-STX-478 in Healthy Male Participants (clinicaltrials.gov) - P1 | N=8 | Completed | Sponsor: Scorpion Therapeutics, a wholly owned subsidiary of Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion

Multi-node inhibition targeting mTORC1, mTORC2 and PI3Kα potently inhibits the PI3K/AKT/mTOR pathway in endometrial and breast cancer models. (PubMed, Br J Cancer) - "Multi-node PI3K/AKT/mTOR pathway inhibition with serabelisib, sapanisertib and ISD is highly effective in preclinical models of endometrial and breast cancer, supporting continued clinical development in these and other solid tumours."

Journal • Preclinical • Breast Cancer • Endometrial Cancer • Oncology • Solid Tumor • EIF4EBP1 • PIK3CA

LAE118, a pan mutant-selective PI3Ka inhibitor with superb activity against both the kinase domain and helical domain mutants (AACR 2025) - "In response to this, pan-mutant selective PI3Ka inhibitors including RLY-2608 and STX-478 are being developed in clinical trials for cancer patients with PIK3CA mutations. Human PK projection indicates LAE118 has the potential to achieve continuous inhibition of pAKT in clinic without causing hyperglycemia. LAE118 is currently in IND enabling stage, positioning it as a promising candidate for the treatment of cancers with PIK3CA mutations."

Late-breaking abstract • Oncology • PIK3CA

Identification and characterization of an allosteric and mutant-selective PI3Kα inhibitor (AACR 2025) - P1, P1/2 | "Orthosteric inhibitors of PI3Kα, such as alpelisib and inavolisib have been approved for the treatment of patients with advanced HR+/HER2− breast cancer. TY-2291 is a potent kinase inhibitor of mutant PI3Kα with high selectivity over WT PI3Kα. In in vitro antiproliferative test, TY-2291 showed better antiproliferative activity against multiple PI3Kα mutant cells than LOXO-783, STX-478, and RLY-2608. In the mouse HCC1954 CDX model, TY-2291 showed potent tumor-inhibitory activity and excellent tolerance."

Breast Cancer • Colon Cancer • Colorectal Cancer • Gastric Cancer • Head and Neck Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Uterine Cancer • HER-2 • PIK3CA

Patient derived cancer organoids as a model to predict clinical response and drug discovery in colorectal cancer (AACR 2025) - "All plates were imaged on Day 0 and Day 2; diameter analysis was performed, and GD was determined for all treatment groups. Seven PDCO lines were treated with FOLFOX or FOLFIRI and a GD range of 0.01-1.61 with a median of 0.75 were observed... PDCOs show exciting potential as a predictive model for patient response and drug discovery. These findings need to be validated in further studies."

Clinical • Colorectal Cancer • Oncology • Solid Tumor

STX-478, a PIK3CA mutant-selective inhibitor, alone and in combination with romidepsin for PIK3CA mutant CRC (AACR 2025) - "This study demonstrates that STX-478, a mutant-selective, allosteric PIK3CA inhibitor, exhibits varying effects on CRC cell lines in both 2D and 3D culture models. The combination of STX-478 and romidepsin is promising and deserves further validation in vivo."

Combination therapy • Colorectal Cancer • Oncology • Solid Tumor • PIK3CA

A Study of LY4064809 [14C]-STX-478 in Healthy Male Participants (clinicaltrials.gov) - P1 | N=8 | Active, not recruiting | Sponsor: Scorpion Therapeutics, a wholly owned subsidiary of Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed

A Study of LY4064809 [14C]-STX-478 in Healthy Male Participants (clinicaltrials.gov) - P1 | N=8 | Recruiting | Sponsor: Scorpion Therapeutics, a wholly owned subsidiary of Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open