tersolisib (LY4064809) / Eli Lilly - LARVOL DELTA

First-in-human results of STX-478, a mutant-selective PI3Ka inhibitor, in advanced solid tumor patients (ESMO 2024) - P1/2 | "In heavily pre-treated patients, STX-478 was well-tolerated with favorable PI3Kα WT toxicity, including in diabetic patients or those intolerant to PI3K inhibitors. STX-478 was active in breast and non-breast cancers, with an ORR exceeding historical comparisons to other PI3K inhibitors. Enrollment is ongoing."

Clinical • Late-breaking abstract • Metastases • P1 data • Breast Cancer • Colorectal Cancer • Gynecologic Cancers • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • 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

PIKALO-1: First-in-Human Study of Tersolisib (STX-478) as Monotherapy and in Combination With Other Antineoplastic Agents in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=400 | Recruiting | Sponsor: Scorpion Therapeutics, Inc. | N=220 ➔ 400 | Trial completion date: Jun 2026 ➔ Apr 2028

Enrollment change • First-in-human • Monotherapy • Trial completion date • Breast Cancer • Head and Neck Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • PI3K

PIKALO-1: First-in-Human Study of Tersolisib (STX-478) as Monotherapy and in Combination With Other Antineoplastic Agents in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=160 | Recruiting | Sponsor: Scorpion Therapeutics, Inc.

First-in-human • Monotherapy • New P1/2 trial • Breast Cancer • Head and Neck Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • PI3K

PIKALO-1: First-in-Human Study of Tersolisib (STX-478) as Monotherapy and in Combination With Other Antineoplastic Agents in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=880 | Recruiting | Sponsor: Eli Lilly and Company | N=178 ➔ 880

Enrollment change • First-in-human • Monotherapy • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • PI3K

PIKALO-1: First-in-Human Study of Tersolisib (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 • PI3K

PIKALO-1: First-in-Human Study of Tersolisib (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 • First-in-human • Monotherapy • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • PI3K

PIKALO-1: First-in-Human Study of Tersolisib (STX-478) as Monotherapy and in Combination With Other Antineoplastic Agents in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=400 | Recruiting | Sponsor: Scorpion Therapeutics, Inc. | Trial completion date: Apr 2028 ➔ Feb 2029 | Trial primary completion date: Apr 2026 ➔ Feb 2027

First-in-human • Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Head and Neck Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • PI3K

PIKALO-1: First-in-Human Study of Tersolisib (STX-478) as Monotherapy and in Combination With Other Antineoplastic Agents in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=220 | Recruiting | Sponsor: Scorpion Therapeutics, Inc. | N=160 ➔ 220

Enrollment change • First-in-human • Monotherapy • Breast Cancer • Head and Neck Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • PI3K

A Study of Food Effect on Tersolisib (LY4064809) in Healthy Participants (clinicaltrials.gov) - P1 | N=60 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion

A Study of Food Effect on Tersolisib (LY4064809) in Healthy Participants (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open

A Study of Food Effect on Tersolisib (LY4064809) in Healthy Participants (clinicaltrials.gov) - P1 | N=60 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P1 trial

A Study of Food Effect on Tersolisib (LY4064809) in Healthy Participants (clinicaltrials.gov) - P1 | N=60 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed

PIKALO-2: A Study of Tersolisib (LY4064809/STX-478) 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 | N=274 ➔ 920

Enrollment change • Trial initiation date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR • PIK3CA

PIKALO-2: A Study of Tersolisib (LY4064809/STX-478) With Other Anti-Cancer Treatments in Participants With Advanced Breast Cancer With a Genetic Change (PIK3CA) (clinicaltrials.gov) - P3 | N=193 | Recruiting | Sponsor: Eli Lilly and Company

New P3 trial • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR • PIK3CA

PIKALO-2: A Study of Tersolisib (LY4064809/STX-478) 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 • ER • HER-2 • PGR • PIK3CA

PIKALO-2: A Study of Tersolisib (LY4064809/STX-478) 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 • ER • HER-2 • PGR • PIK3CA

Molecular architecture responsible for specific inhibition of oncogenic PI3Kα mutants by RLY-2608 and STX-478. (PubMed, Acta Pharm Sin B) - "While both inhibitors occupy this pocket, they have distinct interaction networks and propagate divergent allosteric activities: RLY-2608 induces large-scale remodeling of catalytic and membrane-interacting elements, whereas STX-478 reinforces autoinhibitory interfaces between p110α and p85α subunits. Comparative analysis provides structural insights into their differentiated potency and selectivity."

Journal • Oncology • PIK3CA

A patent review of mutant-selective PI3Kα inhibitors for the treatment of different cancers (2021 - 2025). (PubMed, Expert Opin Ther Pat) - "Specifically, we examine the binding modes across two distinct allosteric domains: an H1047R-specific pocket (exemplified by Eli Lilly's inhibitors) and a pan-mutant cryptic site (engaged by RLY-2608 and STX-478). Furthermore, development of allosteric inhibitor based PROTACs is discussed as a promising frontier for enhancing therapeutic precision. Ultimately, deeper understanding of evolving resistance mechanisms provides the design principles required to develop next-generation PI3Kα therapeutics capable of overcoming clinical resistance."

Journal • Review • Oncology • Solid Tumor • PIK3CA

A phase 1/2 trial of tersolisib (LY4064809/STX-478), a pan-mutant-selective PI3Kα inhibitor (PI3Kαi), in PIK3CA-mutant advanced solid tumors: Updated results from PIKALO-1. (ASCO 2026) - P1/2, P3 | " PIKALO-1 enrolled pts to receive terso (≥1 prior treatment [tx]), terso + fulvestrant (fulv, 1-2 prior txs), or terso + fulv/imlunestrant (imlu) and CDK4/6i (≤2 prior txs)...palbociclib, ribociclib, abemaciclib. Terso, alone or combined with fulv ± CDK4/6i, continues to be well-tolerated, with lower incidence of PI3Ki-class toxicities and no 3 HG in pts with normal baseline glycemic control. Target engagement was robust and clinical benefit continues to mature favorably in heavily pretreated pts with PIK3CAm HR+ HER2- ABC, supporting further study in the Phase 3 PIKALO-2 trial (NCT07174336). Efficacy summary."

Metastases • P1/2 data • Breast Cancer • Dental Disorders • HER2 Breast Cancer • HER2 Positive Breast Cancer • Metabolic Disorders • Neutropenia • Oncology • Solid Tumor • Stomatitis • CDK4 • HER-2 • PIK3CA

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 Study of [14C]-LY4064809 in Healthy Participants (clinicaltrials.gov) - P1 | N=7 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion

A Study of [14C]-LY4064809 in Healthy Participants (clinicaltrials.gov) - P1 | N=8 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed

KAT6i prifetrastat combines with PI3K pathway inhibitors to drive superior efficacy in preclinical models of PIK3CA mutated ER+ BC (AACR 2026) - "In vitro drug combination studies demonstrate synergy between prifetrastat and several PI3Kα inhibitors including alpelisib and inavolisib as well as mutant selective PI3Kα inhibitors such as tersolisib across cell lines harboring PIK3CA helical or kinase domain mutations. Finally, the triple combination of prifetrastat + Fulvesterant with PI3Kα inhibitors drives deeper tumor growth inhibition in PIK3CA mutant ER+ PDX models in vivo. Overall, we find that KAT6A/B inhibitors can effectively be combined with PI3Kα inhibitors and endocrine therapy to further drive efficacy in PIK3CA-mutant ER+BC indicating that the triplet combination could present a promising therapeutic option for this population."

Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • KAT6A • KAT6B • PIK3CA

Identification and characterization of pan-mutant selective PI3Kα inhibitors with the capability of PI3Kα H1047R protein degradation (AACR 2026) - P3 | "Orthosteric inhibitors of PI3Kα, such as alpelisib and inavolisib, have been approved for the treatment of patients with advanced HR+/HER2− breast cancer... Several allosteric and potent pan-mutant PI3Kα inhibitors developed by TYK Medicines exhibited high selectivity over wild-type (WT) PI3Kα. Our observations revealed that the compounds inhibited AKT phosphorylation in the T47D (PI3Kα H1047R) cell line with an IC50 in the single-digit nanomolar range, demonstrating nearly 200 times more selectivity compared to SK-BR-3 (PI3Kα WT) cells at same time. In in vitro antiproliferative assays, the compounds displayed superior antiproliferative activity against various PI3Kα mutant cells, including T47D, HCC1954 (PI3Kα H1047R), and MCF7 (PI3Kα E545K), compared to STX-478 and RLY-2608."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA