STX-478 / Eli Lilly - LARVOL DELTA

PIKALO-1: A phase 1/2 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) - No abstract available

Metastases • P1/2 data • Breast Cancer • Oncology • Solid Tumor • 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

A Study of LY4064809 [14C]-STX-478 in Healthy Male Participants (clinicaltrials.gov) - P1 | N=8 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P1 trial

In silico discovery of a novel potential allosteric PI3Kα inhibitor incorporating 2-oxopropyl urea targeting head and neck squamous cell carcinoma. (PubMed, BMC Chem) - "The allosteric PI3Kα inhibitor STX-478 inhibits the growth of tumor with hotspot mutations in PI3Kα and shows prominent efficacy on the treatment of human HNSCC xenografts without displaying the metabolic dysfunction observed in Alpelisib. After the SciFinder verification, J-53 with novel structure had the value of further study. This study suggested that J-53 could be used as potential inhibitors of PI3Kα, and provides valuable information for the subsequent drug discovery of allosteric PI3Kα inhibitors."

Journal • Head and Neck Cancer • Metabolic Disorders • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PIK3CA

Lilly to acquire Scorpion Therapeutics' mutant-selective PI3Kα inhibitor program (PRNewswire) - "Eli Lilly and Company...and Scorpion Therapeutics...announced a definitive agreement for Lilly to acquire Scorpion's PI3Kα inhibitor program STX-478. STX-478 is a once-daily oral, mutant-selective PI3Kα inhibitor currently being evaluated in a Phase 1/2 clinical trial for breast cancer and other advanced solid tumors....Under the terms of the agreement, Lilly will acquire Scorpion and Scorpion shareholders could receive up to $2.5 billion in cash, inclusive of an upfront payment and subsequent payments upon achievement of certain regulatory and sales milestones. Additionally, as part of the transaction, Scorpion will spin out a new entity to hold its employees and non-PI3Kα pipeline assets. The new, independent company would be owned by Scorpion's current shareholders with Lilly holding a minority equity interest."

M&A • Breast Cancer

Discovery and characterization of ETX-636, a potential best-in-class, oral, small molecule, pan-mutant-selective PI3Kα inhibitor (SABCS 2024) - "Cancer cells with PIK3CA activating mutations are dependent on PI3Kα signaling and HR-positive, HER2-negative breast cancer patients with PIK3CA mutations respond to alpelisib, an approved PI3Kα inhibitor...Compared to other allosteric, pan-mutant-selective PI3Kα inhibitors (ie RLY-2608 and STX-478), ETX-636 has stronger target binding affinity, better on-target potency in biochemical and cellular pharmacodynamic and viability assays, and demonstrates superior anti-tumor activity in vivo...In an ER-positive, HER2-negative, PI3Kα-mutant breast cancer xenograft model, ETX-636 is efficacious as a single agent and shows enhanced activity in combination with fulvestrant, inducing consistent tumor regression while being well-tolerated...In addition, based on pharmacokinetic/pharmacodynamic/efficacy and toxicology studies, ETX-636 is unlikely to pose a significant risk of hyperglycemia at predicted human efficacious doses. These data support clinical exploration of ETX-636 in..."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • ER • HER-2 • PIK3CA

Expansion Study Collaboration Updates (Businesswire) - "Scorpion Therapeutics and Pfizer Inc...entered into a new clinical trial collaboration and supply agreement to evaluate atirmociclib...in combination with STX-478 and fulvestrant in patients with PI3Kα-mutated, HR+/HER2- metastatic breast cancer in the frontline metastatic setting. Under the terms of the agreement, Scorpion and Pfizer will equally share the development costs of the study. In addition, Pfizer will supply atirmociclib for use in the study and Scorpion will manage the conduct of the study. The STX-478 + atirmociclib + fulvestrant triplet combination is planned to begin in 2H25."

Commercial • Trial status • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

Data from the Phase 1/2 Study of STX-478 in Advanced Solid Tumors at SABCS 2024 (Businesswire) - P1/2 | N=400 | NCT05768139 | Sponsor: Scorpion Therapeutics, Inc. | "Scorpion has shown in Phase 1 monotherapy data that STX-478, an oral, once-daily, mutant-selective, allosteric PI3Kα inhibitor, demonstrated robust PI3Kα pathway inhibition as a monotherapy, with anti-tumor activity observed in multiple cancer types, including a 23% overall response rate (ORR) in HR+/HER2- breast cancer (BC) and a 44% ORR in gynecological tumors, amongst others. STX-478 was well-tolerated, including in pre-diabetic, diabetic and heavily pre-treated patients and showed minimal significant wild-type-mediated toxicities."

P1 data • Breast Cancer • Gynecologic Cancers • Oncology

First-in-human results of STX-478, a mutant-selective PI3K alpha inhibitor, in HR+ breast cancer and advanced solid tumor patients. (SABCS 2024) - "In heavily pre-treated patients, STX-478 was well tolerated, with infrequent Grade 1/2 PI3Ka WT-associated toxicities in a high-risk patient population including diabetic patients and those intolerant to PI3K pathway inhibitors. STX-478 was active in HR+ BC and other solid tumors, with a monotherapy ORR generally exceeding historical comparisons to other PI3K inhibitors. Efficacy was observed in both PIK3CA kinase and helical domain mutations, which comprise of 80-90% of all PI3Ka mutations."

Clinical • Metastases • P1 data • 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 • HER-2 • PIK3CA

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

Scorpion Therapeutics Presents Initial Clinical Data From Its Phase 1/2 Trial of STX-478 Demonstrating Potentially Best-in-Class Mutant-Selective PI3Kα Inhibition for the Treatment of Advanced Solid Tumors at ESMO Congress 2024 (Businesswire) - P1/2 | N=400 | NCT05768139 | Sponsor: Scorpion Therapeutics, Inc. | "Scorpion Therapeutics...presented initial, first-in-human clinical results from its Phase 1/2 study of STX-478 in advanced solid tumor patients in a Proffered Paper late-breaking session at the European Society for Medical Oncology...Congress 2024 in Barcelona, Spain...Of the enrolled patients, 29 patients had HR+/HER2- BC and 32 patients had other solid tumors...Preliminary pharmacokinetic analysis supports once-daily dosing of STX-478, with dose proportional and linear STX-478 plasma exposure and an estimated half-life of approximately 60 hours....As of the data cutoff in 43 evaluable patients, the confirmed/unconfirmed overall response rate (ORR) was 23% (5/22) in HR+/HER2- metastatic breast cancer; 21% (9/43) in all tumor types; and 44% (4/9) in gynecologic cancers, which compares favorably to approved PI3Kα pathway inhibitors (monotherapy ORR 4 – 6%)."

P1/2 data • PK/PD data • Breast Cancer • Gynecologic Cancers • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

Free energy landscape of the PI3Kα C-terminal activation. (PubMed, Comput Struct Biotechnol J) - "Moreover, we show that in the H1047R mutant, the cavity, where the allosteric ligands STX-478 and RLY-2608 bind, is more accessible contrary to the WT. This study provides insights into the molecular mechanisms underlying activation of oncogenic PI3Kα by C-terminal mutations and represents a valuable resource for continued efforts in the development of mutant selective inhibitors as therapeutics."

Journal • Oncology • PIK3CA

Scorpion Therapeutics to Present STX-478 Initial Phase 1/2 Data at ESMO Congress 2024 (Businesswire) - "Scorpion Therapeutics...announced that it was selected to present initial, first-in-human clinical results from the Phase 1/2 study of STX-478, a mutant-selective PI3Kα inhibitor, in advanced solid tumor patients in a Proffered Paper late-breaking session at the European Society for Medical Oncology ('ESMO') Congress 2024....'These initial data will provide early insight into how STX-478's differentiated profile translates to potentially superior outcomes in PI3Kα-mutated cancers, and we look forward to presenting initial assessments of safety, pharmacokinetic and pharmacodynamic data and preliminary efficacy data at the ESMO 2024 Congress'."

P1/2 data • Solid Tumor

Scorpion Therapeutics Announces $150 Million Series C Financing to Advance Leading Clinical-stage Precision Oncology Pipeline (Businesswire) - "Scorpion Therapeutics, Inc...announced the closing of a $150 million Series C financing....Scorpion plans to use the proceeds from this financing to advance its pipeline of differentiated small molecule oncology programs, in particular, to expand clinical development of its allosteric, differentiated, mutant-selective PI3Kα inhibitor, STX-478. Further, the Company will continue to advance its clinical-stage EGFR inhibitor franchise, including STX-721 and STX-241, and its discovery pipeline of next-generation precision oncology therapies."

Financing • Oncology • Solid Tumor

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=400 | Recruiting | Sponsor: Scorpion Therapeutics, Inc. | Trial completion date: Apr 2028 ➔ Feb 2029 | Trial primary completion date: Apr 2026 ➔ Feb 2027

Combination therapy • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Gynecologic Cancers • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • PIK3CA

Strategies to overcome resistance to PI3Kalpha-selective inhibitors mediated by acquired alterations in the PI3K/AKT pathway (AACR 2024) - "The PI3Kα-selective orthosteric inhibitor alpelisib is the only drug targeting PIK3CA currently approved in this patient population, in combination with fulvestrant...Among them, we have identified for the first-time secondary mutations in PIK3CA (W780R and Q859K) that decrease the affinity of the PI3Kα-selective inhibitors alpelisib and inavolisib, leading to acquired resistance...Importantly, vertical pathway inhibition or allosteric inhibition with pan-mutant-selective PI3Kα inhibitors such as RLY-2608 or STX-478 could overcome resistance induced by all emerging secondary PIK3CA mutations.Dose-limiting toxicity in the form of hyperglycemia, rash or gastrointestinal issues are common in patients treated with orthosteric PI3Kα inhibitors...Our work suggests that combining orthosteric and allosteric PI3Kα inhibitors as well as downstream pathway deactivation with AKT inhibitors could result in an increased therapeutic index and delay the emergence of resistance in..."

Late-breaking abstract • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA