Scorpion Therapeutics Shares Early Phase 1/2 STX-478 Data Showing Promising PI3Kα Inhibition at ESMO 2024

Scorpion Therapeutics, Inc. ("Scorpion"), a pioneering clinical-stage oncology company, has announced promising initial results from its Phase 1/2 study of STX-478, an oral, once-daily, mutant-selective PI3Kα inhibitor. These results were presented at the European Society for Medical Oncology (ESMO) Congress 2024 in Barcelona, Spain. The study focuses on advanced solid tumor patients and demonstrates significant anti-tumor activity in various cancers, such as HR+/HER2- breast cancer, gynecological tumors, and other solid tumors.

STX-478 has shown potential as a best-in-class PI3Kα inhibitor due to its efficacy and safety profile. The drug was well-tolerated even among pre-diabetic, diabetic, and heavily pre-treated patients, without causing significant wild-type-mediated toxicities. According to Adam Friedman, M.D., Ph.D., Chief Executive Officer of Scorpion, the trial results suggest that STX-478 could overcome the limitations of existing pathway inhibitors, thereby improving clinical outcomes for patients with PI3Kα kinase or helical domain-mutated solid tumors.

Alberto J. Montero, M.D., a trial investigator affiliated with University Hospitals Cleveland, noted that non-selective PI3Kα inhibitors and AKT inhibitors have shown limited therapeutic benefits due to dose-limiting toxicities like hyperglycemia, rash, and diarrhea. In contrast, STX-478 selectively targets mutant PI3Kα, leading to deeper pathway inhibition without the associated toxicities. This could potentially improve the quality of life for patients during treatment, particularly those with breast cancer and other solid tumors.

In the Phase 1/2 study, 61 patients with kinase and helical domain PIK3CA mutations were treated with STX-478 at doses ranging from 20mg to 160mg daily. The data cutoff was on June 21, 2024. Among the participants, 29 had HR+/HER2- breast cancer, and 32 had other solid tumors. Additionally, 54% of the patients were pre-diabetic or diabetic, and a significant proportion had previously been treated with other PI3Kα inhibitors and CDK4/6 inhibitors. On average, patients had received three prior lines of therapy.

Pharmacokinetically, STX-478 supports once-daily dosing, with a linear and dose-proportional plasma exposure and an estimated half-life of approximately 60 hours. At doses of 40mg or higher, the drug achieved exposure levels several times greater than those needed for efficacy in preclinical models and surpassed those of other approved or investigational PI3Kα inhibitors. The maximum tolerated dose was determined to be 100mg daily.

Safety data from the trial indicated that STX-478 was well-tolerated, even among high-risk patients, including those with diabetes and pre-diabetes. Most treatment-related adverse events (TRAEs) were mild to moderate and transient. Common TRAEs included fatigue (30%), hyperglycemia (23%), nausea (20%), and diarrhea (15%). Importantly, no severe PI3Kα wild-type toxicity adverse events were observed.

As of the data cutoff, the overall response rate (ORR) was 23% in HR+/HER2- metastatic breast cancer patients, 21% across all tumor types, and 44% in gynecologic cancers. These rates compare favorably to existing PI3Kα pathway inhibitors, which have monotherapy ORRs of 4-6%. Tumor reductions were observed in 72% of patients, with multiple responses seen in both PI3Kα kinase and helical domain mutant tumors. Additionally, mutant PIK3CA circulating tumor DNA levels decreased significantly in 86% of evaluable patients.

Mark Chao, M.D., Ph.D., Chief Medical Officer of Scorpion, expressed confidence in the profile of STX-478 and emphasized the company's commitment to advancing the trial. Scorpion is actively enrolling patients into multiple expansion cohorts across various solid tumors and exploring combinations with standard care agents like fulvestrant and CDK4/6 inhibitors in HR+/HER2- breast cancer.

STX-478 has been designed to target PI3Kα mutations, which are prevalent drivers of cancer. The ongoing clinical trial aims to evaluate the safety and tolerability of STX-478 in patients with HR+/HER2- breast cancer and other solid tumors driven by these mutations. Scorpion's broader goal is to leverage its advanced platform to deliver optimized therapies for cancer patients, addressing a wide range of targets and improving clinical outcomes.