Scorpion Therapeutics presented initial Phase 1/2 clinical data for STX-478, a mutant-selective, allosteric PI3Kα inhibitor, at the European Society for Medical Oncology (ESMO) Congress 2024. The data suggest promising anti-tumor activity and tolerability in patients with advanced solid tumors.
The Phase 1/2 trial enrolled patients with advanced solid tumors, including HR+/HER2- breast cancer, gynecological tumors, and head and neck squamous cell carcinoma. STX-478, administered orally once daily, demonstrated an overall response rate (ORR) of 23% in HR+/HER2- metastatic breast cancer patients and 21% across all tumor types. Notably, a 44% ORR was observed in gynecologic cancers.
Safety and Tolerability
STX-478 was well-tolerated, even in a high-risk population including pre-diabetic, diabetic, and heavily pre-treated patients. Most treatment-related adverse events (TRAEs) were mild to moderate. Common TRAEs (≥15%) included fatigue (30%), hyperglycemia (23%), nausea (20%), and diarrhea (15%). Importantly, no Grade ≥ 3 PI3Kα wild-type toxicity adverse events (hyperglycemia, diarrhea, and rash) were observed, and no patients discontinued STX-478 due to TRAEs.
Pharmacokinetics and Target Inhibition
Pharmacokinetic analysis supports a once-daily dosing regimen for STX-478, with an estimated half-life of approximately 60 hours. At doses ≥ 40mg once daily, STX-478 achieved exposures several-fold higher than other approved or investigational PI3Kα inhibitors, suggesting robust target coverage. The maximum tolerated dose (MTD) was determined to be 100mg daily.
Clinical Significance
"STX-478 demonstrates potent and potentially best-in-class PI3Kα pathway inhibition as established by our early, differentiated signals of monotherapy efficacy, which exceed benchmarks of other pathway inhibitors," said Adam Friedman, M.D., Ph.D., Chief Executive Officer of Scorpion. The mutant-selective design of STX-478 aims to overcome the limitations of non-selective PI3K inhibitors, which often cause significant side effects due to wild-type PI3Kα inhibition.
Alberto J. Montero, M.D., trial investigator affiliated with University Hospitals Cleveland, noted, "By selectively targeting mutant PI3Kα, one of the most prevalent oncogenes in cancer, STX-478 has the potential to improve clinical outcomes and quality of life for patients during treatment."
Trial Details and Patient Population
The Phase 1/2 study included 61 patients with PIK3CA mutations. 54% of patients were pre-diabetic or diabetic, and 41% of breast cancer patients had prior PI3Kα pathway inhibitor treatment. 97% of breast cancer patients had previously received a CDK4/6 inhibitor. The median number of prior lines of therapy was three (ranging from 1-7).
Future Directions
Scorpion Therapeutics is actively enrolling patients into ongoing expansion cohorts across a range of solid tumors and in combinations with standard-of-care agents, including fulvestrant and CDK4/6 inhibitors in HR+/HER2- breast cancer. Further updates from the study are expected at future medical meetings.
