Scorpion Therapeutics unveils promising Phase 1/2 clinical data for STX-478 in advanced solid tumors

Scorpion Therapeutics, Inc. has presented initial clinical data from its Phase 1/2 trial of STX-478, a mutant-selective PI3Kα inhibitor for the treatment of advanced solid tumors, at the European Society for Medical Oncology (ESMO) Congress 2024 in Barcelona, Spain. The data reveals that STX-478 demonstrated a potentially best-in-class inhibition profile, with significant anti-tumor activity across multiple cancer types, including hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer, gynaecological tumors, and other solid tumors.

Key Findings: Efficacy and Safety of STX-478

The clinical trial data show that STX-478, when administered as a monotherapy, achieved an overall response rate (ORR) of 23% in HR+/HER2- breast cancer and 21% in all tumors, underscoring its potential as a strong contender in precision oncology. Tumor reductions were observed in 72% of patients, while 86% of evaluable patients demonstrated a decline in mutant PIK3CA circulating tumor DNA (ctDNA) levels.

Moreover, the drug was well-tolerated in a high-risk, heavily pre-treated patient population, including those with pre-diabetes and diabetes. Notably, STX-478 exhibited minimal wild-type (WT) PI3Kα-mediated toxicities, a common drawback in existing PI3Kα inhibitors. The trial results showed no treatment discontinuations due to adverse events, highlighting its favourable safety profile.

Adam Friedman, M.D., Ph.D., Chief Executive Officer of Scorpion Therapeutics, remarked, “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.” Friedman emphasised that these results suggest STX-478 could overcome the limitations of current pathway inhibitors and improve clinical outcomes for patients with PI3Kα kinase or helical domain-mutated solid tumors.

Comparative Advantages Over Existing Therapies

The data presented at ESMO highlights that STX-478 achieves several-fold deeper target inhibition than other approved or investigational PI3Kα inhibitors while avoiding their dose-limiting toxicities, such as hyperglycemia, rash, and diarrhoea. Alberto J. Montero, M.D., a trial investigator, pointed out, “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.”

Preliminary pharmacokinetic analyses support once-daily dosing of STX-478, with linear plasma exposure and a half-life of approximately 60 hours. At doses of 40 mg or higher, STX-478 surpassed the average exposures needed for efficacy in preclinical models and achieved target coverage several times higher than other PI3Kα inhibitors.

Safety and Tolerability

In terms of safety, STX-478 was well-tolerated even among patients who were excluded from other PI3Kα studies due to pre-existing conditions like diabetes or intolerance to other pathway inhibitors. The most common treatment-related adverse events (TRAEs) included fatigue (30%), hyperglycemia (23%), nausea (20%), and diarrhoea (15%), with most being mild to moderate and transient. No Grade 3 or higher PI3Kα WT toxicity adverse events were reported.

Ongoing Development and Future Directions

The trial is actively enrolling patients, including those with HR+/HER2- breast cancer in combination with fulvestrant and CDK4/6 inhibitors. Scorpion Therapeutics is expanding its clinical program to include multiple solid tumors to assess the broader potential of STX-478 as both a monotherapy and in combination with standard-of-care agents.

Mark Chao, M.D., Ph.D., Chief Medical Officer of Scorpion, stated, “These exciting data bolster our confidence in the profile of STX-478 and in the continued advancement of the trial as we actively enrol patients into ongoing multiple expansion cohorts across a range of solid tumors.”

Scorpion Therapeutics’ promising Phase 1/2 data for STX-478 suggests a significant advancement in the treatment of PI3Kα-mutant solid tumors. The mutant-selective, WT-sparing properties of STX-478 could potentially address a critical unmet need in oncology, offering a new avenue for patients with limited treatment options. As enrolment continues and more data emerge, STX-478 might set a new standard for targeted cancer therapies.