Dr Montero on Potential Advantages With STX-478 in PI3Kα-Mutant Solid Tumors

Alberto Montero, MD, MBA, CPHQ, clinical director, Breast Cancer Medical Oncology Program, University Hospitals Seidman Cancer Center; associate professor, medicine, Case Western Reserve University School of Medicine, discusses the mechanism of action as well as the potential advantages of treatment with the mutant-selective PI3Kα inhibitor STX-478. He also highlights unmet needs that this agent may address in PI3Kα-mutant solid tumors., including breast cancer.

STX-478 is an oral drug that confers several noteworthy advantages across tumor types, Montero begins. Firstly, it has a long half-life, allowing for once-daily dosing and continuous pathway inhibition, as supported by pharmacokinetic data, he states. This extended half-life reduces the need for dose interruptions or reductions due to toxicity, which has been a limitation with other drugs in this class, Montero explains. Additionally, STX-478 is designed to cross the blood-brain barrier, addressing a significant challenge in metastatic breast cancer and other tumors prone to brain metastasis. Montero notes that this enhances its potential as a more effective treatment in these settings.

Another strength of STX-478 is its mutation-specific inhibition of kinase and helical domains, marking a proof of principle for targeted treatment of aberrantly activated pathways in diverse cancers, Montero continues. Although there are other PI3Kα inhibitors approved in breast cancer, the toxicity associated with these agents has limited their use, he says. STX-478’s reduced toxicity profile enables combination with endocrine therapies, presenting a safer and potentially more effective option for patients with PI3Kα-mutated tumors, Montero asserts.

Beyond breast cancer, STX-478 has also shown single-agent activity in uterine cancer, where PI3Kα mutations are prevalent, Montero reports. Though initial numbers are small, its efficacy is noteworthy, particularly given the limited therapeutic options available for endometrial cancer, he says. As a result, further trials are expected to expand on these early findings, potentially exploring both monotherapy and rational combinations. If the activity holds up, STX-478 may represent a meaningful advance for patients with limited options, particularly in breast and uterine cancers, Montero says. He adds that the agent may also pave the way for improved mutation-specific PI3K inhibition in clinical practice.