Novel PI3Kα Inhibitor STX-478 Offers Precise Treatment and Reduced Toxicity for Solid Tumors

In an interview with OncLive^®, Alberto Montero, MD, MBA, discussed the importance of PI3Kα pathway inhibition in solid tumors and highlighted how STX-478, a mutation-specific PI3Kα inhibitor targeting kinase and helical domain mutations, could uniquely address several limitations of earlier PI3K inhibitors.

“The field has moved towards a more mutation-specific inhibitor,” said Montero. “I believe that is going to open the ability to target this hugely important pathway in cancer and enhance the therapeutic index; [this approach could] block the pathway but have less toxicity at the same time.”

In a concurrent article, Montero detailed current results and future investigations with STX-478 in PIK3CA-mutant breast and gynecologic cancers.

Montero is clinical director of the Breast Cancer Medical Oncology Program and the Diana Hyland Chair for Breast Cancer at University Hospitals Seidman Cancer Center in Cleveland, Ohio. He is also an associate professor of medicine at Case Western Reserve University School of Medicine in Cleveland.

OncLive: What makes STX-478 different from previously evaluated α-specific inhibitors of the PI3K pathway?

Montero: What differentiates STX-478 from [other] PI3K inhibitors is that it’s mutation specific, so the drug has been designed to preferentially bind to the kinase domain as well as the helical domain; those are hotspot mutations in the gene that represent the majority—in the literature there’s a little debate [on whether] it’s 80% or 70%—of PIK3CA mutations. Because [STX-478] preferentially binds to the mutated protein, [investigators] did not see the metabolic toxicities associated with PI3K inhibitors, such as hyperglycemia and mucositis, at least in preclinical studies. That’s the rationale for [developing] this compound.

Why is PI3Kα pathway inhibition an important avenue for targeted therapy development within oncology?

[PI3Kα] activation is common; it’s in most breast cancers but it is also hugely important in other solid tumors. The limitation of that biologic understanding is [in the oncology field’s ability] to develop drugs that target PI3Kα but don’t have such toxicity that you have to discontinue or lower the dose [for patients]. That’s been the limiting factor because drugs like alpelisib [Piqray], which was the first [PI3K inhibitor] to be FDA approved for breast cancer, improved survival in combination with endocrine therapy, which not every drug does. However, it [is associated with] significant toxicities, and a lot of patients had to discontinue [treatment due to] severe hyperglycemia, mucositis, rash, and diarrhea. [The question is]: How can we improve on that?

​​What is the mechanism of action of STX-478?

It’s an oral drug. One of the advantages of STX-478 is it has a long half-life [of approximately 60 hours]. It’s given once daily, and the pharmacokinetic studies support that. One of the advantages [of this agent] is that you can get continuous blockade of the pathway because of its long half-life, [and] it doesn’t have the toxicities we’ve seen with the other [similar drugs].

The other [notable characteristic] is that the chemistry of the compound is such that STX-478 crosses the blood-brain barrier, so that’s another advantage because brain metastases are a common problem in breast cancer and other metastatic solid tumors.

In the phase 1 [portion of the phase 1/2 trial (NCT05768139) evaluating STX-478 in patients with advanced solid tumors], there [have not been] many patients with brain metastases. As the trial continues and more patients are enrolled, [we’re] eagerly looking to see [if there’s activity in that population] but at this point we don’t have enough clinical data. [What we know is] based on the chemistry and preclinical data.

Overall, why are you optimistic about the potential utility of STK-478 in clinical practice?

Through well-designed research, we make a lot of progress. I’m fortunate to be part of research [evaluating STX-478], and I’m excited that scientists have developed a drug that can target the mutated PI3K protein that doesn’t have the toxicities we’re used to seeing with other drugs that have decreased our enthusiasm for using [those drugs]. I’m enthusiastic for this drug and drugs like [it] that can specifically target a mutated protein and spare the toxic off-target effects of the native, non-mutated protein.