Alberto Montero, MD, MBA, CPHQ, discusses the mechanism of action and potential advantages of the mutant-selective PI3Kα inhibitor STX-478 in breast cancer.

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 

-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 

Beyond breast cancer, STX-478 has also shown single-agent activity in uterine cancer, where 

 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.

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Alberto Montero, MD, MBA, CPHQ, discusses the mechanism of action and potential advantages of the mutant-selective PI3Kα inhibitor STX-478 in 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 significance of the FDA approval of elacestrant (Orserdu) in patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer.

On January 27, 2023, the FDA granted approval to elacestrant in adults with ER-positive, HER2-negative, 

-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy. The approval was supported by findings from the phase 3 EMERALD trial (NCT03778931), in which patients with ER-positive, HER2-negative advanced breast cancer who had received 1 or 2 lines of prior endocrine therapy, including a CDK4/6 inhibitor, were randomized to receive either elacestrant or standard-of-care (SOC) endocrine monotherapy with either aromatase inhibitors or fulvestrant (Faslodex).

Dr. Montero on the Significance of an Oral SERD in Breast Cancer

This approval is significant because elacestrant is the first oral selective estrogen receptor degrader (SERD) to be approved in breast cancer, Montero says. Another SERD, fulvestrant, which is administered through intramuscular injection, is already approved in patients with ER-positive, HER2-negative breast cancer, Montero notes. Additionally, elacestrant is the first agent to be approved for patients in this population with 

 mutations, which are a common mechanism of resistance in ER-positive breast cancer, Montero explains.

Dr. Montero on Key Efficacy Data From EMERALD

In the EMERALD study, treatment with elacestrant prolonged progression-free survival (PFS) in all patients, with a HR of 0.70, Montero says. The respective 6- and 12-month PFS rates were 34.3% and 22.3% in patients who received elacestrant vs 20.4% and 9.4% in patients who received SOC.

 mutations also derived greater benefit from elacestrant, with an HR of 0.55 and 6- and 12-month PFS rates of 40.8% and 26.8% vs 19.1% and 8.2% in patients who received SOC, Montero emphasizes. These positive findings in the population with 

 mutations influenced the indication on the FDA label, Montero says.

When comparing elacestrant to fulvestrant specifically, in the entire study population, the respective 6- and 12-month PFS rates were 34.3% and 22.3% with elacestrant vs 22.9% and 10.2% with fulvestrant. Although elacestrant and fulvestrant are both SERDs, these data show elacestrant to be the more favorable option in patients with ER-positive, HER2-negative breast cancer, regardless of 

Alberto Montero, MD, MBA, CPHQ, discusses the significance of the FDA approval of elacestrant in patients with estrogen receptor–positive, HER2-negative metastatic breast cancer.

Alberto Montero, MD, MBA, CPHQ

Articles

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

Dr. Montero on the FDA Approval of Elacestrant in ER+/HER2– Breast Cancer