Potential Mutant-Selective PI3K-Alpha Inhibitor for Patients With PIK3CA-Mutant Solid Tumors And/or HR-Positive, HER2-Negative Breast Cancer
Results from a phase 1/2 study support STX-478, an oral allosteric, central nervous system-penetrant, mutant-selective PI3Ka inhibitor, as a potential best-in-class mutant-selective PI3Ka inhibitor.
These data will be presented by Dejan Juric, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, at the 2024 San Antonio Breast Cancer Symposium.
In this phase 1/2 study, patients with breast cancer and other solid tumors were randomized to receive either STX-478 monotherapy or STX-478 in combination with fulvestrant, or, for patients with advanced PIK3CA-mutant solid tumors and/or HR-positive, HER2-negative breast cancer, fulvestrant plus CDK4/6 inhibitors. As of June 21, 2024, there were 61 patients who were treated with STX-478 monotherapy between 20 mg to 160 mg daily. Patients were required to have a PIK3CA mutation. Patients with pre-diabetes, or Type 2 diabetes controlled on medication including insulin and those intolerant to PI3K pathway inhibitors were allowed.
Among the 61 patients, treatment-related adverse events occurring in ≥15% of patients, or of special interest, included fatigue (30%), hyperglycemia (23%), nausea (20%), diarrhea (15%), rash (10%), and neutropenia (0%). Adverse events associated with PI3Ka wild-type (hyperglycemia, diarrhea, and rash) were all grade 1/2. No patient discontinued due to an adverse event. Among 22 patients with HR-positive, HER2-negative breast cancer with measurable disease, the confirmed/unconfirmed overall response rate was 23%, with 68% of patients exhibiting radiographic tumor reductions. Among patients with other solid tumors, the overall response rate was 19%.
Study authors concluded “in heavily pre-treated patients, STX-478 was well tolerated, with infrequent grade 1/2 PIK3Ka [wild-type]-associated toxicities in a high-risk patient population including diabetic patients and those intolerant to PI3K pathway inhibitors.” They added that “monotherapy ORR generally exceeded historical comparisons to other PI3K inhibitors” and that “efficacy was observed in both PIK3CA kinase and helical domain mutations, which comprise of 80-90% of all PI3Ka mutations.”
Enrollment is ongoing for cohorts evaluating STX-478 in combination with fulvestrant or fulvestrant CDK4/6 inhibitors.
Source:
Juric D. First-in-human results of STX-478, a mutant-selective PI3K alpha inhibitor, in HR+ breast cancer and advanced solid tumor patients. Presented at 2024 SABCS. Dec 10-13, 2024; San Antonio, TX. Abstract: SESS-1084.