STX-478 May Show Preferential Binding in PI3K-Mutated Solid Tumors
STX-478 may avoid adverse effects associated with prior PI3K inhibitors that lack selectivity for the mutated protein vs the wild-type protein.
Alberto J. Montero, MD, MBA, CPHQ, spoke with CancerNetwork® about the rationale for evaluating treatment with STX-478, a novel mutant-selective PI3Ka inhibitor, in patients with advanced solid tumors as part of a phase 1 trial (NCT05768139).
Montero, clinical director of the Breast Cancer Medical Oncology Program and medical director of the Clinical Trials Unit at University Hospitals Seidman Cancer Center, and an associate professor of medicine at Case Western Reserve University School of Medicine, highlighted how PIK3CA is one of the commonly mutated genes in patients with solid tumors, particularly among those with breast cancer. Compared with previously designed PI3K inhibitors, Montero stated that STX-478 can preferentially bind to the mutated kinase domain protein of PI3Kα as well as the helical domain, which may minimize wild-type toxicities associated with other agents in the treatment class.
Based on previously reported findings, investigators of the phase 1 trial highlighted that STX-478 was well-tolerated among a high-risk patient population, which included those with diabetes and patients who cannot tolerate other PI3K inhibitors. Data also showed efficacy and multiple deepening responses in patients with both PIK3CA kinase and helical domain mutations.
Montero previously presented data from the phase 1 trial at the 2024 European Society for Medical Oncology Congress (ESMO).
Transcript:
The rationale for looking at STX-478, which is a mutation-specific PI3K inhibitor, is that PIK3CA, the gene that encodes the PI3K, is one of the most highly mutated genes in cancer and in solid tumors, particularly in breast cancer. The majority of mutations of that gene are in the kinase domain and also the helical domain: the 2 areas that are hot spot mutations in the gene. This drug, STX-478, preferentially binds to the mutated kinase domain protein as well as the helical domain. That was the rationale: because it's a commonly mutated gene. Thus far, prior PI3K-inhibiting drugs did not have selectivity for the mutated protein vs the wild-type protein, which is why they traditionally have more [adverse] effects.
Reference
Montero AJ, Giordano A, Jhaveri K, et al. First-in-human results of STX-478, a mutant-selective PI3Kα inhibitor, in advanced solid tumor patients. Ann Oncol. 2024;35(suppl 2):S1220.
