STX-478 May Improve Therapeutic Index Vs Other PI3K Inhibitors in Cancer

STX-478 has demonstrated clinical activity and tolerability among patients with solid tumors, signaling a new generation of drugs that may be capable of preferentially binding to mutated PI3K, according to Alberto J. Montero, MD, MBA, CPHQ.

CancerNetwork^® spoke with 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, about the implications of data from a phase 1 trial (NCT05768139) assessing treatment with STX-478 for patients with advanced solid tumors harboring PI3Kα mutations.

According to Montero, currently available PI3K inhibitors may be limited by a lack of specificity and toxicities associated with blocking wild-type PI3K. Developers designed STX-478 as an allosteric, mutant-selective PI3K inhibitor that selectively targets PI3Ka mutations, potentially reducing wild-type toxicities in the process. Based on the design of STX-478, Montero stated that the investigational agent may offer a better therapeutic index compared with prior PI3K inhibitors.

Montero previously presented data from the phase 1 trial at the 2024 European Society for Medical Oncology Congress (ESMO).

Transcript:

Much like in non–small cell lung cancer—[where] we have mutation-specific inhibitors for EGFR, which is an important target—one of the key take home messages of this trial is that we can rationally design drugs that specifically and preferentially target mutated PI3K to get that activity. It is a commonly mutated gene and a driver mutation in many solid tumors, but we’ve been limited by the lack of specificity and the [adverse] effects when we block the wild-type PI3K. The take-home message is that we have a newer generation of drugs that preferentially bind to the mutated protein. STX-478 has activity and is well-tolerated [with a] much better therapeutic index than what prior drugs that target PI3K have demonstrated.

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.