STX-478 Phase 1/2 Trial Shows Promising Clinical Progress, With New Pfizer Partnership Targeting Advanced Breast Cancer

Scorpion Therapeutics has unveiled significant developments in its STX-478 program, presenting updated Phase 1/2 clinical data at the San Antonio Breast Cancer Symposium 2024 and announcing a pivotal collaboration with Pfizer to accelerate combination therapy approaches in PI3Kα-mutated hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer.

Clinical Data Demonstrates STX-478’s Favorable Safety Profile and Dose-Response Efficacy

Recent analyses from the ongoing Phase 1/2 study reveal that STX-478, an oral mutant-selective PI3Kα inhibitor, exhibits a robust safety profile with minimal dose modifications required across patient populations. Notably, the trial recorded zero patient discontinuations attributable to adverse events, a significant finding in precision oncology development.

The monotherapy efficacy data supports a clear dose-response relationship in HR+/HER2- breast cancer patients, correlating with strong PI3Kα pathway target coverage. As a single agent, STX-478 demonstrated a 23% overall response rate in this breast cancer population and achieved a 44% response rate in gynecological tumors. The compound exhibited excellent tolerability even in pre-diabetic, diabetic, and heavily pre-treated patient cohorts, with minimal wild-type-mediated toxicities—a critical advantage over existing non-mutant-selective inhibitors currently available in clinical practice.

Strategic Partnership With Pfizer Expands STX-478 Development

Under a newly established clinical trial collaboration and supply agreement, Scorpion and Pfizer will jointly investigate STX-478 in combination with atirmociclib (Pfizer’s selective CDK4 inhibitor) and fulvestrant. This triplet combination targets frontline treatment of PI3Kα-mutated HR+/HER2- metastatic breast cancer, with trial initiation scheduled for the second half of 2025.

Per the agreement terms, both companies will equally bear development costs. Pfizer will provide atirmociclib supply while Scorpion assumes operational responsibility for study conduct. This partnership structure reflects growing industry recognition of the synergistic potential between PI3Kα pathway inhibition, estrogen receptor antagonism, and CDK4/6 blockade in hormone receptor-positive breast cancer.

Ongoing Combination Cohorts Expanding Treatment Options

Beyond the Pfizer collaboration, Scorpion maintains active enrollment in combination studies evaluating STX-478 paired with fulvestrant as a doublet therapy, and with fulvestrant plus CDK4/6 inhibitors as a triplet approach in second-line and frontline HR+/HER2- breast cancer settings respectively. These expansion cohorts represent a systematic evaluation of multi-targeted strategies within the precision oncology framework.

STX-478 Addresses Significant Clinical Unmet Need

STX-478 targets PI3Kα mutations, one of the most prevalent oncogenic alterations across solid tumors, affecting over 166,000 annual new cases in the United States across breast, gynecological, and other cancer types. The compound’s wild-type-sparing mechanism differentiates it from first-generation PI3K pathway inhibitors by potentially delivering sustained deeper responses with reduced treatment burden.

The drug’s CNS-penetrant properties and oral once-daily formulation further enhance its clinical utility compared to available alternatives. Current development encompasses both kinase domain and helical domain PI3Kα mutations, with patient populations spanning those previously treated with alpelisib and pathway-inhibitor naive individuals.