FDA Grants Fast Track Designation to ETX-636 for PIK3CA-Mutant, HR+/HER2-Negative Breast Cancer

October 1, 2025

ETX-636, a selective PI3Kα inhibitor, has received FDA fast track designation for PIK3CA-mutant, HR-positive, HER2-negative advanced breast cancer.

The FDA has granted fast track designation to the pan mutant–specific allosteric PI3Kα inhibitor and degrader ETX-636 for the treatment of adult patients with PIK3CA-mutant, hormone receptor (HR)–positive, HER2-negative advanced breast cancer.1

This agent is currently being evaluated for patients with solid tumors in a first-in-human, phase 1/2 study (NCT06993844).

“Patients with advanced [HR-positive/HER2-negative] breast cancer harboring PIK3CA mutations have poor prognosis, and there is an unmet need for therapies targeting this population that are safer and more efficacious than the current FDA-approved non-mutant selective treatments,” Shengfang Jin, PhD, president, chief executive officer, and cofounder of Ensem Therapeutics Inc—the drug’s developer—stated in a news release. “We are appreciative that the FDA has recognized ETX-636 as a potentially important treatment for this indication, and we remain laser-focused on demonstrating its benefit to patients in our current clinical trials.”

ETX-636 is a novel, pan mutant–specific allosteric PI3Kα inhibitor and degrader that utilizes a dual mechanism of action, selectively inhibiting the enzyme and simultaneously leading to proteasome-dependent degradation of the mutant PI3Kα protein.
The FDA granted fast track designation to ETX-636 for the treatment of adult patients with PIK3CA-mutant, HR-positive, HER2-negative advanced breast cancer, a population currently in need of safer and more efficacious therapies than existing non-mutant selective treatments.
By engineering ETX-636 to selectively inhibit mutant PI3Kα and spare the wild-type form, the drug is expected to offer a significant therapeutic advantage over older generations of PI3Kα inhibitors by potentially reducing dose-limiting AEs like hyperglycemia.

What Are the Unique Advantages of ETX-636’s Dual Mechanism of Action?

ETX-636 is characterized by its highly selective approach to targeting PI3Kα. Utilizing Ensem’s proprietary Kinetic Ensemble platform, ETX-636 was designed to optimally fit into a specific allosteric binding site located in p110α, the catalytic subunit of PI3Kα.

Through this precise targeting, ETX-636 is engineered to selectively inhibit multiple activating mutant forms of PI3Kα and spare wild-type PI3Kα. This selectivity is intended to offer a significant therapeutic advantage over older generations of PI3Kα inhibitors, as non-mutant selective PI3Kα inhibitors often lead to dose-limiting adverse effects (AEs). By specifically targeting the mutant form, the selectivity of ETX-636 is expected to greatly reduce the risk for hyperglycemia and other AEs associated with the inhibition of wild-type PI3Kα.

In addition to inhibiting the enzyme, ETX-636 also leads to proteasome-dependent degradation of mutant PI3Kα. This degradation feature ensures that the active, disease-driving protein is not just temporarily inhibited but also physically eliminated from the cell, a characteristic not observed with other pan-mutant allosteric inhibitors.

What Is the Design of the Phase 1/2 Study Evaluating ETX-636?

The open-label, multicenter, phase 1/2 study is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of ETX-636 in patients with metastatic or locally advanced and unresectable solid tumors harboring a PIK3CA mutation.1,2

The study comprises 3 parts:2

Part A: Escalating doses of ETX-636 as monotherapy in patients with advanced solid tumors
Part B: Escalating doses of ETX-636 as combination therapy with a 500-mg fixed dose of fulvestrant administered intramuscularly to patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer
Part C: Combination therapy expansion cohort of patients in part B

The following eligibility criteria are required for all patients:

Progression on or after at least 1 available therapy
At least 1 measurable lesion or evaluable disease per RECIST 1.1 criteria
An ECOG performance status of 0 or 1
Adequate organ function

Patients enrolled onto parts B and C must also not be amenable to surgical resection with curative intent and must have received at least 1 prior CDK4/6 inhibitor and at least 1 prior anti-estrogen therapy.

The study’s primary end points are to evaluate the safety and tolerability of ETX-636 as monotherapy (part A) and in combination with fulvestrant (part B); identification of the recommended phase 2 dose (part B) for continued exploration in part C; and assessment of overall response rate and clinical benefit rate (part C) according to RECIST 1.1 criteria.

Secondary end points included pharmacokinetic, pharmacodynamic, safety, and other preliminary efficacy measures.

References

Ensem therapeutics announces ETX-636 granted fast track designation by the FDA for advanced breast cancer. News Release. Ensem. October 1, 2025. Accessed October 1, 2025. https://www.businesswire.com/news/home/20251001083267/en/Ensem-Therapeutics-Announces-ETX-636-Granted-Fast-Track-Designation-by-the-FDA-for-Advanced-Breast-Cancer
Phase 1/2 study of ETX-636 in participants with advanced solid tumors. ClinicalTrials.gov. Updated September 17, 2025. Accessed October 1, 2025. https://www.clinicaltrials.gov/study/NCT06993844