AKT Inhibitor May Overcome Chemotherapy Resistance in TNBC

A novel inhibitor that targets the AKT node in the PI3K pathway may offer a treatment option for patients with triple-negative breast cancer (TNBC) who are resistant to chemotherapy. The agent, ipatasertib, developed by Genentech, is being tested in combination with paclitaxel in the randomized phase II/III IPATunity130 clinical trial (NCT03337724).

RATIONALE

Patients with mutations in the PIK3CA, AKT1, or PTEN gene tend to have chemotherapy-resistant TNBC. “The PI3K/AKT pathway is very strongly activated in TNBC, and when you have these alterations, they send strong survival signals [to the cancer], and the cancer cells can survive the onslaught of chemotherapy that we rely on to treat patients in the metastatic setting,” said Joyce O’Shaughnessy, MD, an investigator and a member of the steering committee for the IPATunity130 trial.

Investigators believe that ipatasertib (RG7440) may demonstrate ability to overcome resistance to chemotherapy, which is standard of care for patients with TNBC. Patients with TNBC who are resistant to chemotherapy have limited options for treatment, according to O’Shaughnessy, Celebrating Women Chair in Breast Cancer Research and chair, Breast Cancer Research Program, Baylor University Medical Center, Texas Oncology and US Oncology.

Prior trial results have confirmed the value of combining ipatasertib and paclitaxel for patients who have the relevant gene alterations. If the combination proves successful in the IPATunity130 trial, it could represent an opportunity to build a new platform for treatment of patients with TNBC and PIK3CA/AKT1/PTEN mutations. “If this is successful in a molecularly selected population, the next logical step, in my mind, would be to build a triplet of nab-paclitaxel, ipatasertib, and atezolizumab for a molecularly selected population,” O’Shaughnessy said.”

TRIAL DESIGN

Prior to randomization, patients will be centrally tested for alterations in the PIK3CA/AKT1/ PTEN genes, and for enrollment they must have alterations in at least 1 of these genes. This is because ipatasertib inhibits AKT, a key component of the PI3K pathway that is dysregulated by the loss of the tumor-suppressor PTEN gene.

In the assessment of whether there is a survival benefit with ipatasertib and paclitaxel, the primary endpoint is progression-free survival, with objective response rate, duration of response, clinical benefit rate, and overall survival as secondary endpoints.

WHO IS ELIGIBLE?

The trial is enrolling patients who have locally advanced or metastatic TNBC or hormone receptor—positive, HER2–negative breast cancer. Patients must also have an ECOG performance status of 0 or 1, no previous chemotherapy, and history of known presence of metastases in the brain or spinal cord.

REFERENCE

Ipatasertib (GDC-0068, RG7440). Genentech/Biooncology website. biooncology.com/pipeline-molecules/ipatasertib. html. Accessed March 8, 2018.