There are few therapeutic options for women with metastatic breast cancer, especially those with hormone receptor positive and human epidermal growth factor receptor 2 negative disease that does not respond to endocrine therapy. For many years, patients with hormone receptor positive and HER2 negative disease were treated with endocrine therapy in hopes of inhibiting estrogen, which fuels cell growth and spread. However, these treatments eventually stop working for most patients.

More recently, CDK4/6 inhibitors have been added to endocrine therapy. These inhibitors block the activity of two enzymes, CDK4 and CDK6, important in cell division. While successful at first, tumors eventually become resistant to the combination therapy.

“Acquired resistance has made it difficult to identify effective treatments for this patient population. We’re looking at tumor mutations and pathways in hopes of developing new targeted therapies to meet this need,” said Dr. Heather Han, research director and medical oncologist in Moffitt Cancer Center’s Department of Breast Oncology. She is also the principal investigator of a clinical trial evaluating a new treatment approach for hormone receptor positive and HER2 negative metastatic breast cancer patients whose disease has progressed after treatment with CDK4/6 and aromatase inhibitors.

VIKTORIA-1 is a phase 3 trial evaluating combination therapies including gedatolisib, an investigational drug that when given intravenously blocks the activity of a pathway inside the cell known as PI3K/mTOR. A prior phase 1 b study showed the triple combination using gedatolisib, palbociclib and endocrine therapy (fulvestrant or letrozole) is well tolerated with promising efficacy. PIK3CA mutations are common in breast cancer, occurring in up to 40% of tumors. It is considered a driver mutation, meaning it promotes the growth of tumor cells.

The trial opened in late 2022. The goal is to enroll 701 patients, regardless of PIK3CA mutational status. Eligible patients are assigned to one of three treatment arms depending on their PIK3CA mutational status.

Regimens for patients with no PIK3CA mutations:

• Arm A: gedatolisib (PIK3CA/mTOR inhibitor), palbociclib (CDK4/6 inhibitor) and fulvestrant (SERD, selective estrogen receptor degrader)
• Arm B: gedatolisib and fulvestrant
• Arm C: fulvestrant

Regimens for patients with PIK3CA mutations:

• Arm D: gedatolisib, palbociclib and fulvestrant
• Arm E: alpelisib (PIK3CA inhibitor) and fulvestrant
• Arm F: gedatolisib and fulvestrant

This clinical trial was presented in a trial in progress poster session at the American Association for Cancer Research Annual Meeting.

The trial is expected to conclude in late 2024. The U.S. Food and Drug Administration has granted Breakthrough Therapy designation to gedatolisib for the treatment of hormone receptor positive and HER2 negative advanced breast cancer that has progressed after treatment with a CDK4/6 inhibitor in combination with an aromatase inhibitor. This designation allows for more intensive guidance and a potentially accelerated review and approval from the FDA.