AACR 2015: Dual mTOR Inhibitor-Fulvestrant Combination Feasible, With Clinical Benefit for Advanced Breast Cancer Patients


Key Points

  • Some patients with estrogen receptor–positive breast cancer become resistant to hormonal therapy, and their tumors become dependent on the mTOR cell-signaling pathway.
  • Of the 66 trial participants treated with fulvestrant and the dual mTOR inhibitor AZD2014, 31 had clinical benefit, which included partial responses and stable disease.
  • Intermittent treatment with AZD2014 provided a more optimal safety profile than continuous dosing.

The dual mTOR inhibitor AZD2014, when combined with the hormonal therapy fulvestrant (Faslodex), was found to be safe in patients with advanced estrogen receptor–positive breast cancer, and some of them experienced clinical benefit from the drug combination, according to phase I clinical trial data presented at the AACR Annual Meeting 2015, April 18 to 22 in Philadelphia (Abstract CT233).

Study Background

“Patients with estrogen receptor–positive breast cancer respond to hormonal therapy, but over time, some eventually develop resistance to treatment. Their tumors become dependent on a cell-signaling pathway called the mTOR pathway for survival,” said Manish R. Patel, MD, Associate Director of Drug Development for Sarah Cannon Research Institute and Director of Drug Development at the Florida Cancer Specialists and Research Institute.

“We are testing whether combining the hormonal therapy fulvestrant with the dual mTOR inhibitor AZD2014 can help overcome this resistance. AZD2014 is a new anticancer therapy and represents a potential improvement compared with other drugs that have similar mechanisms of action,” Dr. Patel added.

“In this trial, we tested two dosing schedules of AZD2014: continuous dosing, in which the drug is given every day, and intermittent dosing, in which the drug is given only 2 days of each week,” Dr. Patel explained. “We compared the side-effect profiles of the two dosing schedules. The response of individual patients to treatment was also monitored.”

Dr. Patel and colleagues enrolled 66 patients with metastatic estrogen receptor–positive breast cancer. Forty-three patients received one of the four different dose levels of AZD2014 7 days a week, and 23 received one of the two different dose levels of AZD2014 2 days a week. All patients received fulvestrant on day 1 of each 28-day cycle.

Trial Findings

Of the 49 patients with measurable disease, 8 had confirmed partial responses, and 5 had unconfirmed partial responses. Of the 66 patients, 31 had clinical benefit, which includes partial responses and stable disease. “It was interesting to observe that AZD2014 had encouraging clinical activity whether dosed continuously or intermittently, with the two schedules having different tolerability profiles,” said Dr. Patel.

According to Dr. Patel, overall, treatment with AZD2014 was well tolerated. Common side effects included rash, nausea, vomiting, diarrhea, sore mouth, and fatigue. Intermittent treatment with AZD2014 provided a more optimal safety profile than continuous dosing. While none of the patients dosed on the intermittent schedule needed to discontinue the drug due to toxicity issues, some patients from the continuous dosing schedule discontinued treatment due to adverse events, he explained.

Dr. Patel cautioned that this is a small phase I study that is not statistically powered to determine which schedule has the best efficacy. This is being explored further in a phase II study called MANTA, which compares fulvestrant with or without one of the two schedules of AZD2014, as well as fulvestrant with another mTOR inhibitor, everolimus (Afinitor), he concluded.

This study was funded by AstraZeneca.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.