Safety and Tolerability of Everolimus in Combination With Eribulin in Triple-negative Breast Cancers
Status:
Unknown status
Trial end date:
1969-12-31
Target enrollment:
Participant gender:
Summary
Treatment of triple negative breast cancer (TNBC) relies heavily on different regimes of
chemotherapeutic agents but remains one of the most challenging subtypes to treat because of
the lack of specific therapies. Despite being sensitive to chemotherapy, many women with TNBC
relapse quickly, developing locoregional recurrence or visceral metastasis. Toxicity and
chemotherapy resistance are still major limitations in the treatment of patients with TNBC.
Despite current trend of targeted therapy development, cytotoxic agents are a mainstay of
treatment of patients with breast cancer. Further research into new combination of different
compounds is needed in order to maximise benefit, whilst minimising toxicity.
The phosphoinositide 3-kinase (PI3K) pathway is associated with resistance to a variety of
anti-tumor agents. This has been described pre-clinically with cytotoxic chemotherapeutic
agents with varying mechanisms of action including taxanes, and DNA-damaging agents. In the
clinic, activated PI3K in tumors has been correlated with decreased response to therapy and
worse clinical outcomes.
The recent biological findings suggest that a PI3K/mammalian target of rapamycin (mTOR)
inhibitors may increase the efficacy of chemotherapeutic agents which are considered standard
of care (SOC) for the treatment of several solid tumors.
The study by the Unitaed state Oncology Research of Huston and the Sarah Cannon Cancer Center
randomized 1830 patients with high risk breast cancer to the standard adjuvant treatment with
adriamicin cyclophosphamide followed by paclitaxel versus the experimental adjuvant treatment
with adriamicin taxotere (AT) followed by paclitaxel. At 5-years of follow up, the AT
followed by paclitaxel produced significantly better overall survival (p=0.054) and improved
disease free survival (DFS) (p=0.19). Among TNBC patients both DFS (74% versus 79%, p=0.1)
and overall survival (OS) (79% versus 84%, p=0.037) were better in experimental arm. However,
the main reasons for patients being taken off study treatment were toxicity (85 patients in
the control arm and 128 in the experimental arm) and consent withdrawal (18 patients in the
control arm and 30 patients in the experimental arm). For this reason, research into
alternatives has intensified, thus resulting in the discovery and development of new
compounds with a more tolerable profile as compared with paclitaxel.
Among the total of 762 patients enrolled into Eisai Metastatic Breast Cancer Study Assessing
Physician's Choice Versus E7389 (EMBRACE) trial, 19% had TNBC. Of note, eribulin was most
effective in hormone receptor-negative patients and in TNBC patients, who had a 29% risk
reduction. Treatment with eribulin was well tolerated. Neutropenia, leucopenia, peripheral
neuropathy, and asthenia/fatigue were the most common adverse events reported at Common
Terminology Criteria for Adverse Events (CTCAE) grades 3 and 4. Neutropenia was the most
common adverse events reported at CTCAE grade 4 in the eribulin group (24.1%).
Based on findings to date, eribulin is an attractive agent, and its role in combination with
new compounds such as everolimus deserves further investigations. Their combination might
lead to more profound effects on tumor cell biology of triple negative metastatic breast
cancer.
During the course of the trial, dose reductions for each combination will be permitted in
patients who cannot tolerate the starting dose