Endocrine based therapy is a backbone of treatment with proven clinical benefits for women HR+, HER2- breast cancer. Overtime, disruption of estrogen mediated signaling within the breast cancer cell results in acquired resistance to hormone therapy. Entinostat is thought to re-sensitize these cells to endocrine therapy.

In a phase 2 randomized, placebo-controlled study, ENCORE 301, entinostat demonstrated a significant (8 mo) improvement in overall survival in combination with exemestane vs exemestane alone. This result led to Breakthrough Therapy status from the FDA, and the initiation of E2112, a phase 3 registration enabling study designed to evaluate entinostat in combination with exemestane in HR+, HER2- metastatic. Enrollment in E2112 was recently closed after a total of 608 patients accrued to the trial, and results of the overall survival analysis are anticipated sometime in 2019.

Class 1 HDACs have been shown to impact the number and activity of the population of immuno-suppressive cells known as myeloid-derived suppressor cells, or MDSCs, and regulatory T cells, or Tregs. Thus, entinostat is also being explored in combination several approved PD-1/PD-L1 antagonists as a potential treatment for Melanoma, NSCLC, CRC, Ovarian and TNBC.

By blocking the immuno-suppressive effects of MDSCs and Tregs, we believe entinostat could enhance the body’s immune response to tumors. In preclinical studies, entinostat demonstrated synergistic anti-tumor activity in combination with immune checkpoint inhibitors, suggesting a potential to further increase the ability of the patient’s T cells to attack the tumor.

Syndax is exploring this hypothesis through its suite of ENCORE clinical programs.

A pivotal study exploring the combination of entinostat with pembrolizumab in patients with NSCLC whose disease has progressed following treatment with an anti-PD-(L)1 and chemotherapy is expected to begin 1H19.