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 regulate the number and function of a population of immuno-suppressive cells known as myeloid-derived suppressor cells, or MDSCs, and regulatory T cells, or Tregs. These cells may accumulate in the tumor microenvironment and block the activity of PD1/PD-L1 antagonists. By reducing the number or function of MDSCs and Tregs, we believe entinostat could boost the anti-tumor efficacy of immune checkpoint inhibitors and enhance the body’s immune response to the tumor.

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 which test entinostat in combination with an approved PD-1/PD-L1 antagonists as a potential treatment for Melanoma, NSCLC, CRC, Ovarian and TNBC.

Our phase 2 data from ENCORE 601 (testing entinostat in combination with pembrolizumab) in patients with NSCLC whose disease has progressed following treatment with an anti-PD-(L)1 and chemotherapy indicates that patients with higher levels of a circulating cell called a classical monocyte may have better outcomes than those with lower levels. A pivotal study based on patient selection using the peripheral classical monocyte biomarker to explore 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.