Endocrine based therapy is a backbone of treatment with proven clinical benefits for women HR+, HER2- breast cancer. Over time, 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.
Entinostat, is a selective, oral, once-weekly, class I HDAC inhibitor that has been studied in multiple solid tumors in combination with hormone therapy and several approved PD-1/PD-L1 antagonists.
Entinostat in combination with Hormone Therapy
Entinostat in combination with Checkpoint Therapy
Class 1 HDACs have been shown to influence the anti-tumor immune response through down-regulation of immune suppressive cell number and function, increased antigen presentation on cancer cells and enhanced cytotoxic T cell activity.
In preclinical studies, entinostat demonstrated synergistic anti-tumor activity in combination with immune checkpoint inhibitors in multiple tumor models including lung, breast, colon, kidney and pancreatic cancers, suggesting a potential to further increase the ability of the patient’s T cells to attack the tumor.
To translate these preclinical findings to a clinical setting, Syndax set up a number of collaborations testing entinostat in combination with approved PD-1/PD-L1 antagonists with a goal of targeting resistance to immune checkpoint therapy across a range of immune phenotypes. Both “hot” or inflamed and “cold” or non-inflamed tumor types were chosen as well as settings in which immune checkpoints had been administered with limited clinical benefit.
Through the ENCORE I/O program, our results indicate that entinostat combined with immune checkpoint therapies may be most effective in “inflamed” tumors such as NSCLC and melanoma where immune checkpoint therapies have been previously tried but the disease nonetheless progressed.
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 also indicate that patients with higher levels of a circulating cell called a classical monocyte may have better outcomes than those with lower levels.