Nivolumab Plus Entinostat Provide Gateway for Future PDAC Treatments

Pancreatic tumors are surrounded by a so-called immune desert environment, in which the microenvironment surrounding the tumors has suppressed immune activity. The cancer attracts suppressive cells into the tumor, which results in limited access of T cells.

Due to this microenvironment, pancreatic ductal adenocarcinoma (PDAC) is resistant to immune-based therapies that often prove successful in the treatment of other forms of cancer.

A recent phase II trial led by Nilofer Azad, MD, and Marina Baretti, MD, has examined the safety and efficacy of nivolumab with the histone deacetylase inhibitor entinostat. While nivolumab is commonly used in combination with other treatments for PDAC, entinostat has been utilized in other solid tumors for its ability to induce the inhibition of cell proliferation, terminal differentiation, and apoptosis.

A total of 27 patients with advanced PDAC who had previously been treated with chemotherapy were included in the trial. Each patients received entinostat 5 mg orally once a week for a 14-day lead-in, followed by entinostat and nivolumab.

The primary endpoint was objective response rate (ORR), while secondary endpoints included safety, duration of response, progression-free survival (PFS), and overall survival (OS).

Partial responses were seen in 3 patients (11% ORR, 95% CI, 2.4%-29.2%) with a median response duration of 10.2 months. The median PFS and OS were 1.89 (95% CI, 1.381-2.301) and 2.729 (95% CI, 1.841-5.622) months, respectively.

Treatment-related adverse events grade 3 or higher occurred in 19 patients (63%), and include decreased lymphocyte count, anemia, hypoalbuminemia, and hyponatremia. As part of an exploratory analysis, peripheral and tumor immune profile changes were assessed using cytometry by time of flight, multiplex immunohistochemistry, and RNA sequencing.

Entinostat was found to increase dendritic cell activation and maturation, and gene expression analysis showed an enrichment in inflammatory response pathways with combination treatment.

While the primary endpoint was not met, entinostat and nivolumab provided durable responses in a small subset of patients with PDAC. The results of this study can provide a basis for future combination therapies to enhance clinical benefits in PDAC.