Entinostat Combo Fails to Meet End Point in Phase 3 HR+/HER2– Breast Cancer Study

Statistically significant improvement in overall survival was not achieved with the combination of entinostat plus exemestame (Aromasin) compared with hormone therapy alone in patients with hormone receptor (HR)–positive, HER2-negative breast cancer, missing the primary end point of the phase 3 E2112 trial (NCT02115282).¹

"We're disappointed that the combination of entinostat and exemestane did not demonstrate a survival benefit in this historically difficult-to-treat patient population," said Briggs W. Morrison, MD, CEO of Syndax, in a statement. "On behalf of the entire Syndax team, we extend our sincerest gratitude to all the patients, their families, and the investigators who participated in this important trial, as well as our colleagues at ECOG-ACRIN and the NCI [National Cancer Institute]. Based on these results, we will not be filing a New Drug Application with the U.S. Food and Drug Administration for metastatic breast cancer."

Prior results from the study showed that the combination also failed to improve progression-free survival (PFS); however, researchers at Fox Cancer Research Center remained hopeful because PFS prolongation was not the goal of the study, even though it was a coprimary end point. Additionally, prior data from the phase 2b ENCORE 301 trial signaled that entinostat plus exemestame could improve OS. The hypothesis was proven wrong.²

E2112 is a double-blind, placebo-controlled, trial of 608 patients with HR-positive, HER2-negative breast cancer. The study was sponsored by the National Cancer Institute and independently designed and carried out by ECOG-ARIN. In the study, patients received exemestane on days 1, 8, 5, and 22 of a 28-day cycle with entinostat on days 1 through 28, in the experimental arm. In the comparator arm, placebo was administered on the same days as exemestane.

The secondary end points being assessed in the trial are objective response rate, toxicity, and time to treatment deterioration. The exploratory study outcomes include the percent of change in protein lysine acetylation, overall health-related quality of life, and adherence to study protocol.

Patients were eligible for enrollment into E2112 if they had histologically confirmed disease that was measurable or non-measurable, adequate laboratory values, an ECOG performance status of 0 or 1, and a life expectancy of at least 12 weeks. Patients could not have prior concurrent anti-cancer therapy, valproic acid treatment, or central nervous system metastasis.

Entinostat is currently being evaluated in combination with axatilimab, a monoclonal antibody, as a potential treatment for adult patients with relapsed or refractory acute leukemias. Full data from the phase 3 E2112 study are expected in the second half of 2020.

_References:

_{1. ECOG-ACRIN Provides Syndax Pharmaceuticals With Results of Phase 3 E2112 trial of entinostat plus exemestane in patients with hr+, her2- breast cancer [news release]. Whalthan, Massachusetts: Syndax Pharmaceuticals; May 21, 2020. https://bit.ly/2XubvDC. Accessed May 26, 2020.}

_{2. Syndax to host conference call to provide update on the phase 3 breast cancer trial (e2112) and to announce its registration trial of entinostat with keytruda in pd-(l)1 refractory non-small cell lung cancer [news release]. Waltham, Massachusetts: Syndax Pharmaceuticals; October 25, 2018. https://bit.ly/2THvo97. Accessed May 26, 2020.}