The combination of entinostat and exemestane did not show a statistically significant improvement in overall survival compared with exemestane alone in patients with advanced hormone receptor—positive, HER2-negative breast cancer who have progressed on a nonsteroidal aromatase inhibitor, missing the primary endpoint of the phase 3 E2112 trial.
Briggs W. Morrison, MD, chief executive officer of Syndax
Briggs W. Morrison, MD
The combination of entinostat and exemestane did not show a statistically significant improvement in overall survival (OS) compared with exemestane alone in patients with advanced hormone receptor (HR)—positive, HER2-negative breast cancer who have progressed on a nonsteroidal aromatase inhibitor, missing the primary endpoint of the phase 3 E2112 trial (NCT02115282).1
Based on these results, Syndax, the manufacturer of entinostat, which is a class I HDAC inhibitor, stated that it will not be filing a new drug application with the FDA for metastatic breast cancer. In 2013, the FDA granted a breakthrough therapy designation to the combination of entinostat and exemestane as a treatment for patients with advanced HR-positive breast cancer, based on data from the phase 2 ENCORE301 trial.
"We're disappointed that the combination of entinostat and exemestane did not demonstrate a survival benefit in this historically difficult-to-treat patient population," Briggs W. Morrison, MD, chief executive officer of Syndax, stated in a press release. "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. Based on these results, we will not be filing a New Drug Application with the US Food and Drug Administration for metastatic breast cancer."
The E2112 study was designed and conducted independently by ECOG-ACRIN under the sponsorship of the National Cancer Institute. In the double-blind, placebo-controlled trial, 608 patients with HR-positive, HER2-advanced breast cancer were randomized to receive exemestane in combination with entinostat or placebo.
To be eligible for enrollment, patients must have had estrogen receptor (ER)— and/or progesterone receptor–positive histologically confirmed adenocarcinoma of the breast with 1% or more positive cells, and have measurable or non-measurable stage III/locally advanced or metastatic breast carcinoma.
Those whose tumors had HER2 IHC 3+, in situ hybridization (ISH) of more than 2.0, or an average HER2 copy number of 6.0 signals per cell were not eligible for enrollment. Additionally, patients could not have had central nervous system (CNS) metastasis.
Exemestane or placebo was given orally twice daily on days 1 to 28, and entinostat orally on days 1, 8, 15, and 22 in 28-day cycles until disease progression or unacceptable toxicity. For pre/perimenopausal female patients, and all male patients, goserelin acetate was given subcutaneously on day 1.
The coprimary endpoints were progression-free survival (PFS) and OS; secondary endpoints were objective response rate, incidence of toxicity, time to treatment deterioration. Percent change in protein lysine acetylation, overall health-related quality of life score, and adherence to study were additional outcome measures.
Findings from the phase 2 ENCORE301 trial previously showed that entinostat added to exemestane demonstrated activity in patients with ER-positive advanced breast cancer.2 In the intent-to-treat analysis, treatment with entinostat plus exemestane led to a median PFS of 4.3 months versus 2.3 months with exemestane/placebo (HR, 0.73; 95% CI, 0.50-1.07; one-sided P = .055; two-sided P = .11; predefined significance level of .10, one-sided).
Moreover, the median OS was 28.1 months with entinostat/exemestane versus 19.8 months with exemestane and placebo (HR, 0.59; 95% CI, 0.36-0.97; P = .036).
Regarding safety, the most frequent grade 3/4 adverse events (AEs) were fatigue and neutropenia. Treatment discontinuation due to AEs was 11% and 2% with entinostat/exemestane and exemestane/placebo, respectively.
"We remain focused on advancing our broader portfolio, including our targeted therapy, SNDX-5613, an inhibitor of the Menin-MLL interaction, and axatilimab, our anti-CSF-1R monoclonal antibody,” Morrison added in the press release. “Later this year, we expect to present additional clinical data from the AUGMENT-101 trial of SNDX-5613 in adults with relapsed/refractory acute leukemias.”