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Efficacy and exploratory biomarker analysis of entinostat plus exemestane in advanced or recurrent breast cancer:
Hiroji Iwata1, Rikiya Nakamura2, Norikazu Masuda3
1Department of Breast Oncology, Aichi Cancer Center Hospital, Aichi, Japan.
Background:
We aimed to confirm the efficacy and safety of the oral histone deacetylase inhibitor entinostat in Japanese patients with hormone receptor-positive advanced/recurrent breast cancer and to explore potential biomarkers.
Methods:
This phase II, double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov; NCT03291886) was conducted at 28 Japanese sites (September 2017-July 2020; interim analysis cutoff: April 2019). Patients with progression/relapse following non-steroidal aromatase inhibitors were randomized 1:1 to entinostat (5 mg/week) or placebo, plus exemestane (25 mg/day). Primary endpoint was progression-free survival; secondary endpoints included overall survival and safety. Exploratory biomarker outcomes included lysine acetylation, immune cell profiles, estrogen receptor 1 mutations and plasma chemokines.
Results:
Of 133 randomized patients, 131 (65 entinostat, 66 placebo) who received study drug were analyzed. Median (95% confidence interval) progression-free survival was 5.8 (3.2-7.8) months for entinostat and 3.3 (3.1-5.8) months for placebo (hazard ratio [95% confidence interval]: 0.75 [0.50 - 1.14]; P = 0.189). Median overall survival was not reached in either group. Entinostat tended to prolong progression-free survival in patients aged ≥65 years, not endocrine resistant, or with estrogen receptor 1 Y537S mutation. Candidate biomarkers of efficacy (progression-free survival) included lysine acetylation in CD3+ cells, plasma interferon gamma-induced protein 10, dendritic cell CD86 expression, and CD4+ cell expression of human leukocyte antigen-DR and inducible T-cell co-stimulator. Safety was similar to non-Japanese populations; however, seven entinostat-treated patients (10.8%) had reversible lung injury.
Conclusions:
In Japanese patients, the safety of entinostat plus exemestane was acceptable and progression-free survival was prolonged, although not significantly. Exploratory analyses identified potential biomarkers, including lysine acetylation, of efficacy.
Insights
Entinostat plus exemestane showed acceptable safety and tended to prolong progression-free survival in Japanese patients with advanced breast cancer. Lysine acetylation and other biomarkers may predict treatment efficacy.
Area of Science:
- Oncology
- Pharmacology
Background:
- Hormone receptor-positive (HR+) advanced or recurrent breast cancer is a significant clinical challenge.
- Estrogen receptor (ER) targeted therapies like exemestane are standard, but resistance develops.
- Histone deacetylase inhibitors (HDACi) like entinostat offer a novel therapeutic strategy.
Purpose of the Study:
- To evaluate the efficacy and safety of entinostat combined with exemestane in Japanese patients with HR+ advanced/recurrent breast cancer.
- To identify predictive biomarkers for treatment response.
Main Methods:
- A phase II, double-blind, randomized, placebo-controlled trial involving 133 Japanese patients.
- Patients received either entinostat (5 mg/week) or placebo, plus exemestane (25 mg/day).
- Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival and safety. Biomarker analyses included lysine acetylation, immune profiles, and ER1 mutations.
Main Results:
- Median PFS was 5.8 months with entinostat vs. 3.3 months with placebo (HR: 0.75; P=0.189), indicating a trend towards improvement.
- Entinostat showed potential benefit in subgroups: patients aged ≥65 years, those not resistant to endocrine therapy, or with ER1 Y537S mutation.
- Candidate biomarkers of efficacy included lysine acetylation, IP-10, CD86, HLA-DR, and ICOS expression. Safety was acceptable, with reversible lung injury in 10.8% of entinostat-treated patients.
Conclusions:
- Entinostat plus exemestane demonstrated acceptable safety in Japanese patients with HR+ advanced breast cancer.
- While not statistically significant, entinostat tended to prolong progression-free survival.
- Exploratory analyses identified lysine acetylation and other markers as potential predictive biomarkers for efficacy.
