Phase 3 results from a cohort of patients in China show a progression-free survival benefit with entinostat/exemestane.
In a phase 3 study conducted in Chinese patients with hormone receptor (HR)–positive breast cancer, the combination of entinostat and exemestane led to a significant improvement in progression-free survival (PFS) compared with placebo and exemestane, according to a presentation given during the 2021 San Antonio Breast Cancer Symposium.1
Results showed that the median PFS was 6.32 months (95% CI, 5.30-9.11) with the addition of entinostat vs 3.72 months (95% CI, 1.91-5.49) with placebo/exemestane, resulting in a 26% reduction in the risk of disease progression or death in the full analysis set (HR, 0.74; 95% CI, 0.58-0.96; P = .021).
When the PFS was assessed in the per protocol set, the median PFS was 7.34 months (95% CI, 5.46-9.18) in the entinostat arm compared with 3.72 months (95% CI, 1.91-5.49) in the placebo/exemestane arm (HR, 0.70; 95% CI, 0.53-0.91; P = .009).
“As a class I selective oral HDAC inhibitor, entinostat proved to have a PFS benefit [when combined with] exemestane [in this pivotal study,] with manageable adverse effects [AEs], in [patients with] HR-positive advanced breast cancer who had progressed after prior endocrine therapy,” lead study author Binghe Xu, MD, of the Department of Medical Oncology, National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China, said in a presentation on the data.
Entinostat has been shown to have a long half-life and the agent is administered once weekly at a 5-mg dosing schedule. In breast cancer, disruption of estrogen-mediated signaling occurs within the breast cancer cell, which results in acquired resistance to hormonal therapy. Entinostat is targeted to re-sensitive these cells to endocrine treatment, Xu explained.
The controlled trial (NCT03538171) enrolled pre- or postmenopausal Chinese women with advanced HR-positive, HER2-negative advanced breast cancer who had an ECOG performance status of 0 or 1. Participants were randomized 2:1 to receive entinostat at 5 mg weekly plus exemestane at 25 mg daily (n = 235) or placebo at 5 mg weekly plus exemestane at 25 mg daily (n = 119). Treatment was given until disease progression or unacceptable toxicity.
Independent review committee–assessed PFS was the primary end point of the trial; overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety served as secondary end points. Tumor assessments were performed every 8 weeks.
Patients who were pre/perimenopausal received goserelin as a 3.6-mg injection on day 1 of each treatment cycle. Stratification factors included previous treatment with CDK4/6 inhibitors (yes vs no), fulvestrant (Faslodex; yes vs no), chemotherapy (yes vs no), and the presence of visceral metastases (yes vs no).
At the data cutoff of May 4, 2021, 198 patients on the entinostat arm and 105 on the placebo arm discontinued treatment due to disease progression (n = 149 vs 88, respectively), AEs (n = 21 vs 4), or loss of follow-up (n = 4 vs 0), compliance (COVID-19; n = 7 vs 2), and other (n = 17 vs 11).
Treatment is ongoing in 37 and 14 of patients on entinostat and placebo, respectively.
Baseline characteristics were similar between the treatment arms. The median age was 52 years (range, 28-75), more than half of patients (53.1%) had an ECOG performance status of 0, and 68.9% of patients had visceral metastases (P = .996). Moreover, 38.5% of patients had received prior chemotherapy (P = .808) and patients had received either 0 (24.8%), 1 (33.6%), 2 (28.1%), 3 (10.2%), or 4 (3.4%) prior treatments for their advanced disease. Primary endocrine resistance occurred in 31.7% of patients, 6.6% previously received a CDK4/6 inhibitor, and 25.8% previously received fulvestrant.
Further findings showed that, although currently immature, the median OS had not yet been reached (NR) with either entinostat (95% CI, NR–NR) or placebo (95% CI, 19.70–NR), translating to a 25% reduction in the risk of death (HR, 0.75; 95% CI, 0.49-1.15). Xu noted that more mature OS data will be available in 2022.
The IRC-assessed ORR with entinostat was 15.7% compared with 10.1% with exemestane (P = .192); the investigator-assessed ORRs were 17.4% and 10.9% with entinostat and exemestane/placebo (P = .119), respectively.
The IRC-assessed CBR achieved with entinostat/exemestane was 37.4% compared with 32.8% with placebo/exemestane (P = .413). In the investigator assessment, the CBRs were 45.1% and 31.9%, respectively (P = .022).
An ad-hoc analysis also explored the disease control rate (DCR) and duration of response (DOR) in both arms. The DCR via IRC was 70.2% with entinostat/exemestane vs 55.5% with placebo/exemestane (P = .007). The investigator-assessed DCR was 71.9% and 60.5% in the entinostat and placebo arms, respectively (P = .040).
The IRC-assessed DOR was NR with entinostat/exemestane vs 7.47 months with placebo/exemestane (P = .571); in the investigator assessment, the DOR was 12.96 months in the investigative arm vs 5.56 months in the control arm (P = .013).
Furthermore, an ad-hoc subgroup analysis of PFS showed that the entinostat/exemestane combination improved PFS over exemestane alone across all prespecified subgroups, except for those who received prior fulvestrant (HR, 1.06, 95% CI, 0.66-1.72; P = .101).
Regarding safety, the most common AEs were hematologic toxicities, including neutropenia (73.2% with entinostat vs 3.4% with placebo), leukopenia (63.8% vs 5.0%, respectively), thrombocytopenia (66.8% vs 12.6%), and anemia (21.3% vs 6.7%). These toxicities were mostly asymptomatic and were managed through supportive care, Xu added.
All-grade treatment-emergent AEs (TEAEs) occurred in 99.1% of exemestane-treated patients compared with 88.2% of those treated with placebo. Grade 3 TEAEs that were found to be related to treatment occurred in 55.7% of patients on entinostat/exemestane and 10.1% of those on placebo/exemestane; grade 4 AEs occurred in 4.3% and 2.5% of patients, respectively. Five deaths (2.1%) occurred on the entinostat arm vs 0 on the placebo arm.
Xu B, Zhang Q, Hu X, et al. A randomized control phase III trial of entinostat, a once weekly, class I selective histone deacetylase inhibitor, in combination with exemestane in patients with hormone receptor positive advanced breast cancer. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS1-06.