As breast cancer continues to rank as the most frequently diagnosed cancer among women worldwide, hormone receptor-positive, HER2-negative (HR+/HER2⁻) disease remains its most common subtype. In recent years, combining CDK4/6 inhibitors with endocrine therapy has become the frontline standard. Yet, for patients who experience disease progression after such treatment, new options are urgently needed.On April 24, 2024, a major milestone was achieved in China’s oncology landscape. The National Medical Products Administration (NMPA) granted official approval for entinostat, a domestically developed, selective histone deacetylase inhibitor (HDACi), to be used in combination with aromatase inhibitors for patients with HR+/HER2⁻ locally advanced or metastatic breast cancer that has progressed following prior endocrine therapy. Notably, this approval introduced the first weekly oral HDACi regimen into clinical practice.
Just days after regulatory approval, entinostat prescriptions began rolling out across major Chinese provinces and cities including Beijing, Guangdong, and Guangxi—signaling not only its clinical availability but also the beginning of a potentially transformative era in breast cancer care.
In this feature, Oncology Frontier is honored to welcome Dr. Nanlin Li, a leading breast cancer expert from Xijing Hospital, Air Force Medical University, who offers in-depth commentary on the latest clinical trial data surrounding entinostat. Through his insights, we explore how this innovative therapy fits into the evolving treatment landscape and how clinicians can leverage it to improve outcomes for HR+/HER2⁻ breast cancer patients.
Entinostat: An HDACi Extending Median OS Beyond 38 Months
HDACs are the first epigenetic targets to be clinically validated in oncology. As a novel HDAC inhibitor, entinostat selectively targets HDACs and has demonstrated the ability to overcome CDK4/6 inhibitor resistance through mechanisms such as induction of p21 expression and upregulation of PTEN.
Entinostat also functionally activates estrogen receptor alpha (ERα) and aromatase, enhancing sensitivity to aromatase inhibitors. It can restore silenced ER promoters by remodeling chromatin-associated proteins. Beyond these mechanisms, entinostat induces tumor cell apoptosis, autophagy, necrosis, and modulates immune responses, thereby ensuring sustained antitumor efficacy.
The Phase III randomized, double-blind, placebo-controlled trial (EOC103A3101) [¹] evaluating entinostat in Chinese patients with breast cancer was led by Academician Binghe Xu from the Cancer Hospital, Chinese Academy of Medical Sciences.
The study enrolled patients aged 18–75 years with HR+/HER2⁻ locally advanced or metastatic breast cancer who had experienced relapse or progression after prior endocrine therapy. Both premenopausal and postmenopausal patients were included, with pre- and perimenopausal patients required to receive concurrent ovarian suppression therapy.
Patients were randomized in a 2:1 ratio to receive entinostat plus exemestane (n=235) or placebo plus exemestane (n=119). Tumor response was assessed every 8 weeks according to RECIST v1.1 criteria. The primary endpoint was progression-free survival (PFS) assessed by an Independent Review Committee (IRC). Secondary endpoints included investigator-assessed PFS, overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety.
With a median follow-up of 15.7 months, comparison between the entinostat group and the placebo group showed a significant improvement in IRC-assessed median progression-free survival (mPFS), reaching 6.32 vs. 3.72 months, corresponding to a 24% reduction in the risk of disease progression or death (HR = 0.76, 95% CI: 0.58–0.98, P = 0.046).
In the entinostat group, the median overall survival (mOS) reached 38.39 months, representing an extension of over 9 months compared to the placebo group and a 17% reduction in the risk of death (HR = 0.83, 95% CI: 0.62–1.10, P = 0.184), indicating a favorable survival benefit. Notably, patients with CDK4/6 inhibitor resistance and those who had previously received salvage chemotherapy also demonstrated encouraging efficacy outcomes.
Subgroup analyses showed that the benefits of entinostat were consistent across all subgroups and aligned with the overall population. Notably, greater benefits were observed in patients without visceral metastases, those with primary endocrine resistance, and those who had not previously received fulvestrant.
In terms of safety, most adverse events in the entinostat group were mild to moderate in severity. The main adverse events leading to treatment discontinuation included neutropenia, elevated gamma-glutamyl transferase (GGT), and anemia, but overall, the safety profile was considered manageable.
This study represents the first Phase III clinical trial of an HDAC inhibitor to demonstrate an OS benefit in HR+/HER2⁻ breast cancer. It enrolled both premenopausal and postmenopausal patients, reflecting a real-world clinical population. The findings confirm the efficacy and safety of entinostat in previously treated patients with advanced HR+/HER2⁻ breast cancer in China.
Based on these results, on April 24, 2024, the NMPA approved entinostat in combination with an aromatase inhibitor for the treatment of HR+/HER2⁻ locally advanced or metastatic breast cancer patients who have relapsed or progressed following endocrine therapy [²].
Strengthening Safety Oversight and Optimizing Clinical Use
In 2011, China’s Ministry of Health issued the Administrative Measures for the Reporting and Monitoring of Adverse Drug Reactions [³], followed by the National Medical Products Administration (NMPA)’s release of the Good Pharmacovigilance Practice Guidelines in 2021 [⁴], both emphasizing the need for strengthened safety monitoring of innovative drugs to ensure public health. Now that the domestically developed HDAC inhibitor entinostat has become clinically accessible, understanding its most common adverse reactions, along with timely anticipation, proactive monitoring, and effective management during use, is essential to optimizing its application and maximizing clinical benefit for patients.
According to findings from the EOC103A3101 trial, the incidence of grade ≥3 treatment-related adverse events (TRAEs) was 65.5% in the entinostat group compared to 19.3% in the placebo group. In the entinostat plus exemestane arm, the most common grade ≥3 hematologic adverse events were neutropenia (43.8%), thrombocytopenia (8.5%), and leukopenia (6.4%). Among non-hematologic events, elevated aspartate aminotransferase (AST) was the most frequently reported, occurring in 2.6% of patients.
Although the rate of grade ≥3 TRAEs was higher in the entinostat group, patient tolerability remained acceptable. The median treatment duration was 20 weeks in the entinostat arm and 16 weeks in the placebo arm, and treatment discontinuation due to adverse events occurred in 14% and 5% of patients, respectively. The primary adverse events leading to treatment discontinuation in the entinostat group were neutropenia (9.4%), elevated gamma-glutamyl transferase (1.7%), and anemia (1.3%).
Only two grade 5 adverse events in the entinostat group were considered possibly treatment-related. These included one case of autoimmune encephalopathy and one case of febrile neutropenia (FN); however, investigators noted that disease progression may have also played a role.
These results highlight the importance of integrating safety protocols and close pharmacovigilance into clinical practice to ensure the safe and effective use of entinostat as it becomes part of routine care.
The adverse events commonly associated with entinostat are frequently observed in oncology clinical practice and are relatively well-understood, with established management strategies. Currently, there are two HDAC inhibitors available in China that share similar mechanisms of action and adverse event profiles, making it possible to draw on shared clinical experience. In 2021, the CSCO Lymphoma Expert Committee and the CSCO Breast Cancer Expert Committee jointly released an expert consensus on the management of HDACi-related adverse events [⁵].
For neutropenia, continued treatment is recommended for Grade 1 cases. For Grade 2, treatment may continue with prophylactic administration of granulocyte colony-stimulating factor (G-CSF) or pegylated recombinant human G-CSF (PEG-rhG-CSF). In Grade 3 neutropenia, several approaches can be considered: pausing treatment and providing supportive care with G-CSF or PEG-rhG-CSF, with treatment resumed if symptoms improve within two weeks; continuing treatment with supportive care and close monitoring; dose reduction with supportive care and regular assessment; or pausing treatment and administering symptomatic therapy if accompanied by fever, with treatment resumed once the condition improves within two weeks. For Grade 4, treatment should be paused and symptomatic therapy given, with resumption once the condition improves within two weeks.
For thrombocytopenia, continued treatment with close observation is recommended for Grade 1–2 cases. In Grade 3, options include pausing treatment and administering interleukin-11 (IL-11) or thrombopoietin (TPO) for supportive care, resuming treatment within two weeks if improvement is observed; continuing treatment with supportive care and close monitoring; dose reduction with supportive care and regular assessment; or, in the presence of bleeding tendencies, pausing treatment and using transfusions, IL-11, or TPO for symptom management, with treatment resumed at a reduced dose once recovery occurs within two weeks. In Grade 4, treatment should be paused, symptomatic treatment provided, and resumed at a reduced dose upon recovery within two weeks.
For hepatotoxicity, management should be based on the severity of liver function abnormalities. In Grade 1 cases (AST or ALT <2.5× ULN and total bilirubin <1.5× ULN), continued treatment with hepatoprotective therapy and close monitoring is advised. For Grade 2 (AST or ALT 2.5–5× ULN and total bilirubin 1.5–3× ULN), treatment may continue with hepatoprotective and anti-inflammatory therapy and close observation. In Grade 3 (AST or ALT 5–20× ULN and total bilirubin 3–10× ULN), treatment should be paused and symptomatic therapy given, with treatment resumed upon improvement within two weeks. In Grade 4 cases (AST or ALT >20× ULN and total bilirubin >10× ULN), treatment should be discontinued, and the patient referred to a specialist for emergency care.
For other common adverse events, early evaluation, appropriate prevention, enhanced monitoring, and timely intervention are key to effective management. Proactive and effective adverse event management supports rational drug use, improves patient adherence, and enhances treatment outcomes.
Summary and Outlook
As the first HDAC inhibitor in China to demonstrate an overall survival (OS) benefit, entinostat shows efficacy comparable to other HDAC inhibitors, with a numerically lower incidence of Grade ≥3 adverse events [⁶]. The 2024 edition of the Chinese Anti-Cancer Association’s Guidelines and Standards for the Diagnosis and Treatment of Breast Cancer recommends HDAC inhibitors as a treatment option for HR+/HER2⁻ advanced breast cancer patients who have progressed following CDK4/6 inhibitor therapy [⁷].
The most common adverse events associated with entinostat in combination with exemestane—neutropenia, thrombocytopenia, and hepatotoxicity—can be effectively managed through preventive or symptomatic treatment, thereby improving the overall treatment experience for patients. Moreover, with an extended half-life of 61.9 hours, entinostat requires only weekly dosing, offering a convenience advantage over other HDAC inhibitors that require daily administration. This feature significantly enhances patient adherence.
In conclusion, the successful approval and clinical availability of entinostat in China has provided a new treatment option for patients with HR+/HER2⁻ advanced breast cancer. The issuance of the first batch of prescriptions marks the beginning of entinostat’s journey toward benefiting patients. It is hoped that, in clinical practice, healthcare professionals will apply this therapy rationally, monitor adverse events proactively, and secure better survival outcomes for patients.
References
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Dr. Nanlin Li
Associate Chief Physician, Associate Professor, MD, Supervisor of Master’s Students Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Air Force Medical University
- Deputy Chair, Breast Tumor Committee, China Primary Health Care Foundation
- Member, Breast Cancer Committee, Chinese Anti-Cancer Association
- Member, Breast Cancer Expert Committee, Chinese Society of Clinical Oncology (CSCO)
- Member, Patient Education Expert Committee, CSCO
- Standing Committee Member, Breast Cancer Committee, Shaanxi Anti-Cancer Association
- Standing Committee Member, Anticancer Drug Committee, Shaanxi Anti-Cancer Association
- Member, Comprehensive Cancer Therapy Committee, Shaanxi Anti-Cancer Association
- Health Science Popularization Expert of Shaanxi Province
Professor Li graduated from the Fourth Military Medical University in 1997. He has long been engaged in clinical work in general surgery and specializes in the diagnosis and standardized treatment of breast and thyroid cancers. He currently leads multiple research projects funded by the National Natural Science Foundation of China and various provincial and ministerial-level foundations.
In 2008, he was recognized as an “Outstanding Course Instructor” at his institution. In April 2009, he was selected for the university’s first “Young Talent Support Program.” In 2014, he was awarded a third-class individual merit citation.
He has published over 30 SCI-indexed papers as first author or corresponding author, holds 13 national patents, and has served as chief editor or translator of 8 academic books.
