Editor’s Note: Hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) breast cancer accounts for approximately 70% of all breast cancer cases. Treatment for this subtype has entered the era of precision “endocrine plus” therapy. Endocrine therapy combined with CDK4/6 inhibitors has become the standard first-line treatment for advanced disease; however, differences in efficacy and safety exist among available agents.Lerociclib, a novel imported CDK4/6 inhibitor, has demonstrated significant clinical value in breast cancer treatment owing to its unique molecular structure, marking an important milestone in the management of HR+/HER2− advanced breast cancer. Following the establishment of endocrine therapy plus CDK4/6 inhibitors as the standard first-line approach, treatment selection after disease progression has become increasingly critical, yet no unified strategy currently exists.
For patients suitable for continued endocrine therapy, the HDAC inhibitor entinostat regimen has not only significantly prolonged survival—achieving a median overall survival (mOS) of 38.39 months in the EOC103A3101 study—but also introduced the first once-weekly dosing schedule in this setting. This offers greater convenience, improved adherence, and enhanced quality of life.
Breakthroughs in research and clinical validation of lerociclib (CDK4/6 inhibitor) and entinostat (HDAC inhibitor) have provided superior options for both first-line and subsequent-line treatment of HR+/HER2− advanced breast cancer. Notably, both drugs have now been included in the National Reimbursement Drug List (2025) (effective January 1, 2026), offering patients potent, convenient, and more affordable treatment options across the disease continuum.
This milestone signifies alignment of China’s breast cancer treatment standards with international practice and ensures broader access to high-efficacy, low-toxicity, and convenient regimens—ultimately improving both survival outcomes and quality of life.
From First-Line to Second-Line, From Efficacy to Accessibility: Lerociclib Redefines Treatment Standards with High Efficacy and Improved Affordability
The introduction of CDK4/6 inhibitors has transformed the treatment paradigm for HR+/HER2− advanced breast cancer, becoming indispensable in both first- and second-line settings. However, differences in efficacy and safety remain among agents.
As a novel imported CDK4/6 inhibitor, lerociclib features a distinctive “tricyclic plus spirocyclic” structure, conferring higher affinity and selectivity for CDK4. This translates into stronger antitumor activity and reduced off-target toxicity.
Lerociclib’s approval in China was initially driven by its outstanding performance in second-line therapy. The phase III LEONARDA-1 trial evaluated lerociclib plus fulvestrant in patients with HR+/HER2− advanced breast cancer who had progressed on prior endocrine therapy. Presented by Professor Binghe Xu at the 2023 ASCO Annual Meeting and featured in ASCO Daily News, the study attracted global attention. The results were later published in Nature Communications in January 2025, further strengthening its academic impact.
The LEONARDA-1 trial demonstrated that lerociclib plus fulvestrant significantly improved median progression-free survival (mPFS) to 11.07 months compared with 5.49 months in the control group, reducing the risk of disease progression by 55% (HR 0.451). Subgroup analyses showed consistent benefits even in difficult-to-treat populations, including those with liver metastases, primary endocrine resistance, and high tumor burden.
First-line approval of lerociclib was based on the phase III LEONARDA-2 trial, a multicenter, randomized, double-blind study in Chinese patients. This study evaluated lerociclib plus letrozole as initial endocrine therapy. Results presented at the 2024 ASCO Annual Meeting showed a significant improvement in mPFS (not reached vs. 16.56 months), with a 54% reduction in the risk of progression or death (HR 0.464). These findings confirm the robust efficacy of lerociclib in the first-line setting and suggest prolonged disease control.
In terms of safety, both LEONARDA-1 and LEONARDA-2 reported that the main adverse events were hematologic toxicities, with relatively low incidence rates and an overall favorable safety profile.
The inclusion of lerociclib in the national reimbursement list represents a major breakthrough in drug accessibility, offering patients a treatment option characterized by “greater efficacy at a better price.”
Preferred Option After Progression: First Inclusion in Reimbursement—Entinostat Opens a New Chapter in HDAC Inhibitor Therapy
In HR+ advanced breast cancer, first-line treatment with CDK4/6 inhibitors plus endocrine therapy typically achieves an mPFS of 23.8–33.6 months. However, most patients eventually develop resistance within 2–3 years.
After disease progression, multiple strategies exist—such as CDK4/6 inhibitor continuation, PI3K inhibitors, and AKT inhibitors—but overall survival remains suboptimal. Moreover, treatment selection is often limited by the need for genetic testing, drug accessibility, or absence of actionable mutations.
The emergence of HDAC inhibitors provides a new therapeutic direction. Notably, entinostat does not require biomarker testing, making it a more convenient option in clinical practice.
The phase III randomized, double-blind EOC103A3101 trial conducted in Chinese patients demonstrated that entinostat plus exemestane significantly improved mPFS compared with placebo plus exemestane (6.32 vs. 3.72 months), reducing the risk of progression or death by 24% (HR 0.76).
Importantly, the combination achieved a median overall survival of 38.39 months—over 9 months longer than the control group—with a 17% reduction in mortality risk (HR 0.83). This represents one of the few studies in HR+ advanced breast cancer with mature overall survival data, aligning with global treatment goals of prolonging survival.
Beyond survival benefits, entinostat offers a unique once-weekly dosing regimen (one tablet per week), significantly improving convenience. Its long half-life (approximately 52–62 hours) reduces dosing frequency, enhances adherence, and supports the concept of treating cancer as a chronic disease while prioritizing quality of life.
As the first HDAC inhibitor included in China’s reimbursement system, entinostat provides clear clinical benefit for patients with endocrine-resistant HR+/HER2− advanced breast cancer.
Empowering Access Through Reimbursement: From Innovation to Broad Availability
The true value of a treatment lies not only in its efficacy and safety but also in its accessibility and affordability. Inclusion in the national reimbursement list is a critical step in improving patient access.
Since 2024, both entinostat and lerociclib have been approved by China’s National Medical Products Administration. With strong clinical evidence in Chinese populations and demonstrated clinical value, both drugs have now been incorporated into the National Reimbursement Drug List (2025).
This enables clinicians to make more informed, guideline-based treatment decisions—drawing on recommendations such as the CBCS and CSCO guidelines—while tailoring therapy to individual patient needs and optimizing the full treatment pathway for HR+ advanced breast cancer.
The development, validation, and reimbursement of lerociclib and entinostat exemplify China’s transition in oncology innovation from “follower” to “peer” and even “leader.” With their inclusion in the reimbursement list, patients with HR+/HER2− advanced breast cancer are entering a new era of comprehensive management that balances efficacy with accessibility.
Looking ahead, broader clinical application of these innovative therapies is expected to further improve treatment outcomes. These advances will support the goals of the “Healthy China 2030” initiative—enhancing both survival rates and quality of life for cancer patients—allowing more individuals to live longer, healthier lives.
