Editor’s Note: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have become a key component of treatment for patients with HR+/HER2– advanced breast cancer (ABC), spanning first-line, second-line, and even post-line reuse settings. However, differences in efficacy and safety among CDK4/6 inhibitors remain, and there is still a need for more potent and safer agents that allow long-term maintenance therapy to improve patient outcomes. Recently, China’s National Medical Products Administration (NMPA) approved Lerociclib, a novel CDK4/6 inhibitor, in combination with an aromatase inhibitor (AI) or fulvestrant for the treatment of adult patients with HR+/HER2– locally advanced or metastatic breast cancer in both first-line and second-line settings. What are the mechanistic advantages of this new CDK4/6i? What key clinical evidence supports its approval? And how will it reshape China’s breast cancer treatment landscape? Oncology Frontier interviewed Prof. Qingyuan Zhang from Harbin Medical University Cancer Hospital for an in-depth discussion.Message from Prof. Qingyuan Zhang:
“Patients with HR+/HER2– advanced breast cancer have an urgent need for more effective and tolerable therapies. As a structurally optimized new-generation CDK4/6 inhibitor, Lerociclib has demonstrated ‘high selectivity, potent inhibition, broad benefit, and low discontinuation rates’ across a series of studies. Its approval and clinical application in China will provide oncologists with a powerful therapeutic tool and bring tangible benefits to breast cancer patients.”
Comprehensive Care, Combination Therapy — The Foundational Role of CDK4/6 Inhibitors
Oncology Frontier: CDK4/6 inhibitors have been used in clinical practice for breast cancer for nearly a decade globally and about seven years in China. How do you view their role in HR+/HER2– advanced breast cancer treatment?
Prof. Zhang: Breast cancer remains the most common malignancy among women worldwide, with the HR+/HER2– subtype accounting for roughly 70% of all cases — representing the largest therapeutic population. Since the FDA’s first approval of a CDK4/6 inhibitor (palbociclib) in 2015 and the NMPA’s approval in 2018, multiple agents and substantial clinical evidence have emerged, establishing CDK4/6 inhibitors as a cornerstone therapy for HR+/HER2– advanced breast cancer.
International and domestic guidelines consistently recommend CDK4/6i + endocrine therapy (ET) both for first-line and second-line settings after ET failure. Moreover, for patients previously treated with CDK4/6i, studies such as MAINTAIN and postMONARCH have shown that rechallenge or continuation of CDK4/6 inhibition may still yield benefits. Additionally, with the advent of targeted therapies against the PI3K/AKT/mTOR pathway, such as in the INAVO120 study, combining PI3K inhibitors with CDK4/6i + ET has demonstrated additional efficacy in the first-line setting.
Altogether, these findings reinforce that CDK4/6i + ET has become a therapeutic foundation in HR+/HER2– breast cancer — extending from first-line to second-line and cross-line therapy, with potential for synergistic combinations with other novel agents.
Chinese Evidence, Global Quality — Lerociclib Enters Clinical Practice in China
Oncology Frontier: There are several CDK4/6 inhibitors already available worldwide. What clinical evidence supported Lerociclib’s approval in China, and what are its efficacy and safety characteristics?
Prof. Zhang: Lerociclib is a highly selective, next-generation, orally available CDK4/6 inhibitor, developed through China–U.S. collaboration. Its approval in China for use with fulvestrant in patients who progressed on prior endocrine therapy was primarily supported by the phase III LEONARDA-1 trial, led by Academician Binghe Xu, published in Nature Communications in 2025 and previously presented at ASCO 2023.
This pivotal study was one of the few phase III trials conducted exclusively in Chinese patients — with a broad, real-world-representative enrollment, including high-risk, treatment-refractory populations such as those with liver metastases (40.9%), primary endocrine resistance (24.8%), ≥4 metastatic organs (26.3%), and prior chemotherapy for recurrent/metastatic disease (29.2%). Lerociclib demonstrated clear advantages in both efficacy and tolerability.
- Efficacy: Investigator-assessed median PFS was 11.07 vs 5.49 months for Lerociclib + fulvestrant vs placebo + fulvestrant, respectively (HR=0.451, 95% CI: 0.311–0.656, P<0.0001). The blinded independent review committee (BIRC) confirmed consistent results (mPFS 11.93 vs 5.73 months, HR=0.353, P<0.0001). Subgroup analyses showed consistent benefit across all groups, including high-risk patients: liver metastases (HR 0.487), primary endocrine resistance (HR 0.374), ≥4 metastatic organs (HR 0.326), and prior chemotherapy (HR 0.286) — indicating sustained benefit even in difficult-to-treat populations.
- Safety: Lerociclib demonstrated low hematologic and gastrointestinal toxicity. Grade 4 neutropenia occurred in only 5.1%, and no ≥grade 3 diarrhea was reported. Treatment discontinuation due to adverse events was extremely rare (0.7%). Moreover, no QT prolongation, hepatotoxicity, VTE, or interstitial lung disease (ILD) was observed, eliminating the need for extra monitoring — in contrast to most other CDK4/6 inhibitors currently used in clinical practice.
High Selectivity, Strong Inhibition — Lerociclib’s Mechanistic Advantages
Oncology Frontier: LEONARDA-1 showed that Lerociclib achieves both “high efficacy and low discontinuation.” What mechanisms underlie this profile?
Prof. Zhang: CDKs are critical regulators of cell division. Specifically, CDK4 and CDK6 control the transition from G1 to S phase in the cell cycle. While CDK6 plays a stronger role in hematopoietic cells, breast cancer cells primarily depend on cyclin D1–CDK4 signaling. Excessive inhibition of other kinases (e.g., CDK9) may contribute to off-target toxicities, including gastrointestinal and hematologic side effects.
Through iterative design, Lerociclib introduces a unique tricyclic and spirocyclic scaffold, enhancing binding affinity for CDK4 while minimizing off-target interactions. Kinase selectivity profiling shows that Lerociclib primarily inhibits CDK4 only, while palbociclib inhibits 3 kinases and abemaciclib inhibits more than 50 kinases. Additionally, Lerociclib exerts no functional inhibition of CDK9, contributing to its lower hematologic and GI toxicity.
Furthermore, Lerociclib demonstrates:
- Lower IC50 for CDK4 compared to other CDK4/6 inhibitors, indicating stronger potency.
- Higher tumor tissue penetration and prolonged retention, with sustained tumor suppression over time — consistent with the clinical outcomes seen in LEONARDA-1.
Earlier Use, Broader Benefit — Lerociclib Builds a Comprehensive Treatment Strategy
Oncology Frontier: The phase III LEONARDA-2 study evaluated Lerociclib in first-line HR+/HER2– ABC patients. How might this impact future clinical practice?
Prof. Zhang: Indeed, CDK4/6 inhibitors play roles across multiple treatment lines — first-line, second-line, and beyond. Lerociclib will likely become a cornerstone therapy across these settings.
The LEONARDA-2 trial, presented at ASCO 2024, enrolled HR+/HER2– advanced breast cancer patients who had not received prior systemic therapy for advanced disease. Patients were randomized to Lerociclib + letrozole vs placebo + letrozole.
- The study met its primary endpoint at the interim analysis: investigator-assessed mPFS was not reached (NR) vs 16.56 months, with a 53.6% reduction in risk of disease progression or death (HR 0.464, 95% CI: 0.293–0.733, P=0.0004).
- Independent review confirmed consistent benefit (HR 0.457, P=0.0011).
- Compared with other first-line CDK4/6i trials, Lerociclib’s HR (0.464) ranks among the most favorable, indicating substantial clinical benefit.
Both LEONARDA-1 and LEONARDA-2 consistently demonstrate Lerociclib’s hallmark features — high selectivity, strong inhibition, broad benefit, and low discontinuation. With its first-line approval, Lerociclib now provides a comprehensive CDK4/6i option for Chinese patients across all stages of HR+/HER2– advanced breast cancer.
About Prof. Qingyuan Zhang
- Chief Physician, Professor (Second-Class), and Doctoral Supervisor
- Discipline Leader, National Key Specialty of Oncology
- Member, National “Hundred-Thousand-Talent Project”
- National Outstanding Young and Middle-Aged Expert
- Chair, Chinese Anti-Cancer Association Lymphoma Committee
- Vice-Chair, Chinese Anti-Cancer Association Breast Cancer Committee
- Vice-Chair, Chinese Society of Clinical Oncology (CSCO) Breast Cancer Expert Committee
- Vice-Chair, CACA Chemotherapy Professional Committee
