Editor’s Note: On May 29, 2025, China’s National Medical Products Administration (NMPA) simultaneously approved Lerociclib (汝佳宁®, Lerociclib) for two indications in adult patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) locally advanced or metastatic breast cancer:
- in combination with an aromatase inhibitor (AI) as initial endocrine therapy; and
- in combination with fulvestrant for patients whose disease has progressed after prior endocrine therapy.
This dual approval was primarily based on the positive results of the multicenter phase III LEONARDA-1 study, marking another milestone in China’s progress in targeted therapy for HR+/HER2– breast cancer and providing patients with a novel treatment option that balances both efficacy and safety. To further interpret the clinical and scientific significance of Lerociclib, Oncology Frontier invited Prof. Jian Huang, Executive Vice President of the Second Affiliated Hospital, Zhejiang University School of Medicine, to share his insights.
CDK4/6 Inhibitors Reshape HR+/HER2– Breast Cancer Treatment—but Unmet Needs Remain
Breast cancer is the most common malignancy among women worldwide. The HR+/HER2– subtype accounts for approximately 70% of all breast cancer cases, representing the largest patient population. While endocrine therapy (ET) remains the cornerstone of systemic treatment for these patients, the development of endocrine resistance continues to pose a major clinical challenge.
The advent of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has fundamentally transformed the therapeutic landscape of HR+/HER2– advanced breast cancer. By blocking the transition of tumor cells from the G1 phase to the S phase, CDK4/6 inhibitors effectively suppress tumor cell proliferation and have significantly improved patient outcomes.
Today, CDK4/6i + ET has become the standard first-line therapy for HR+/HER2– advanced breast cancer. However, while these agents are generally well tolerated, hematologic toxicity, gastrointestinal (GI) toxicity, and hepatotoxicity are not uncommon. Such adverse events can compromise patient adherence and quality of life, occasionally leading to dose adjustments or treatment interruptions that diminish therapeutic outcomes. Therefore, developing next-generation CDK4/6 inhibitors that are both more potent and less toxic remains an essential goal in advancing breast cancer treatment.
Lerociclib Demonstrates High Selectivity and Potent Inhibition of CDK4/6
Lerociclib is a novel, highly selective, oral CDK4/6 inhibitor that embodies a combination of global scientific expertise and Chinese innovation. Its core innovation lies in the introduction of a unique tricyclic and spirocyclic structure, designed to enhance selectivity for CDK4/6 while reducing bone marrow suppression and off-target effects.
At a concentration of 100 nM, Lerociclib shows highly selective inhibition of CDK4–cyclin D1 and CDK6–cyclin D3, with negligible activity against other cell-cycle or mitotic kinases—minimizing unintended inhibition of non-target enzymes.
Preclinical data demonstrate that Lerociclib achieves significantly higher concentrations in tumor tissue than in plasma, maintaining elevated intratumoral drug levels even when plasma concentrations fall to minimal levels. This indicates superior tumor tissue penetration and retention, ensuring sustained antitumor activity. Additionally, Lerociclib’s prolonged half-life supports continuous inhibition of retinoblastoma (RB) protein phosphorylation, offering stable pharmacokinetics for long-term therapy. These features underscore Lerociclib’s high selectivity, strong inhibition, and durable anticancer efficacy.
Global Quality, Chinese Evidence — LEONARDA-1 Offers a New Standard for HR+/HER2– Advanced Breast Cancer
The phase III LEONARDA-1 trial evaluated Lerociclib + fulvestrant in endocrine-resistant HR+/HER2– advanced breast cancer. A total of 275 patients previously treated with one or two lines of endocrine therapy were randomized 1:1 to receive Lerociclib + fulvestrant or placebo + fulvestrant. The primary endpoint was investigator-assessed progression-free survival (PFS); secondary endpoints included blinded independent central review (BICR)-assessed PFS, overall survival (OS), objective response rate (ORR), duration of response (DoR), disease control rate (DCR), clinical benefit rate (CBR), safety, tolerability, and pharmacokinetics.
The results—published in Nature Communications—were striking. Baseline characteristics were well balanced between groups: 64.2% had visceral metastases, 40.9% had liver metastases, 26.3% had ≥4 metastatic sites, and 75.2% exhibited secondary endocrine resistance, reflecting a real-world, high-risk population.
- Efficacy: Investigator-assessed median PFS was 11.07 vs 5.49 months (HR=0.451; P=0.000016), effectively doubling the PFS and reducing the risk of disease progression or death by 55%. BICR-assessed median PFS was 11.93 vs 5.75 months (HR=0.353; P=0.000002), a 65% risk reduction. Subgroup analyses showed consistent benefits across all patient groups, including those with primary endocrine resistance, visceral metastases, and multiple metastatic sites. The ORR and CBR were also significantly higher with Lerociclib.
- Safety: The incidence of serious adverse events (SAEs) was lower in the Lerociclib group (5.8%) than in the placebo group (8.0%). Only one patient (0.7%) discontinued due to treatment-related events. The most common treatment-emergent adverse events were neutropenia and leukopenia, both manageable and reversible. No significant increases in hepatotoxicity, QT prolongation, or rash were observed, and no venous thromboembolism (VTE) events occurred. The favorable safety profile and low discontinuation rate support long-term use and improve quality of life and adherence for patients.
Overall, LEONARDA-1 firmly establishes Lerociclib as an effective and safe treatment for HR+/HER2– advanced breast cancer in Chinese patients, offering a new therapeutic standard.
A Milestone of Global Wisdom and Chinese Innovation
The approval of Lerociclib represents not only the culmination of global scientific collaboration but also the growing strength of Chinese pharmaceutical innovation. The LEONARDA-1 trial not only delivered a breakthrough treatment for HR+/HER2– advanced breast cancer but also highlighted China’s increasing leadership in oncology research. It exemplifies how Chinese investigators are contributing high-quality evidence to global oncology and shaping international standards.
As more large-scale clinical trials led by Chinese experts gain recognition on the world stage, China’s influence in global oncology research will continue to expand—fueling the momentum of medical innovation.
Conclusion
The approval and launch of Lerociclib offer a new, effective, and well-tolerated option for patients with HR+/HER2– advanced breast cancer, marking a significant leap forward in the field. Combining global scientific wisdom with Chinese innovation, Lerociclib exemplifies the strength of China’s biopharmaceutical R&D capabilities. With its clinical rollout, it is expected to benefit thousands of patients across the country and contribute meaningfully to the global advancement of breast cancer therapy.
Prof. Jian Huang
- MD, PhD; Professor and Doctoral Supervisor
- Executive Vice President, The Second Affiliated Hospital, Zhejiang University School of Medicine
