Introduction
CDK4/6 inhibitors (CDK4/6i) have become the cornerstone of standard therapy for patients with HR+/HER2- advanced breast cancer. However, differences in efficacy and safety profiles exist among currently approved CDK4/6 inhibitors.
Lerociclib, a novel CDK4/6 inhibitor with a unique molecular structure and original global development background, was approved by China’s National Medical Products Administration (NMPA) on May 29, 2025 for the treatment of HR+/HER2- locally advanced or metastatic breast cancer in adult patients—both as first-line and second-line therapy.
This milestone not only adds a new therapeutic option for patients with HR+ advanced breast cancer but also represents a significant step forward for China in breast cancer treatment innovation. In this special feature, Oncology Frontier invited Professor Binghe Xu, Principal Investigator of the Phase III LEONARDA-1 trial and Director at the Cancer Hospital, Chinese Academy of Medical Sciences, to provide an in-depth interpretation of the clinical and scientific significance of Lerociclib’s approval.
Breast Cancer in China: Unmet Needs Despite Therapeutic Advances
Breast cancer remains one of the most common malignancies among women worldwide. In China, there were approximately 357,000 new cases and 75,000 deaths in 2022. Of these, 5–10% of patients already had distant metastases at diagnosis, and 20–30% of early-stage patients eventually progressed to advanced disease.
The HR+/HER2- subtype accounts for roughly 70% of all breast cancers. Although endocrine therapy remains the standard of care, resistance inevitably develops over time, leading to disease progression.
The advent of CDK4/6 inhibitors has revolutionized the treatment paradigm for HR+/HER2- advanced breast cancer, delivering unprecedented survival benefits. However, clinical experience has revealed that existing CDK4/6 inhibitors are associated with varying degrees of hematologic, gastrointestinal, and hepatic toxicities. Thus, the development of a more potent yet less toxic next-generation CDK4/6 inhibitor has become an urgent need in the field.
Global Quality, Chinese Evidence: The Only Imported CDK4/6 Inhibitor Approved Based on a China-Exclusive Phase III Study
Lerociclib was co-developed by G1 Therapeutics (U.S.) and Jahwa Bio (China) to address key clinical limitations of earlier CDK4/6 inhibitors. Its distinct tricyclic and spiro-ring molecular structure enhances target-binding affinity, resulting in high selectivity and strong inhibitory potency against CDK4.
The innovative structure also confers unique pharmacokinetic/pharmacodynamic (PK/PD) characteristics—notably, minimal bone marrow suppression, reduced incidence of severe neutropenia, and continuous target inhibition through uninterrupted dosing, ensuring sustained antitumor activity.
Lerociclib demonstrates exceptional tumor tissue penetration, achieving tumor concentrations up to 18 times higher than plasma exposure. Even 24 hours after administration, when plasma levels drop to minimal levels, tumor tissue concentrations remain over 100 times higher, supporting continuous tumor suppression.
LEONARDA-1 Trial: China’s Landmark Phase III Study
LEONARDA-1 (NCT05054751) was a randomized, double-blind, Phase III study led by Professor Binghe Xu at the Cancer Hospital, Chinese Academy of Medical Sciences. It enrolled 275 Chinese patients with HR+/HER2- locally advanced or metastatic breast cancer who had relapsed or progressed after prior endocrine therapy. Patients were randomized 1:1 to receive Lerociclib (150 mg twice daily, n=137) or placebo (n=138), both in combination with fulvestrant.
At the 2023 ASCO Annual Meeting, LEONARDA-1 data were featured in the ASCO Daily News under the headline “Lerociclib/Fulvestrant Reduces Risk of Disease Progression in Advanced HR+/HER2- Breast Cancer.” The article summarized key results and quoted Professor Xu’s commentary, marking international recognition of this China-led study.
A New Benchmark for CDK4/6 Inhibitors: Efficacy and Safety in Balance
The final results of LEONARDA-1 were published in Nature Communications in January 2025. According to investigator-assessed outcomes, progression-free survival (PFS) was significantly improved in the Lerociclib group versus placebo:
Median PFS: 11.07 vs. 5.49 months Hazard Ratio (HR): 0.451 (95% CI, 0.311–0.656; P=0.000016)
The trial met its primary endpoint. Predefined subgroup analyses showed consistent benefit across all patient subgroups, including age, menopausal status, hormone receptor expression, prior endocrine resistance, prior chemotherapy, and visceral or hepatic metastases. Notably, even in high-risk populations (≥4 metastatic sites, prior chemotherapy, or primary endocrine resistance), Lerociclib demonstrated robust efficacy.
Safety results were equally impressive:
- Grade ≥3 adverse events (AEs): 57.7%
- Grade 4 neutropenia: 5.1%
- Diarrhea incidence: 19.7%, with no Grade ≥3 events
- No increased risk of hepatotoxicity, QT prolongation, rash, or thrombosis
- Treatment discontinuation due to AEs: only 0.7%
This favorable safety profile enables continuous dosing and improves patient adherence, reflecting Lerociclib’s differentiated pharmacological design.
Dual Indications Approved in China: Expanding Options for HR+ Advanced Breast Cancer
On May 29, 2025, the NMPA approved Lerociclib for:
- First-line treatment — in combination with an aromatase inhibitor as initial endocrine therapy for HR+/HER2- locally advanced or metastatic breast cancer.
- Second-line treatment — in combination with fulvestrant for patients whose disease progressed following prior endocrine therapy.
Expert Insight | Professor Binghe Xu
“The approval of the novel CDK4/6 inhibitor Lerociclib marks another milestone in the field of breast cancer therapy,” said Professor Binghe Xu, Principal Investigator of LEONARDA-1. “Lerociclib, combined with either an aromatase inhibitor or fulvestrant, offers patients with HR+/HER2- advanced breast cancer an effective and well-tolerated therapeutic option—bringing renewed hope for prolonged disease control and improved quality of life.”
“As the first imported CDK4/6 inhibitor approved in China based on a full Chinese population study, Lerociclib exemplifies global innovation supported by Chinese clinical evidence. The LEONARDA-1 trial confirmed that Lerociclib combined with fulvestrant significantly improved PFS while maintaining excellent tolerability—no Grade ≥3 diarrhea, continuous dosing, and high treatment adherence.”
“Its dual indication approval underscores China’s growing capability and global influence in oncology research and drug development. I firmly believe that with its broad adoption, Lerociclib will benefit more patients, empower them to overcome disease, and mark a new chapter in the management of HR+ advanced breast cancer.”
