Editor’s Note: CDK4/6 inhibitors (CDK4/6i) play a pivotal role in the treatment of HR+/HER2– advanced breast cancer (ABC). However, their efficacy and safety profiles vary across different agents. There remains a strong clinical need for more effective and safer CDK4/6 inhibitors to enable long-term maintenance therapy and improve patient outcomes.
Recently, the original imported novel CDK4/6 inhibitor Lerociclib was approved in China for both first-line and second-line indications in HR+/HER2– advanced breast cancer. With its unique structural and pharmacological advantages, Lerociclib has demonstrated significant efficacy improvements while markedly reducing adverse reactions.
Oncology Frontier invited Prof. Zhongsheng Tong from Tianjin Medical University Cancer Institute and Hospital to provide his expert interpretation of Lerociclib’s key strengths and discuss its transformative impact on breast cancer management in China.
01. Oncology Frontier:
Currently, CDK4/6 inhibitors are a standard component of therapy for HR+/HER2– advanced breast cancer. However, differences in molecular design lead to variations in efficacy and tolerability among agents. As a structurally innovative CDK4/6 inhibitor, what are Lerociclib’s key advantages, and what clinical value does it offer to patients?
Prof. Tong Zhongsheng: Indeed, CDK4/6 inhibitors combined with endocrine therapy have become the standard of care for both first-line and second-line treatment in HR+/HER2– breast cancer.
Each CDK4/6 inhibitor differs structurally, resulting in variations in efficacy, safety, and pharmacokinetic profiles. Lerociclib represents a new generation of CDK4/6 inhibitors with structural innovation, showing distinct clinical advantages.
At our department (Breast Oncology, Tianjin Medical University Cancer Institute and Hospital), we participated in both LEONARDA-1 and LEONARDA-2, two pivotal phase III trials investigating Lerociclib in HR+/HER2– advanced breast cancer. Across both studies, Lerociclib consistently demonstrated dual benefits in efficacy and safety, providing meaningful clinical value for patients.
Structurally, Lerociclib introduces a tricyclic and spirocyclic scaffold, which enhances its binding affinity and lowers its half-maximal inhibitory concentration (IC50) for CDK4 compared with other CDK4/6 inhibitors. This results in higher CDK4 selectivity, improved antitumor potency, and reduced bone marrow suppression.
Additionally, Lerociclib exhibits greater tumor tissue penetration, achieving high and sustained drug concentrations within tumor tissue. This enables potent and durable tumor inhibition.
Thanks to its high selectivity and superior tissue permeability, Lerociclib effectively maximizes therapeutic benefit while minimizing adverse events such as bone marrow suppression. These advantages allow patients to continue long-term oral therapy comfortably, thereby improving both quality of life and survival outcomes. I believe Lerociclib will bring even greater benefits to patients in the near future.
02. Oncology Frontier:
The LEONARDA-1 study was a key phase III trial evaluating Lerociclib in endocrine therapy–pretreated HR+/HER2– mBC patients. Could you elaborate on the efficacy and safety outcomes of this study, especially in difficult-to-treat populations?
Prof. Tong Zhongsheng: The LEONARDA-1 trial, led by Academician Binghe Xu, was a landmark phase III study. Our hospital participated as one of the enrolling centers. This was the only phase III trial conducted exclusively in Chinese patients with HR+/HER2– advanced or metastatic breast cancer who experienced disease progression after prior endocrine therapy.
The study population was highly representative of real-world clinical practice—encompassing both pre- and postmenopausal women, as well as those with visceral metastases, prior chemotherapy, and primary or secondary endocrine resistance—making its findings particularly applicable to Chinese clinical settings.
Efficacy: Investigator-assessed median PFS was 11.07 months for the Lerociclib + fulvestrant group versus 5.49 months for placebo + fulvestrant (HR 0.451; P<0.0001). The blinded independent central review (BICR) confirmed these results: 11.93 vs 5.75 months (HR 0.353; P<0.0001).
Subgroup analyses showed consistent benefits across all patient populations, including those with liver metastases (HR 0.487), primary endocrine resistance (HR 0.374), high tumor burden (≥4 metastatic organs, HR 0.326), and prior chemotherapy (HR 0.286). These findings demonstrate significant improvements in PFS and reductions in disease progression and death risk, even among heavily pretreated or refractory patients. We anticipate that long-term follow-up will yield equally encouraging overall survival (OS) results.
Safety: Lerociclib exhibited an excellent safety profile. Grade ≥3 adverse events occurred in 57.7% of patients, with grade 4 neutropenia at only 5.1%, effectively avoiding treatment interruptions due to neutropenia. Gastrointestinal toxicity was mild—diarrhea occurred in 19.7%, with no grade ≥3 events. No venous thromboembolism (VTE) or other serious adverse events were observed.
Importantly, Lerociclib did not increase risks of hepatotoxicity, QT prolongation, interstitial lung disease (ILD), or rash. The treatment discontinuation rate due to adverse events was just 0.7%, underscoring its excellent tolerability and safety.
Overall, Lerociclib demonstrated significant efficacy, strong tolerability, and superior patient compliance, suggesting that it will provide physicians and patients with an improved treatment experience and outcomes in real-world settings.
03. Oncology Frontier:
Given Lerociclib’s approval in China and its promising LEONARDA-1 results, what role do you foresee for this agent in the future of breast cancer treatment in China? How will it influence patient experience and long-term outcomes?
Prof. Tong Zhongsheng: The LEONARDA-1 trial, designed specifically for Chinese patients, provides data highly reflective of local clinical realities. Its findings confirm that Lerociclib + fulvestrant delivers dual benefits in efficacy and safety, potentially reshaping future treatment practices in China.
With several CDK4/6 inhibitors already approved in China, Lerociclib—through its structural innovation and optimized pharmacologic design—adds a valuable new option for HR+/HER2– advanced breast cancer patients. Subgroup results from LEONARDA-1 showed that both previously resistant and difficult-to-treat populations achieved meaningful PFS improvement, highlighting its broad clinical utility.
Moreover, Lerociclib’s minimal adverse events, absence of hepatotoxicity, QT prolongation, ILD, or rash, and low discontinuation rate (0.7%) support long-term use and better quality of life for patients—while potentially reducing healthcare costs through decreased monitoring requirements.
From an efficacy standpoint, Lerociclib’s strong CDK4 inhibition and sustained antitumor activity significantly extend PFS, translating into a higher likelihood of prolonged survival. For HR+/HER2– breast cancer, where patients often live longer, maintaining efficacy with good tolerability is critical. LEONARDA-1 demonstrated PFS benefits even among those with prior chemotherapy and endocrine therapy resistance, underscoring Lerociclib’s potential to meet unmet needs.
It is also worth emphasizing that LEONARDA-1 was conducted entirely among Chinese patients, making its findings particularly applicable to real-world practice in China. With Lerociclib’s domestic approval, clinical accessibility will expand substantially, enabling more patients to benefit from this highly effective, safe, and convenient therapy.
Prof. Zhongsheng Tong
Professor, MD, PhD Chief Physician, Department of Breast Oncology Tianjin Medical University Cancer Institute and Hospital
