The emergence of CDK4/6 inhibitors has marked a significant breakthrough in the treatment of HR+/HER2− advanced breast cancer. However, current CDK4/6 inhibitors still present room for improvement in terms of efficacy and safety, particularly regarding hematologic toxicity, gastrointestinal side effects, and liver toxicity. In recent years, researchers around the world have made remarkable progress in breast cancer treatment. Among these efforts, the publication of results from the phase III LEONARDA-1 trial, led by Academician Binghe Xu of the Cancer Hospital Chinese Academy of Medical Sciences, not only showcased the impressive efficacy and safety profile of the CDK4/6 inhibitor lerociclib, but also highlighted China's growing innovation and international influence in the field of breast cancer therapeutics. Academician Xu shares insights into the current status of CDK4/6 inhibitor use in HR+/HER2− breast cancer, the mechanism of action of lerociclib, and the major breakthroughs from the LEONARDA-1 trial—demonstrating the unique value and therapeutic significance of lerociclib.01
Current Landscape and Challenges in HR+/HER2− Breast Cancer: Clinical Use and Safety Considerations of CDK4/6 Inhibitors
Oncology Frontier: CDK4/6 inhibitors have played an increasingly pivotal role in the treatment of breast cancer. Could you provide an overview of their current position in the management of HR+ advanced breast cancer and explain why there is a need to develop new, innovative CDK4/6 inhibitors?
Academician Binghe Xu: Breast cancer is one of the most common malignancies among women. According to GLOBOCAN data, there were 357,200 new cases of breast cancer in China in 2022, with a median age of onset at 51 years[¹]. Among these new cases, approximately 3%–10% of patients had distant metastases at diagnosis[²], and about 30% of early-stage patients eventually progress to advanced disease[³]. The prognosis for patients with advanced breast cancer remains poor, with previous reports indicating a five-year survival rate of just 20% and a median overall survival of 2–3 years[⁴]. Among all breast cancer patients, 50% to 70% are classified as HR+/HER2− subtype[⁵].
In recent years, the approval and widespread application of CDK4/6 inhibitors have significantly reshaped the clinical treatment paradigm for HR+/HER2− advanced breast cancer, leading to notable improvements in patient survival. As a key class of endocrine-targeted agents, CDK4/6 inhibitors work by blocking cyclin-dependent kinases 4 and 6, thereby halting the transition of tumor cells from the G1 phase to the S phase of the cell cycle, effectively inhibiting tumor proliferation.
At present, CDK4/6 inhibitors combined with endocrine therapy (ET) have become the standard first-line treatment for HR+/HER2− advanced breast cancer, significantly extending both progression-free survival (PFS) and overall survival (OS). However, despite generally favorable tolerability, these agents can still cause adverse effects such as hematologic toxicity, gastrointestinal side effects, and liver function abnormalities. These side effects not only diminish patients’ quality of life but may also lead to treatment interruptions or dose reductions, ultimately compromising efficacy.
As a result, the development of more potent and less toxic CDK4/6 inhibitors has become a critical area of research in the ongoing effort to improve outcomes for breast cancer patients.
02 Lerociclib Demonstrates Durable Antitumor Activity as a Potent and Safer CDK4/6 Inhibitor
Oncology Frontier: Could you tell us about the unique features and advantages of lerociclib’s mechanism of action?
Academician Binghe Xu: Lerociclib is a highly potent, selective oral CDK4/6 inhibitor that exhibits strong inhibitory activity against CDK4/cyclin D1 and CDK6/cyclin D3, with IC₅₀ values of 1 nM and 2 nM, respectively—demonstrating greater potency compared to other CDK4/6 inhibitors [⁶][⁷]. Its activity against CDK9/cyclin T is moderate, with an IC₅₀ of 28 nM. In vitro studies have shown that lerociclib precisely induces G1 phase arrest, suppresses Rb phosphorylation, and inhibits tumor cell proliferation [⁶].
In xenograft models of breast cancer, non-small cell lung cancer, and prostate cancer, daily oral administration of lerociclib significantly inhibited tumor growth [⁶][⁸]. Notably, lerociclib has a much larger apparent volume of distribution compared to other drugs, enabling extensive tissue penetration and high drug accumulation in tumor tissues. In fact, tumor exposure is 18 times higher than plasma exposure. At 24 hours post-administration, drug concentrations in tumor tissues were more than 100 times higher than in plasma, and by 48 hours, tumor concentrations could reach approximately 65 ng/mL, while the drug was no longer detectable in the plasma [⁹]. This favorable tumor distribution enhances its tumor-suppressive effect.
Structurally, lerociclib has been optimized to reduce hematologic and gastrointestinal toxicity. A phase I/II trial involving patients with HR+/HER2− advanced breast cancer showed that continuous lerociclib combined with fulvestrant had a favorable safety profile, with low incidences of grade 4 neutropenia, GI toxicity, fatigue, stomatitis, and alopecia [⁶]. Its pharmacokinetic and safety characteristics support continuous dosing without treatment breaks, allowing for sustained target inhibition and antitumor activity. This leads to better long-term tolerability, improved treatment adherence, and enhanced quality of life for patients.
03 LEONARDA-1: A Study Reflecting China’s Real-World Clinical Challenges and Advancing the Standard of Care
Oncology Frontier: The results of the phase III LEONARDA-1 trial, which you led in a Chinese patient population, were recently published in Nature Communications. How would you evaluate these findings, especially in terms of the efficacy and safety of lerociclib in combination with fulvestrant?
Academician Binghe Xu: LEONARDA-1 is a randomized, double-blind, phase III study that we initiated to evaluate the efficacy and safety of lerociclib in combination with fulvestrant in patients with HR+/HER2− locally advanced or metastatic breast cancer who had relapsed or progressed following prior endocrine therapy. A total of 275 patients were enrolled in the study. Notably, this population included a substantial proportion of patients with high-risk clinical features. Specifically, 40.9% of patients had liver metastases, 24.8% had primary endocrine resistance, 26.3% had metastases involving four or more organs, and 29.2% had received first-line chemotherapy for recurrent or metastatic disease. These characteristics reflect the complexity and severity commonly seen in real-world clinical settings in China.
The study design and patient inclusion criteria were thus well-aligned with actual treatment scenarios, increasing the clinical relevance and applicability of the findings. The LEONARDA-1 trial results, which were recently published in Nature Communications, demonstrated the robust clinical potential of lerociclib in this difficult-to-treat population, particularly when used in combination with fulvestrant.
The results of the LEONARDA-1 study showed that lerociclib combined with fulvestrant significantly prolonged progression-free survival (PFS) in patients with HR+/HER2− advanced breast cancer. According to investigator assessment, the median PFS, which was the primary endpoint, reached 11.07 months in the lerociclib group, more than double that of the placebo group, which had a median PFS of 5.49 months. This corresponds to a 55% reduction in the risk of disease progression or death (HR 0.451, P < 0.0001). PFS assessed by the Blinded Independent Central Review (BICR), a key secondary endpoint, also showed consistent improvement, with a 65% reduction in the risk of progression or death (HR 0.353, P < 0.0001).
Moreover, patients in the lerociclib group experienced notably better tumor responses. The objective response rate (ORR) and clinical benefit rate (CBR), as assessed by investigators, were both significantly higher compared to the placebo group. Specifically, the ORR was 23.4% vs. 8.7%, and the CBR was 48.2% vs. 24.6%. These findings highlight the strong clinical efficacy of lerociclib in combination with fulvestrant for this patient population.
The prespecified subgroup analysis of progression-free survival (PFS) revealed that the benefits of lerociclib combined with fulvestrant were consistently observed across all patient subgroups, aligning with the overall study results. These subgroups included patients stratified by age (<65 or ≥65 years), menopausal status, hormone receptor profile, prior endocrine therapy resistance status, prior endocrine therapy purpose, whether chemotherapy was administered during the recurrent/metastatic stage, presence of visceral or liver metastases, measurable disease status, and baseline Eastern Cooperative Oncology Group (ECOG) performance status. Importantly, the PFS subgroup analysis also showed that lerociclib plus fulvestrant led to substantial improvements in PFS and significantly reduced the risk of disease progression or death even in difficult-to-treat populations, such as those with liver metastases, primary endocrine resistance, four or more metastatic organs, and those who had received chemotherapy during the recurrent or metastatic phase. These results further support the robust and broad clinical efficacy of lerociclib across a diverse range of patient profiles.
The safety profiles of CDK4/6 inhibitors vary in terms of hematologic toxicity, gastrointestinal side effects, and QT interval prolongation. For example, abemaciclib is generally associated with less hematologic toxicity but more gastrointestinal symptoms. In contrast, palbociclib and dalpiciclib have been linked to higher rates of grade 3 or 4 neutropenia, while ribociclib has been associated with potential QT interval prolongation. In this context, lerociclib also stands out for its favorable safety profile. In the LEONARDA-1 study, the most common grade 3 or 4 treatment-related adverse events were hematologic toxicities, primarily neutropenia and leukopenia. The incidence of grade 3 or 4 neutropenia in the lerociclib group was 46.7%, with grade 4 neutropenia occurring in only 5.1% of patients. Notably, no cases of febrile neutropenia were reported. Neutropenia was effectively managed through dose interruption or reduction and/or the use of granulocyte colony-stimulating factor (G-CSF), and no patients discontinued treatment due to neutropenia. Gastrointestinal toxicities—such as diarrhea, nausea, and vomiting, which are commonly seen with abemaciclib and ribociclib—were observed in fewer than 20% of patients treated with lerociclib, and no grade 3 or 4 diarrhea was reported. Although cross-trial comparisons are inherently challenging and subject to bias, these findings suggest that lerociclib may offer an overall safety advantage in terms of gastrointestinal and hematologic toxicity [¹⁰].
Furthermore, only 0.7% of patients in the lerociclib group discontinued treatment due to adverse events, a rate lower than those reported in previous CDK4/6i trials, which ranged from 2.5% to 15.9% [¹⁰–¹⁴].
04 LEONARDA-1 Highlights China’s Innovation and Global Impact in Breast Cancer Research
Oncology Frontier: The publication of the LEONARDA-1 results has brought new hope with the novel CDK4/6 inhibitor lerociclib for Chinese patients. How do you think this study reflects China’s growing innovation and international influence in the field of breast cancer research?
Academician Binghe Xu: As the first study of a new CDK4/6 inhibitor specifically targeting the Chinese patient population, the LEONARDA-1 trial not only confirmed the efficacy and safety of lerociclib in Chinese patients but also demonstrated the remarkable capabilities of Chinese researchers in clinical trial design, data analysis, and result interpretation. We presented the preliminary findings of LEONARDA-1 at the 2023 ASCO Annual Meeting [¹⁵]. In January of this year, the final results were successfully published in the internationally renowned journal Nature Communications, further showcasing the scientific innovation and global presence of Chinese researchers in the field of breast cancer treatment. This achievement strengthens China’s voice in global discussions on breast cancer management.
The outstanding performance of lerociclib not only provides a new treatment option for patients with HR+/HER2− advanced breast cancer but also contributes Chinese wisdom and solutions to the global breast cancer field. The development of lerociclib and the success of the LEONARDA-1 trial mark a major innovation milestone for China in the field of breast cancer therapy. With the accumulation of additional clinical data and broader adoption in practice, lerociclib is expected to become a key treatment option for patients with HR+/HER2− advanced breast cancer, helping to further prolong survival and improve quality of life.
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Academician Binghe Xu
- Member of the Chinese Academy of Engineering
- Academic Committee Member, Chinese Academy of Medical Sciences
- Tenured Professor, Peking Union Medical College
- Director, National Clinical Research Center for Antineoplastic Drugs
- Honorary Chair, Breast Cancer and Clinical Research Committees of the Chinese Anti-Cancer Association
- President, Beijing Society of Oncology and Beijing Society for Breast Disease Prevention and Treatment
