Editor’s Note: As a standard treatment for hormone receptor–positive, HER2–negative metastatic breast cancer (HR+/HER2- MBC), CDK4/6 inhibitors (CDK4/6i) have significantly improved therapeutic outcomes and expanded treatment options. However, developing next-generation CDK4/6 inhibitors with higher efficacy and lower toxicity remains essential to improve long-term patient survival and quality of life.
On this note, the China National Medical Products Administration (NMPA) has officially approved the novel, originator CDK4/6 inhibitor Lerociclib for use in adult patients with HR+/HER2- MBC—
- in combination with an aromatase inhibitor (AI) as first-line endocrine therapy, and
- in combination with fulvestrant for patients with disease progression after prior endocrine therapy.
This milestone marks a new era for HR+/HER2- breast cancer treatment in China. In this special interview, Oncology Frontier invited Professor Xichun Hu, chief investigator of the LEONARDA-2 study and professor at Fudan University Shanghai Cancer Center, to provide an in-depth analysis of the clinical evidence and pharmacologic advantages of Lerociclib, as well as insights into its future clinical role.
01. LEONARDA-2: Lerociclib Plus Letrozole Shows Significant Efficacy in HR+/HER2- Advanced Breast Cancer
Oncology Frontier: In the LEONARDA-2 study, the combination of Lerociclib and letrozole demonstrated remarkable efficacy in patients with HR+/HER2- locally advanced or metastatic breast cancer. Could you share the main efficacy results and their significance for first-line treatment in Chinese patients?
Prof. Xichun Hu: Lerociclib is a novel CDK4/6 inhibitor that has undergone a series of clinical studies. The first pivotal Phase III trial conducted in Chinese patients was LEONARDA-1, which enrolled HR+/HER2- advanced or metastatic breast cancer patients whose disease had recurred or progressed following prior endocrine therapy.
In that study, Lerociclib + fulvestrant significantly improved progression-free survival (PFS) compared with placebo + fulvestrant (investigator-assessed median PFS: 11.07 months vs. 5.49 months; HR 0.451, 95% CI 0.311–0.656; P = 0.000016).
Building on these positive findings in the second-line setting, we initiated the Phase III LEONARDA-2 study in Chinese patients with previously untreated HR+/HER2- advanced or metastatic breast cancer. Patients were randomized 1:1 to receive Lerociclib + letrozole (treatment arm) or placebo + letrozole (control arm). The primary endpoint was investigator-assessed PFS; secondary endpoints included blinded independent central review (BICR)-assessed PFS, objective response rate (ORR), overall survival (OS), and safety.
The results were consistent and compelling. Compared with the control arm, the treatment arm achieved a median PFS not reached (NR) vs. 16.56 months; HR 0.464 (95% CI 0.293–0.733; P = 0.0004), corresponding to a 54% reduction in risk of progression or death. Both investigator and independent reviews confirmed the same trend of benefit. Additionally, ORR and clinical benefit rate (CBR) were superior in the Lerociclib + letrozole arm.
Taken together, across first-line (LEONARDA-2) and second-line (LEONARDA-1) studies, Lerociclib consistently improved response rates and prolonged PFS, providing a new and highly effective therapeutic option for Chinese patients with HR+/HER2- advanced breast cancer.
02. Structural Innovation Drives Superior Efficacy and Safety
Oncology Frontier: As a structurally innovative CDK4/6 inhibitor, how does Lerociclib’s molecular design contribute to its clinical advantages in efficacy and safety?
Prof. Xichun Hu: Currently, four CDK4/6 inhibitors—palbociclib, abemaciclib, ribociclib, and dalpiciclib—have been approved in China. The field continues to pursue “me-better” and “me-best” drugs with higher potency and improved tolerability. Lerociclib is precisely such a next-generation agent, designed to achieve an optimal balance of efficacy and safety.
Its tricyclic and spirocyclic molecular structure enhances affinity for the CDK4 target (high selectivity) and reduces binding to non-target kinases, thereby minimizing off-target effects. Preclinical studies demonstrated high tumor tissue permeability—tumor drug concentrations far exceed plasma levels, even when plasma concentrations become undetectable. This results in sustained intratumoral inhibition with lower systemic accumulation, explaining the milder bone marrow suppression observed in patients.
These pharmacokinetic and pharmacodynamic advantages underlie its “me-better” profile.
In the LEONARDA-2 study, Lerociclib + letrozole achieved a PFS HR of 0.464 (95% CI 0.293–0.733)—among the lowest reported in first-line CDK4/6i trials globally. Subgroup analysis revealed consistent benefits, including in patients with visceral metastases (HR 0.420) and those with ≥3 metastatic sites (HR 0.399), further supporting its high-selectivity, high-penetration mechanism of action.
Regarding safety, the incidence of grade 4 neutropenia was only 5.1%, and gastrointestinal adverse events were mostly mild. Importantly, no venous thromboembolism (VTE) was observed, and QT interval prolongation rates were comparable to control. Only one patient (0.7%) discontinued due to treatment-emergent adverse events, confirming excellent tolerability.
Overall, the innovative structural design enables Lerociclib to deliver stronger tumor suppression with lower toxicity, effectively prolonging PFS while maintaining quality of life for HR+/HER2- breast cancer patients in China.
03. Expanding First-Line Treatment Options and Shaping Future Clinical Practice
Oncology Frontier: With the approval of the Lerociclib + letrozole regimen in China, what long-term impact do you foresee on first-line HR+ MBC treatment and clinical practice?
Prof. Xichun Hu: HR+/HER2- breast cancer accounts for roughly 70% of all breast cancer cases. Although four CDK4/6 inhibitors are already available in China, unmet clinical needs remain—particularly the need for agents with less hematologic toxicity, minimal QT prolongation, and no VTE or hepatic toxicity.
Both the LEONARDA-1 and LEONARDA-2 trials, along with other published studies, demonstrate that Lerociclib + endocrine therapy provides comparable or superior efficacy with fewer adverse events, particularly in hematologic and cardiac safety.
According to current clinical guidelines and expert consensus, CDK4/6 inhibitors are the standard of care in both first- and second-line settings for HR+/HER2- MBC. The approval of Lerociclib broadens the therapeutic arsenal, offering clinicians a potent yet well-tolerated option. Given its favorable efficacy-to-safety balance, Lerociclib-based combinations can be prioritized when selecting therapy for appropriate patients.
To definitively establish which CDK4/6 inhibitor is the “me-best” agent, future head-to-head trials will be essential. In the meantime, real-world evidence will further validate Lerociclib’s role as an effective and safe next-generation CDK4/6 inhibitor.
Professor Xichun Hu Fudan University Shanghai Cancer Center Doctoral Supervisor
