Editor’s note: CDK4/6 inhibitors (CDK4/6i) have become a cornerstone of treatment for hormone receptor–positive, HER2-negative (HR+/HER2-) advanced breast cancer and have substantially improved patient outcomes. On 29 May 2025, China’s National Medical Products Administration (NMPA) approved the novel originator CDK4/6 inhibitor lerociclib for two indications in adults with HR+/HER2- locally advanced or metastatic breast cancer: as a first-line option combined with an aromatase inhibitor (AI), and as a second-line option combined with fulvestrant for patients whose disease progressed after prior endocrine therapy. These approvals are supported by the LEONARDA-1 and LEONARDA-2 phase III trials, which primarily enrolled Chinese patients and demonstrated meaningful efficacy with manageable safety. Oncology Frontier invited Professor Sun Tao of Liaoning Cancer Hospital to interpret the key data and discuss the implications for clinical practice.01 What distinguishes lerociclib’s molecular design and mechanism from traditional CDK4/6 inhibitors?
Professor Sun Tao: As we know, CDK4/6 inhibitors combined with endocrine therapy are established as a standard first-line treatment for HR+/HER2- advanced breast cancer. The recent NMPA approval of lerociclib in combination with endocrine therapy for both first- and second-line settings adds an important new option for clinicians.
Lerociclib differs from earlier CDK4/6 inhibitors in several important ways. First, its molecular scaffold is substantially modified: lerociclib incorporates a tricyclic and spirocyclic structural motif rather than the more common bicyclic/fused-ring scaffolds used by many existing agents. That structural novelty reduces the probability of binding non-target proteins and therefore lowers off-target effects while improving target selectivity.
Second, lerociclib shows high selectivity and potent inhibition of CDK4. Its half-maximal inhibitory concentration (IC50) against CDK4 is lower than many comparators, which mechanistically translates into stronger target suppression.
Third, lerociclib exhibits markedly increased tumor penetration and tissue exposure. Tumor exposure to lerociclib is reported to be approximately 18-fold higher than plasma exposure, allowing for high accumulation and prolonged retention in tumor tissue and supporting sustained target inhibition.
These design features produce distinctive pharmacokinetic and pharmacodynamic properties: clinically, lerociclib tends to cause less marrow suppression, supports continuous dosing, and yields persistent antitumor effects.
02 Clinical efficacy: what benefits will lerociclib bring to Chinese patients?
Professor Sun Tao: Leveraging its mechanism, lerociclib has demonstrated meaningful clinical benefits in both first- and second-line settings.
In the first-line LEONARDA-2 trial (279 treatment-naïve Chinese patients, randomized 1:1 to lerociclib + letrozole versus placebo + letrozole), the trial reached a prespecified efficacy threshold: median progression-free survival (PFS) was not reached in the lerociclib arm versus 16.56 months in the control arm, with a hazard ratio (HR) of 0.464 (95% CI 0.293–0.733), representing a 53.6% reduction in the risk of progression or death.
LEONARDA-1, conducted in patients with disease progression after prior endocrine therapy (randomized 1:1 to lerociclib + fulvestrant versus placebo + fulvestrant; led by Academician Xu Binghe), also produced robust results. The independent central review reported median PFS of 11.93 months versus 5.75 months (HR 0.353; P < 0.0001), a 64.7% reduction in the risk of progression or recurrence. Taken together, the two trials show consistent HR benefits across lines of therapy and offer clinicians an effective new option for a broad spectrum of HR+/HER2- patients.
03 Safety profile: how does lerociclib address unmet clinical needs?
Professor Sun Tao: As patients live longer, tolerance and quality-of-life considerations become increasingly important. Different CDK4/6 inhibitors carry distinct adverse-event spectrums—hematologic toxicity, gastrointestinal events, hepatic effects, cardiac QT prolongation, and venous thromboembolism (VTE) are among the concerns that influence real-world use.
LEONARDA-1 demonstrated that lerociclib’s safety profile is manageable and addresses several clinical needs. The incidence of grade ≥3 adverse events in the lerociclib arm was 57.7%. Importantly, the rate of grade-4 neutropenia was only 5.1%, which helps minimize treatment interruptions. Diarrhea occurred in 19.7% of patients with no grade ≥3 events reported, improving the feasibility of continuous dosing and adherence. No excess hepatic toxicity, QT prolongation, interstitial lung disease (ILD), or VTE signals were observed compared with control. Serious adverse events occurred in 5.8% of patients, and discontinuation due to treatment-related adverse events was 0.7% in LEONARDA-1 (with no discontinuations noted in LEONARDA-2). These findings suggest that lerociclib combines meaningful efficacy with good tolerability and reduces the need for special safety monitoring in routine clinical practice.
04 Impact on the treatment landscape in China
Professor Sun Tao: Lerociclib’s approvals for both first- and second-line therapy—backed by LEONARDA-2 and LEONARDA-1 data—mean it has broad clinical applicability. Because these trials enrolled predominantly Chinese patients, the evidence base is particularly relevant for domestic practice and helps close evidence gaps specific to Chinese patient populations. With its favorable balance of efficacy and safety, lerociclib may reshape the CDK4/6 inhibitor landscape in China and become an important option for clinicians. Under a patient-centered treatment model, the drug’s manageable safety profile, capacity for continuous dosing, and improved treatment experience should help raise the standard of care for HR+/HER2- advanced breast cancer in China.
Professor Sun Tao
Director, Breast Medicine, Liaoning Cancer Hospital Chief Physician, Professor, PhD Supervisor
