Editor’s Note: CDK4/6 inhibitors (CDK4/6i) have dramatically improved outcomes for patients with hormone receptor–positive, HER2–negative (HR+/HER2-) advanced breast cancer, yet differences remain among available agents in terms of efficacy, safety, and tolerability. There is an unmet need for a CDK4/6 inhibitor that is more potent, safer, and more suitable for long-term use.Lerociclib, a next-generation, independently developed CDK4/6 inhibitor from China, features a unique pharmacologic profile described as “high selectivity, high penetration, high benefit, and low interruption.” The drug demonstrated impressive results in the LEONARDA clinical program. On May 29, 2025, the NMPA approved Lerociclib in combination with an aromatase inhibitor (AI) and Lerociclib in combination with fulvestrant for the first-line and second-line treatment, respectively, of HR+/HER2- locally advanced or metastatic breast cancer in adults.This dual approval marks Lerociclib’s official entry into clinical practice and provides Chinese patients with a more effective, safer, and long-term treatment option. In this feature, Oncology Frontier invited Professor Yueyin Pan, Vice President of Anhui Provincial Cancer Hospital and Professor at the First Affiliated Hospital of the University of Science and Technology of China, to discuss Lerociclib’s mechanistic advantages, clinical evidence, and its potential impact on China’s breast cancer treatment landscape.High Selectivity, High Penetration — Lerociclib Demonstrates Distinctive Potency
Oncology Frontier: On May 29, Lerociclib received NMPA approval for dual indications—first-line and second-line treatment of HR+/HER2- advanced breast cancer. Based on current evidence, how do you evaluate Lerociclib’s efficacy compared with other CDK4/6 inhibitors?
Prof. Pan Yueyin: CDK4/6 inhibitors in combination with endocrine therapy (CDK4/6i + ET) have become the cornerstone for HR+/HER2- advanced breast cancer management. Multiple CDK4/6 inhibitors are already approved globally, but their mechanisms and efficacy differ. Progression-free survival (PFS) improvements vary, and only a few Phase III studies have demonstrated a statistically significant overall survival (OS) benefit.
Lerociclib stands out as a differentiated CDK4/6 inhibitor that incorporates a tricyclic and spiro-ring structure, leading to notable pharmacologic advantages. Firstly, Lerociclib demonstrates high selectivity and potent CDK4 inhibition. CDK4/6 inhibitors function by preventing phosphorylation of the retinoblastoma protein (Rb), halting the cell cycle in tumor cells. Among the CDK family, selective inhibition of CDK4 over CDK6 is particularly beneficial in breast cancer. Lerociclib’s structural innovation allows for strong CDK4 inhibition with minimal off-target kinase activity, and its half-maximal inhibitory concentration (IC50) for CDK4 is lower than that of other agents, reflecting stronger potency.
Secondly, Lerociclib shows superior tumor tissue penetration and retention, achieving sustained intratumoral concentrations and prolonged antitumor activity.
These mechanistic advantages translated into clinical benefit in the LEONARDA-1 study — a multicenter, Phase III trial conducted exclusively in Chinese patients with HR+/HER2- advanced breast cancer that had progressed on prior endocrine therapy.
The trial population was broad and representative of real-world Chinese practice, including both first-line and second-line patients, pre/perimenopausal and postmenopausal women, chemotherapy-experienced patients, and those with visceral metastases or endocrine resistance.
Published in Nature Communications, LEONARDA-1 met its primary endpoint of PFS. Median PFS was 11.07 months with Lerociclib + fulvestrant versus 5.49 months with fulvestrant alone (HR = 0.451; 95% CI: 0.311–0.656; P < 0.0001). Independent review confirmed consistent results (11.93 vs. 5.75 months; HR = 0.353; 95% CI: 0.228–0.547; P < 0.0001).
Subgroup analyses showed uniform PFS benefit across all patient groups, 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 exposure (HR 0.286).
Compared with other CDK4-selective inhibitors, Lerociclib’s PFS hazard ratio is among the lowest reported, reaffirming its high selectivity and potent efficacy.
High Benefit, Low Discontinuation — Excellent Tolerability Profile
Oncology Frontier: CDK4/6 inhibitors differ in toxicity profiles. How does Lerociclib perform in terms of safety and tolerability based on its mechanism and the LEONARDA-1 results?
Prof. Pan Yueyin: Indeed, different CDK4/6 inhibitors have distinct safety characteristics. Both Abemaciclib and Lerociclib show stronger inhibition of CDK4 than CDK6, while inhibition of CDK6 is often associated with hematologic toxicity. Because Lerociclib is highly selective for CDK4, bone marrow suppression and hematologic toxicity are minimal.
Furthermore, some CDK4/6 inhibitors cause gastrointestinal toxicity due to off-target CDK9 inhibition, but Lerociclib exhibits negligible CDK9 activity, resulting in significantly fewer gastrointestinal side effects.
LEONARDA-1 confirmed these advantages.
- Grade 4 neutropenia occurred in only 5.1% of patients.
- No Grade ≥3 diarrhea was observed.
- No QT prolongation, hepatotoxicity, venous thromboembolism (VTE), or interstitial lung disease (ILD) occurred.
- No heart, lung, or coagulation monitoring was required during treatment.
These findings demonstrate that Lerociclib is well-tolerated, enabling continuous dosing without treatment holidays and improving patient quality of life and adherence.
In ET-resistant patients, Lerociclib exhibited a truly balanced profile — “high selectivity, high penetration, high benefit, and low interruption.” It has now been approved for combination therapy with fulvestrant in second-line treatment, providing durable disease control and dual benefits in survival and quality of life.
From Second-Line to First-Line — Establishing a Continuous Therapeutic Defense
Oncology Frontier: The Phase III LEONARDA-2 study evaluating Lerociclib in the first-line setting has also achieved positive results. What do these findings mean for future clinical practice?
Prof. Pan Yueyin: Lerociclib’s research program also targeted endocrine-sensitive populations. LEONARDA-2 was a Phase III study comparing Lerociclib + letrozole versus letrozole alone as first-line therapy in HR+/HER2- advanced breast cancer.
At the 2024 ASCO Annual Meeting, interim results showed statistically significant PFS improvement: Median PFS was not reached with Lerociclib + letrozole versus 16.56 months with letrozole alone (HR = 0.464; P = 0.0004), with consistent benefit by independent review (HR = 0.457; P = 0.0011).
Among first-line CDK4/6 inhibitor studies, Lerociclib’s HR ranks among the lowest reported, confirming substantial PFS improvement. Based on these findings, Lerociclib + AI has been approved as a first-line indication in China.
Differentiation and Data Gaps — Multi-Dimensional Benefits of Lerociclib
Oncology Frontier: With multiple CDK4/6 inhibitors now available in China, how should clinicians differentiate between them in practice?
Prof. Pan Yueyin: The median age of breast cancer onset in China is younger than in Western countries, with a higher incidence of premenopausal patients. These patients often have more aggressive disease biology and poorer prognosis.
LEONARDA-1 enrolled a broad population, including premenopausal, perimenopausal, and postmenopausal women, as well as those with liver metastases, prior chemotherapy, and high tumor burden (≥4 metastatic organs) — features not comprehensively represented in other China-based CDK4/6 inhibitor studies.
Importantly, Lerociclib showed significant PFS improvement in these difficult-to-treat subgroups, filling critical evidence gaps.
From a safety perspective, tolerability is essential in second-line settings where patients may be frail. Unlike other CDK4/6 inhibitors associated with severe diarrhea or hematologic toxicity requiring supportive medications, Lerociclib’s mild safety profile allows for better adherence, improved quality of life, and reduced monitoring costs.
As HR+/HER2- advanced breast cancer becomes a chronic, controllable disease, the treatment goal shifts toward long-term efficacy with minimal toxicity and lifestyle disruption. Among CDK4/6 inhibitors supported by China-specific evidence, Lerociclib distinguishes itself with its “high selectivity, high penetration, high benefit, and low interruption” characteristics, addressing unmet needs and bringing multidimensional clinical benefits.
Its dual-indication approval will further transform clinical practice and bring renewed hope to thousands of breast cancer patients in China.
Professor Yueyin Pan
Chief Physician, Professor, Doctoral Supervisor Vice President, Anhui Provincial Cancer Hospital The First Affiliated Hospital of the University of Science and Technology of China
