Editor’s Note: The China National Medical Products Administration (NMPA) has officially approved the novel CDK4/6 inhibitor (CDK4/6i) Lerociclib for two indications in adult patients with hormone receptor–positive, HER2–negative (HR+/HER2-) locally advanced or metastatic breast cancer:
- In combination with an aromatase inhibitor (AI) as initial endocrine therapy, and
- In combination with fulvestrant for patients with disease progression following prior endocrine therapy (ET).
In this exclusive interview, Professor Xinhong Wu, Vice President of Hubei Cancer Hospital, discusses the mechanistic innovations underlying Lerociclib’s optimized design and interprets clinical findings from its two pivotal Phase III trials, highlighting its efficacy and safety in the treatment of HR+/HER2- advanced breast cancer.
01. CDK4/6 Inhibitors: Evolution and Role in HR+/HER2- Breast Cancer
Oncology Frontier: Could you give an overview of the development of CDK4/6 inhibitors and their current clinical role in HR+/HER2- breast cancer?
Prof. Wu Xinhong: Cyclin-dependent kinases (CDKs) are key regulators of cell cycle progression. Early-generation broad-spectrum CDK tyrosine kinase inhibitors (TKIs) targeted multiple kinases and caused severe toxicity, preventing clinical application.
Subsequent research focused on selective CDK inhibitors—such as palbociclib, abemaciclib, and ribociclib—which specifically inhibit CDK4 and CDK6, achieving significant gains in both efficacy and safety. After decades of refinement, the evolution from broad CDK inhibition to selective CDK4/6 inhibition has greatly improved therapeutic outcomes and tolerability in breast cancer.
With accumulating clinical evidence, CDK4/6 inhibitors have become a cornerstone therapy in HR+/HER2- breast cancer. Their current indications cover first-line treatment for both premenopausal and postmenopausal advanced patients, as well as adjuvant therapy for high-risk early-stage disease.
However, the pursuit of more potent and safer CDK4/6 inhibitors continues. Recent developments have focused on precisely targeted, next-generation CDK4/6 inhibitors with enhanced efficacy and reduced toxicity, offering clinicians more refined and individualized options.
02. Mechanistic Advantages: The Design of the Novel CDK4/6 Inhibitor Lerociclib
Oncology Frontier: The newly approved Lerociclib was co-developed by Chinese and U.S. partners. What differentiates it structurally and mechanistically from earlier CDK4/6 inhibitors?
Prof. Wu Xinhong: The development trend in this drug class is toward greater target precision—enhancing CDK4 inhibition while minimizing off-target effects to improve efficacy and reduce toxicity. Enhanced CDK4 selectivity is thought to correlate with improved outcomes in breast cancer.
Existing CDK4/6 inhibitors differ in both efficacy and safety, with some associated with notable hematologic and gastrointestinal toxicity, leading to treatment interruptions. Additionally, certain inhibitors may cause venous thromboembolism (VTE), interstitial lung disease (ILD), QT prolongation, or elevated liver enzymes, all of which require specialized monitoring and increase medical costs.
Lerociclib introduces a unique tricyclic and spiro-ring molecular structure, which enhances binding affinity for the CDK4 target while reducing off-target interactions. Kinase selectivity profiling shows that Lerociclib selectively inhibits CDK4 with minimal cross-reactivity to other kinases—unlike many CDK4/6 inhibitors that inhibit multiple kinases. Moreover, its IC50 for CDK4 is only 1 nM, and it achieves high tumor tissue accumulation and prolonged retention, conferring potent, sustained antitumor activity with a favorable safety margin.
In short, Lerociclib embodies the concept of “high selectivity, strong inhibition, and low toxicity”, representing a new generation of optimized CDK4/6 inhibitors.
03. Dual Indications: Key Phase III Clinical Evidence Supporting Lerociclib’s Approval
Oncology Frontier: The two approved indications are based on the LEONARDA-1 and LEONARDA-2 Phase III trials. Could you summarize their efficacy and safety outcomes?
Prof. Wu Xinhong: Both LEONARDA-1 (ET-pretreated) and LEONARDA-2 (treatment-naïve) were Phase III studies conducted exclusively in Chinese patients. The inclusion criteria were broad, enrolling both premenopausal and postmenopausal women, as well as those with visceral metastases and high tumor burden, reflecting real-world clinical practice in China.
Efficacy:
- In LEONARDA-2, which enrolled treatment-naïve patients, investigator-assessed PFS was not reached in the Lerociclib + letrozole arm versus 16.56 months in the placebo + letrozole arm, corresponding to a 53.6% reduction in risk of progression or death (HR 0.464; 95% CI: 0.293–0.733; P = 0.0004). Subgroups with visceral metastases (HR 0.420) and high tumor burden (≥3 metastatic sites, HR 0.399) also achieved substantial PFS benefit.
- In LEONARDA-1, which enrolled patients with disease progression following endocrine therapy, median PFS was 11.07 vs. 5.49 months, reflecting a 54.9% reduction in progression or death (HR 0.451; 95% CI: 0.311–0.656; P < 0.0001). Consistent benefit was observed in challenging subgroups, including liver metastases (HR 0.487), primary endocrine resistance (HR 0.374), high tumor burden (HR 0.326), and prior chemotherapy (HR 0.286).
Safety: Lerociclib demonstrated a favorable tolerability profile across both trials:
- Grade 4 neutropenia occurred in only 5.1% of patients.
- No Grade ≥3 diarrhea events were reported.
- Only one discontinuation (0.7%) occurred, unrelated to Lerociclib.
- No ILD, VTE, or clinically meaningful QT prolongation events were observed, and hepatic enzyme elevations were minimal.
These results confirm that Lerociclib offers a balance of potent efficacy and excellent tolerability, enabling continuous dosing and long-term therapy without the need for intensive safety monitoring.
04. Differentiation and Clinical Value: Lerociclib’s Role in Meeting China’s Treatment Needs
Oncology Frontier: Based on these findings, what unique advantages does Lerociclib offer in addressing the unmet needs of Chinese patients with HR+/HER2- advanced breast cancer?
Prof. Wu Xinhong: Most pivotal trials of existing CDK4/6 inhibitors did not include premenopausal patients, yet the median age of breast cancer onset in China is younger, and premenopausal patients account for a substantial proportion of cases. These patients often have more aggressive disease biology and visceral or high-burden metastases, which require more potent CDK4/6 inhibition for optimal disease control.
The LEONARDA program enrolled a broad and representative patient population and achieved remarkably low hazard ratios (HRs) across subgroups, demonstrating wide applicability and high clinical benefit.
Moreover, Lerociclib’s low hematologic and gastrointestinal toxicity, minimal treatment interruptions, and no need for special monitoring for ILD, VTE, or QT prolongation significantly enhance patient adherence and reduce treatment burden.
Taken together, the efficacy, safety, and pragmatic clinical advantages of Lerociclib establish it as a powerful and patient-friendly treatment option. Its dual approval in China will help achieve durable disease control and improve long-term survival outcomes for more patients with HR+/HER2- advanced breast cancer.
Professor Xinhong Wu
Vice President, Hubei Cancer Hospital Director, Hubei Clinical Research Center for Breast Cancer
