Written by DengyuePharma

As cancer treatment enters the era of precision medicine, the emergence of each novel targeted therapy has brought renewed hope to countless patients. CDK4/6 inhibitors, a class of targeted agents focusing on cell cycle regulation, have established a central role in the treatment of hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) breast cancer due to their precise mechanism of action and significant clinical efficacy. At the same time, they have demonstrated considerable potential in the treatment of other malignancies, becoming a major research focus and a landmark breakthrough in oncology in recent years.

Decoding the Mechanism of Action: Precisely Blocking the “Proliferation Switch” of Tumor Cells

The cell cycle is the complete process by which cells progress from division and proliferation to apoptosis. Among its phases, the G1 phase (pre–DNA synthesis phase) represents a critical checkpoint for cell proliferation. Dysregulation at this checkpoint leads to uncontrolled cell division, which is a fundamental characteristic of malignant tumors.

Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) are key enzymes regulating the transition from the G1 phase to the S phase (DNA synthesis phase). Under physiological conditions, CDK4/6 must bind to cyclin D to form an active complex, which phosphorylates the retinoblastoma (Rb) protein. This phosphorylation releases the transcription factor E2F, initiating DNA synthesis and cellular proliferation.

In HR+/HER2– breast cancer and other malignancies, cyclin D is frequently overexpressed, resulting in aberrant activation of the CDK4/6–Rb signaling pathway and driving tumor cells into a vicious cycle of unchecked proliferation.

The core function of CDK4/6 inhibitors is to selectively target CDK4/6 kinases by binding to their ATP-binding pockets, thereby preventing the formation of the active CDK4/6–cyclin D complex. This inhibits Rb phosphorylation and arrests tumor cells in the G1 phase, effectively blocking proliferation while largely sparing normal cellular functions. This precision-targeting property explains why CDK4/6 inhibitors demonstrate superior efficacy and a more favorable safety profile compared with traditional chemotherapy, firmly establishing their role in precision oncology.

Deepening Clinical Applications: Comprehensive Protection from Advanced to Early-Stage Breast Cancer

Breast cancer has served as the primary breakthrough area for the clinical application of CDK4/6 inhibitors. To date, a comprehensive treatment paradigm has been established, encompassing first- and second-line therapy for advanced disease as well as adjuvant therapy in early-stage disease. This has been particularly transformative for patients with HR+/HER2– breast cancer, who account for approximately 70% of all breast cancer cases.

In advanced breast cancer, CDK4/6 inhibitors combined with endocrine therapy (such as aromatase inhibitors or fulvestrant) have become the standard first-line treatment for HR+/HER2– advanced or metastatic disease. Compared with endocrine therapy alone, combination regimens significantly prolong progression-free survival (PFS), and in some cases, survival outcomes have nearly doubled. For example, Pfizer’s palbociclib combined with letrozole achieved a median PFS of 24.8 months versus 10.3 months in the control group, while Eli Lilly’s abemaciclib combination therapy achieved a median PFS of 28.2 months, offering advanced-stage patients substantially improved treatment opportunities and hope.

Notably, abemaciclib has demonstrated the ability to penetrate the blood–brain barrier, providing a novel therapeutic option for patients with breast cancer brain metastases and addressing an important unmet clinical need.

Significant progress has also been achieved in early-stage breast cancer. In 2025, Novartis’s CDK4/6 inhibitor ribociclib (Kisqali®, ribociclib succinate tablets) was approved by China’s National Medical Products Administration for adjuvant treatment of early breast cancer. It became the first and currently only CDK4/6 inhibitor globally approved for broad adjuvant treatment in stage II–III HR+/HER2– breast cancer, including select node-negative populations. This approval was based on the pivotal phase III NATALEE trial, which demonstrated a 28.5% reduction in the risk of recurrence and distant metastasis at four years compared with endocrine therapy alone, with consistent benefit across all subgroups and favorable long-term tolerability, supporting a shift from prolonged survival toward the possibility of cure.

Beyond breast cancer, CDK4/6 inhibitors are also being explored in other malignancies, including non–small cell lung cancer, pancreatic cancer, ovarian cancer, and melanoma. Early studies suggest that combination strategies involving CDK4/6 inhibitors with immunotherapy or other targeted agents may enhance therapeutic efficacy. However, these approaches remain under investigation and have not yet become standard of care.

The CDK4/6 Inhibitor Landscape: Imported Leadership and the Rise of Domestic Innovation

Since the approval of the first CDK4/6 inhibitor in 2015, multiple agents have been approved globally, forming a diversified clinical landscape characterized by three imported and two domestically developed drugs, each with distinct profiles in efficacy, safety, and indications, enabling individualized treatment strategies.

Among imported agents:

• Palbociclib (Ibrance®), developed by Pfizer and approved by the U.S. FDA in 2015, was the world’s first CDK4/6 inhibitor. It is widely used in combination with endocrine therapy for HR+/HER2– advanced breast cancer. While hematologic toxicity is relatively prominent, its clinical efficacy is well established.

• Ribociclib (Kisqali®), developed by Novartis and approved by the FDA in 2017, gained approval in China in 2025 for early-stage adjuvant therapy. It is effective across premenopausal and perimenopausal populations, with strong CDK4/6 inhibition and favorable long-term tolerability.

• Abemaciclib (Verzenio®), developed by Eli Lilly and approved by the FDA in 2017, is the only CDK4/6 inhibitor approved as monotherapy for endocrine-resistant breast cancer. Its ability to cross the blood–brain barrier provides a unique advantage in patients with brain metastases, although gastrointestinal toxicity is more prominent.

Domestic CDK4/6 inhibitors have rapidly emerged, breaking the dominance of imported drugs through optimized designs tailored to Chinese patients:

• Dalpiciclib (AiRuiKang®), developed by Hengrui Medicine and approved in December 2021, became China’s first domestically developed CDK4/6 inhibitor. It is indicated in combination with fulvestrant for endocrine-resistant HR+/HER2– advanced breast cancer. Structural optimization reduced hepatotoxicity, with a low incidence of grade ≥3 transaminase elevation, and its clinical data are based entirely on Chinese patient populations.

• Tireciclib (KangMeiNa®), developed by Betta Pharmaceuticals and approved in July 2025, is indicated in combination with fulvestrant for endocrine-progressed HR+/HER2– advanced breast cancer. Phase III trials demonstrated a median PFS of 16.53 months and a disease control rate of 89.1%, with manageable safety.

Several additional CDK4/6 inhibitors remain in development, including Fosun Pharma’s FCN-437c, a second-generation agent capable of crossing the blood–brain barrier with promising activity against brain metastases, and G1 Therapeutics’ trilaciclib, which has expanded indications for reducing chemotherapy-induced myelosuppression, broadening the clinical applications of CDK4/6 inhibition.

Safety and Challenges: Rational Management of Adverse Events and Overcoming Resistance

Compared with traditional chemotherapy, CDK4/6 inhibitors are generally associated with milder adverse events, most of which are grade 1–2 and manageable. However, toxicity profiles vary among agents, requiring careful monitoring in clinical practice.

Common adverse events include hematologic and non-hematologic toxicities. Neutropenia is the most frequent hematologic toxicity, with higher incidence reported in Asian populations. Palbociclib shows the strongest hematologic toxicity signal, followed by ribociclib, while abemaciclib is relatively milder. Among non-hematologic toxicities, diarrhea is most common with abemaciclib, ribociclib requires close monitoring of hepatotoxicity (notably elevated γ-glutamyl transferase), and palbociclib has comparatively lower gastrointestinal and hepatic/renal toxicity. Recent studies have also identified erythema multiforme as a potential new safety signal associated with abemaciclib. Overall, most adverse events are controllable through dose adjustment and supportive care without compromising long-term quality of life.

The greatest clinical challenge with CDK4/6 inhibitors remains drug resistance. Resistance may be primary (lack of initial response) or acquired (disease progression after an initial response). Mechanisms are complex and heterogeneous, involving Rb loss or mutation, cyclin E overexpression, CDK2 activation, and aberrant activation of the PI3K/Akt/mTOR signaling pathway, resulting in limited post-resistance treatment options.

To address resistance, ongoing research focuses on combination strategies with other targeted agents (e.g., PI3K or mTOR inhibitors) or immunotherapies, development of next-generation CDK4/6 inhibitors with optimized structures and enhanced activity, and biomarker-driven individualized treatment approaches based on genomic profiling.

Future Perspectives: Precision Iteration, Expanded Indications, and Broader Patient Benefit

From the approval of the first CDK4/6 inhibitor in 2015 to comprehensive breast cancer treatment coverage today, and from reliance on imported drugs to the rise of domestic innovation, the evolution of CDK4/6 inhibitors reflects continuous progress in precision oncology. Future development is expected to focus on three key directions.

First, expansion of indications. While breast cancer remains the core application, ongoing trials aim to extend CDK4/6 inhibitors to lung cancer, pancreatic cancer, ovarian cancer, and other malignancies, as well as to refine patient selection within breast cancer to further improve cure rates.

Second, continuous drug innovation. Next-generation CDK4/6 inhibitors will aim to overcome resistance and reduce toxicity through structural optimization and enhanced target specificity. Combination regimens with immunotherapy and other targeted agents are expected to play a central role in overcoming the limitations of monotherapy.

Third, improved accessibility. With the approval of more domestically developed CDK4/6 inhibitors and expanded insurance coverage, affordability and access will continue to improve. As clinical evidence accumulates, standardized treatment guidelines will further mature, facilitating broader adoption even in primary care settings.

From foundational research in cell cycle regulation to major clinical breakthroughs, the advent of CDK4/6 inhibitors has fundamentally reshaped the treatment landscape of HR+/HER2– breast cancer and brought renewed hope to countless patients. Despite ongoing challenges such as resistance, continued advances in medical science will propel CDK4/6 inhibitors forward, expanding the boundaries of precision oncology and safeguarding the lives and health of more patients worldwide.