What are Cyclin-Dependent Kinase 4/6 (CDK4/6) inhibitors?

From the Guidelines

CDK4/6 inhibitors are the standard-of-care for ER-positive, HER2-negative metastatic breast cancer, and should be used in combination with endocrine therapy (ET) as first-line treatment, as they have significantly improved progression-free survival (PFS) and overall survival (OS) compared to ET alone. The three FDA-approved CDK4/6 inhibitors are palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio), which work by blocking specific proteins called cyclin-dependent kinases 4 and 6, preventing cancer cells from multiplying uncontrollably 1. These medications are typically prescribed in combination with hormone therapies like aromatase inhibitors (letrozole, anastrozole) or fulvestrant, and have been shown to be effective in de novo or recurrent metastatic breast cancer, in cases of primary or secondary endocrine resistance, in postmenopausal or premenopausal women, and in men 1.

Some key points to consider when using CDK4/6 inhibitors include:

• Standard dosing varies: palbociclib is 125 mg daily for 21 days followed by 7 days off, ribociclib is 600 mg daily for 21 days followed by 7 days off, and abemaciclib is 150 mg twice daily continuously 1.
• Common side effects include neutropenia (low white blood cell count), fatigue, nausea, and diarrhea, with regular blood monitoring required during treatment 1.
• CDK4/6 inhibitors have significantly improved PFS in breast cancer patients compared to hormone therapy alone, with a good toxicity profile seen in several trials 1.
• The efficacy and overall tolerability of CDK4/6 inhibitors in combination with ET have changed treatment options for patients with HR-positive MBC, and are now the preferred first-line treatment for most patients 1.

It's also important to note that:

• Older patients (≥ 75 years) may experience more toxicity, including fatigue, diarrhea, neutropenia, and hepatotoxicity, and may require dose reductions or treatment interruptions due to side effects 1.
• Patients with limited disease burden, long disease-free interval, and other factors such as treatment tolerance may be candidates for endocrine monotherapy as first-line therapy, with CDK4/6 inhibitors combined with second-line ET 1.
• Optimal sequencing of CDK4/6 inhibitors and ET is an ongoing research question, and clinicians should be aware of the potential benefits and risks of these medications when making treatment decisions 1.

From the FDA Drug Label

Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). Ribociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. CDK4/6 inhibitors are a class of drugs that inhibit the activity of cyclin-dependent kinases 4 and 6, which are involved in cell cycle progression and cellular proliferation.

• They work by decreasing the phosphorylation of the retinoblastoma protein (pRb), resulting in arrest in the G1 phase of the cell cycle and reduced proliferation in breast cancer-derived models.
• CDK4/6 inhibitors, such as abemaciclib and ribociclib, are used in the treatment of breast cancer, particularly in combination with antiestrogen therapies.
• The mechanism of action of CDK4/6 inhibitors involves the inhibition of the cyclin D-CDK4/6 complex, which regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb) 2 3.

From the Research

CDK4/6 Inhibitors Overview

• CDK4/6 inhibitors are a class of drugs used in the treatment of hormone receptor-positive (HR+) breast cancer, particularly in cases where the cancer has progressed to an advanced or metastatic stage 4, 5, 6.
• These inhibitors work by targeting the cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved in the cell cycle progression, thereby inhibiting cancer cell growth 7, 8.

Approved CDK4/6 Inhibitors

• There are three main CDK4/6 inhibitors approved for use: palbociclib, ribociclib, and abemaciclib 4, 5, 8.
• These drugs are often used in combination with endocrine therapy, such as aromatase inhibitors (AIs) or fulvestrant, to treat HR+/HER2- metastatic breast cancer 4, 5, 8.

Efficacy and Safety

• Clinical trials have shown that CDK4/6 inhibitors, when used in combination with endocrine therapy, can significantly prolong progression-free survival and, in some cases, overall survival in patients with HR+/HER2- metastatic breast cancer 4, 5, 8.
• The safety profile of these drugs is generally manageable, with common side effects including hematological toxicities (such as neutropenia) and diarrhea (particularly with abemaciclib) 4, 5, 8.

Real-World Effectiveness

• Real-world evidence has confirmed the effectiveness of CDK4/6 inhibitors in the first-line treatment of HR+/HER2- advanced or metastatic breast cancer, with median progression-free survival and overall survival rates consistent with those reported in clinical trials 5.
• Further research is needed to fully understand the long-term benefits and potential differences between the available CDK4/6 inhibitors 5, 7.