Breast cancer is the most common type of cancer in women, with more than 276,000 new cases estimated in 2020. Hormone receptor–positive (HR+) breast cancer, which accounts for more than 70% of these cases, historically has been treated with endocrine therapy (ET). In recent years, several new targeted therapy options have been developed to combat resistance to the traditional endocrine therapy. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are a newer class of medicines used to treat certain types of metastatic breast cancer.
In normal individuals, there is a precise mechanism that regulates cell growth, proliferation or death, which is called cell cycle regulation.
In essence, malignant tumor is a cell cycle related disease. The destruction of cell cycle regulation leads to uncontrolled cell growth is a common feature of tumorigenesis.
The mammalian cell cycle is the regulatory point from G1 phase to S phase, and the R point is the key point for the regulation of cell proliferation. Only breaking through the R point can trigger DNA replication in the S phase and achieve cell proliferation. Therefore, drugs that can effectively block the progression from the G1 phase to the S phase have become one of the hotspots in the development of anti-tumor drugs.
The cell cycle development process is mainly driven by the complex of cyclin and CDK (both are positively driven). CDK is the core of the regulatory network, leading the initiation, progress and results of the cycle.
Studies have found that during the occurrence and development of a variety of tumors, overexpression of cyclin/CDK or decreased expression of endogenous inhibitors (such as p16) can lead to inactivation of CDK activity, resulting in uncontrolled growth. Since CDK plays a key role in the cell cycle process, CDK inhibitors have become the key to cell cycle regulation drugs.
The CDKS family has 13 members (CDK1~CDK13), all of which belong to the serine/threonine protein kinase family and play a key role in the proliferation and death of all cells. Therefore, broad-spectrum CDK inhibitors are very toxic and have a narrow therapeutic window for patients.
Therefore, it is extremely important to selectively suppress part of the CDK. After careful selection by medicinal chemists, they discovered drugs that can inhibit the two subtypes of CDK4 and CDK6, called CDK4/6 inhibitors.
The CDK inhibitors work by specifically inhibiting CDK4/6 proteins and blocking the transition from the G1 to the S phase of the cell cycle. This drug class inhibits kinase activity, which phosphorylates the retinoblastoma protein pathway. By blocking this path, CDK4/6 inhibitors are able to block cell-cycle progression in the middle of the G1 phase and prevent cancer cell progression. In recent years, three CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) have been approved for patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer.
CDK4/6 Inhibitors: Mechanism of Action Image Source: https://www.ncbi.nlm.nih.gov/
| Drug Name | Brand Name | Company | Approved Area | Dosing | Drug Interaction |
| Palbociclib | Ibrance | Pfizer | United States (2015) European Union (2016) China (2018) |
125mg po once daily for 21 days in a 28-day cycle with food | CYP3A4 substrate |
| Ribociclib | Kisqali | Novartis | United States (2017) European Union (2017) |
600mg po daily for 21 days in a 28-day cycle with or without food | CYP3A4 substrate |
| Abemaciclib | Verzenio | Eli Lilly | United States (2017) European Union (2018) China (Submit a listing application in Nov. 2019) |
600mg or 200mg po bid with or without food | CYP3A4, Pgp, BCRP substrate |
Table 1: Approved CDK4/6 Inhibitors
Among the three approved CDK4/6 inhibotors, abemaciclib has the highest activity and is the only one that has been clinically proven to be used alone without a combination of estrogen receptor inhibitors to show good clinical effects. In terms of administration method, abemaciclib can be administered continuously, while palbociclib and ribociclib are administered for 3 weeks and then stopped for 1 week. In terms of toxicities, the three were similar and mostly showed targeted related toxic reactions, such as neutropenia, thrombocytopenia, fatigue, diarrhea, etc., without serious adverse reactions. The three are similar in terms of overall efficacy (Table 2).
Table 2 Comparative analysis of the efficacy of Palbociclib, Abemaciclib and Rribociclib in the treatment of advanced breast cancer
Remarks: ABC, advanced breast cancer; ABE, abemaciclib; AI, aromatase inhibitor; CBR, clinical benefit rate; LET, letrozole; NCRNPD, neither complete remission nor progressive disease; NSAI, non-steroidal aromatase inhibitor ; ORR, objective response rate; PAL, palbociclib; PBO, placebo; PFS, progression-free survival; RIB, ribociclib; SD, stable disease; TAM, tamoxifen.
In 2019, the global CDK4/6 inhibitor market share reached US$6.019.6 million. From 2015 to 2019, the five-year compound annual growth rate was 52.79%. Among them, Pfizer's Ibrance, as the first CDK4/6 inhibitor drug to be marketed, has global sales of nearly US$5 billion by 2019, occupying approximately 80% of the market share (Figure 3).
By 2017, Novartis’s Kisqal and Eli Lilly’s Verzenio were approved for listing. In 2019, Kisqal's sales grew by 104% year-on-year, and Verzenio's sales grew by 127% year-on-year. Despite this, the combined sales of the two in the first three years of their listing were about 1/3 of Ibrance's same period.
Figure 3: Sales of CDK4/6 inhibitor drugs on the market over the years, unit: million US dollars
The approvals of palbociclib, ribociclib, and abemaciclib in recent years have expanded treatment options for patients with advanced breast cancer. As of February 2020, there are 21 CDK4/6 inhibitors that are under research and entering clinical trials worldwide. The potential of these agents to expand the use of CDK4/6 inhibitors into settings other than HR+, HER2– advanced breast cancer appears promising.
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References:
1. VanArsdale T , Boshoff C , Arndt KT , Abraham RT. Molecular pathways: targeting the cyclin D-CDK4/6 axis for cancer treatment. Clin Cancer Res 2015 ; 21 : 2905 – 10.3
2. Dickson MA. Molecular pathways: CDK4 inhibitorsfor cancer therapy. Clin Cancer Res 2014 ; 20 : 3379 – 83
3. Mahtani RL, Vogel CL. Addressing physician barriersto administering cyclin-dependent kinases 4 and 6 inhibitors in first-linetreatment of hormone receptor–positive, human epidermal growth factor receptor2–negative advanced breast cancer. Cancer Manag Res. 2019;11:513-524
4. A Review of CDK4/6 Inhibitors US Pharm. 2020;45(5)(Specialty&Oncology suppl):3-8.
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