Medically reviewed by Dr. C.H. Weaver M.D. 3/2019
The majority of breast cancers are hormone receptor-positive. These cancers are stimulated to grow by the circulating female hormones estrogen and/or progesterone. Treatment of hormone receptor-positive breast cancer often involves hormonal therapies that suppress or block the action of estrogen.
Cyclin-dependent kinase (CDK) inhibitors work by blocking the action of enzymes called kinases which are involved in the growth of HR-positive breast cancer. Kinases are involved in many cell functions, including cell signaling, growth, and division. These enzymes may be too active or found at high levels in some types of cancer cells, and blocking them may help keep cancer cells from growing.
A major hallmark of cancer cells is their ability to multiply rapidly; CDK inhibitors interfere with this process by blocking the activity of enzymes known as CDKs, particularly CDK 4 and CDK 6, that help to regulate cell division. For effectively treating breast cancer, CDK inhibitors are usually combined with endocrine therapy, which works by preventing hormones from binding with their respective receptors on the cancer cells.(1)
CDK Inhibitors Approved for the Treatment of Breast Cancer
According to a report published in The Oncologist, CDK inhibitors are very well tolerated with minimal side effects. CDK inhibitors will replace traditional endocrine therapies in many situations, and have a unique set of side effects.(2-6)
The most common side effect is neutropenia, a low level of white blood cells, which can increase the chance of infection. Neutropenia is temporary and dose-dependent with the white blood count usually return to normal with dose-interruption or dose-reduction of the drug. Other side effects include diarrhea, fatigue, nausea, and alopecia (hair loss), which are usually mild and reversible by reducing the dose and taking regular breaks.
Patients and physicians should also be aware of certain drug-drug interactions with CDK 4/6 inhibitors, particularly for substances that inhibit the activity of an enzyme known as CYP3A, such as the antibiotic clarithromycin and grape juice. CYP3A is the prime enzyme responsible for breaking down CDK 4/6 inhibitors in the liver, and thus inhibiting its activity could lead to the build-up of high levels of the drug.
The combination of Ibrance® (palbociclib) and Faslodex® (fulvestrant) improves progression-free survival in women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER)-negative metastatic breast cancer.(3)
The phase III clinical trial known as the PALOMA3 trial directly compared Ibrance in combination with Faslodex to Faslodex alone for the treatment of advanced hormone-receptor-positive breast cancer. Faslodex is a type of hormonal therapy known as an estrogen receptor antagonist, which blocks the actions of estrogen. Women who were near menopause (pre- and perimenopausal) also received a drug called Zoladex® (goserelin). Zoladex is approved for the treatment of advanced breast cancer in pre- and perimenopausal women to reduce the production of estrogen.
The trial enrolled 521 patients with metastatic ER-positive, HER2-negative breast cancer. In all of the patients, cancer had come back or progressed after previous hormonal therapy.
Ibrance more than double progression-free survival. Women treated with Ibrance plus Faslodex had a median progression-free survival of 9.2 months, compared with 3.8 months for those who received placebo plus Faslodex.
Kisqali is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably.
The Phase III MONALEESA-7 clinical trial evaluated Kisqali® in combination endocrine-based therapy in premenopausal or perimenopausal women with hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer who had not previously received endocrine therapy for advanced disease.(4,5,6)
Kisqali in combination with tamoxifen or an aromatase inhibitor plus goserelin demonstrated an improved time of survival without cancer progression of 23.8 months compared to 13.0 months for tamoxifen or an aromatase inhibitor plus goserelin.
The Kisqali combination was well tolerated and women taking Kisqali also had a clinically meaningful improvement in pain symptoms as early as eight weeks; this improvement was sustained. The most significant side effect observed in patients receiving Kisqali combination therapy compared to endocrine therapy alone was neutropenia which occurred in 60.6% compared to 3.6% of endocrine only treated patients.
FDA Approves First-of-its-kind Kisqali® Femara® Co-Pak For Initial Treatment Of HR+/HER2- Advanced or Metastatic Breast Cancer
The US Food and Drug Administration (FDA) has approved the Kisqali ®Femara ® Co-Pack (ribociclib tablets; letrozole tablets) for the treatment of hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer in postmenopausal women.
The packaging of the Kisqali-Femara Co-Pack allows patients the convenience of obtaining a full 28-day cycle of the two medicines in one package with one prescription and one co-pay. The Kisqali-Femara Co-Pack is available at the same cost as Kisqali alone. The Kisqali-Femara Co-Pack will be available in the US later this month at both specialty and retail pharmacies, and does not change the indication for either medicine.
Verzenio is a CDK inhibitor designed to block the growth of cancer cells by specifically inhibiting CDK 4 and 6.
The Phase 3 MONARCH 2 study showed that Verzenio (abemaciclib), a cyclin-dependent kinase (CDK) 4 & 6 inhibitor, when administered in combination with fulvestrant, significantly improves the time to cancer progression compared to treatment with fulvestrant alone in women with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), advanced breast cancer.
In the current MONARCH 2 clinical trial 669 patients with advanced breast cancer were treated with either Verzenio plus fulvestrant, or fulvestrant alone and directly compared. The combination therapy achieved an objective response rate of 48.1% compared to 21.3% in patients treated with fulvestrant alone. This translated into a delay in the time to cancer progression. Patients treated with the combination survived 16.4 compared to 9.3 months for fulvestrant alone without cancer progression.Cyclin-dependent kinases play a key role in regulating the replication and growth of breast cancer cells and several medicines that target this growth pathway have either been recently approved or are in the development process.
approval of Verzenio as initial therapy in combination with an AI is based on the pivotal MONARCH 3 clinical trial. MONARCH 3 evaluated Verzenio in combination with an AI as initial endocrine-based therapy in 493 postmenopausal women with HR+, HER2- advanced breast cancer whom had no prior systemic treatment for advanced disease.2
Verzenio demonstrated a greater than 28-month median progression-free survival (PFS) in patients who received initial endocrine-based therapy for metastatic disease compared to 14.8 months for treatment with an AI alone. Verzenio plus an AI had an objective response rate of 55.4 percent compared to 40.2 percent for treatment with an AI alone. The median duration of response was 27.4 months with Verzenio plus an AI versus 17.5 months for treatment with an AI alone.2
Verzenio is now indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer:
- in combination with an aromatase inhibitor for postmenopausal women as initial endocrine-based therapy
- in combination with fulvestrant for women with disease progression following endocrine therapy
- as a single agent for adult patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting
Dana Farber Oncologists Explain CDK 4/6
In the brief time that drugs known as CDK4/6 inhibitors have been approved for the treatment of metastatic breast cancer, doctors have made a startling observation: in certain patients, the drugs – designed to halt cancer cell division – do not just stop tumors from growing but can cause them to shrink, in some cases markedly.
New research by scientists at Dana-Farber Cancer Institute and Brigham and Women’s Hospital reveals an unexpected mechanism behind these tumor regressions. In a study published in the journal Nature, the investigators show that CDK4/6 inhibitors not only stymie the division of cancer cells but can also spur the immune system to attack and kill the cells. When the drugs were coupled with other immunotherapy agents, the anti-cancer effect can be even greater, they report.
The findings, which follow Dana-Farber scientists’ recent discovery that CDK4/6 inhibitors can slow the growth of cancer cells carrying a surplus of a certain protein, suggest that the drugs’ potential in cancer treatment has only begun to be tapped. If their effectiveness increases in combination with immunotherapies, as early evidence indicates, that potential may be greater than is even now apparent.
“The CDK4 and 6 proteins are critical drivers of the cell-division cycle and are required for the formation and growth of various types of solid tumors,” says Dana-Farber’s Shom Goel, MD, PhD, co-first author of the study with Molly DeCristo.
“Agents that block the proteins – CDK4/6 inhibitors – have received Food and Drug administration approval for some patients with metastatic breast cancer, but they’ve also shown promise against others types of tumors in clinical trials. In early clinical trials of these drugs, we noticed that in some breast cancer patients the tumors didn’t just remain the same size ¬–¬ as would be expected with drugs that interfere with cell division – but began to recede, sometimes quite dramatically, said Goel.”
To understand why this occurs, they examined the effect of a CDK4/6 inhibitor called abemaciclib in mice with breast or other solid tumors. They found the agent not only stalled the tumor cell cycle but also caused the immune system to mount an attack on the tumors. They confirmed the finding by analyzing tissue samples from women participating in a clinical trial of a CDK4/6 inhibitor for breast cancer.
The drugs trigger an anti-tumor immune response in two ways, the researchers discovered. In cancer cells, the drugs produce a substantial increase in the display of abnormal proteins on the cells’ surface. These proteins, called antigens, serve as a signal to the immune system that a diseased or cancerous cell is present and needs to be eliminated. At the same time, the drugs can spark a reduction in immune system cells known as T regulatory cells (Tregs), which usually tamp down the immune response to disease or infection. Fewer Tregs results in a fiercer immune system attack. The cumulative effect of these processes is a halting or reversal of tumor growth.
“The anti-tumor immune response with CDK4/6 inhibition was somewhat unexpected — some had previously thought that CDK4/6 inhibitors would block anti-tumor immunity, due to effects on T cell proliferation, but our findings demonstrate quite the opposite,” DeCristo states. “This surprising finding opens the door for combining immunotherapy with CDK4/6 inhibitors.”
In clinical trials, about 20 percent of breast cancer patients treated with abemaciclib by itself have a significant response to the drug and another 20 to 30 percent have stabilizations of tumor growth, the authors explained. The responses have tended to appear within four months of starting the therapy, they added.
In the current research, even better results have been obtained in mice when the drugs are used in combination with immunotherapy agents known as checkpoint inhibitors, which can foil cancer’s ability to evade an immune system attack. “It appears that the CDK4/6 inhibitors might be able to sensitize some patients’ cancers to the anti-tumor effects of immune checkpoint inhibitors,” the authors state. “The result might be especially encouraging for breast cancer patients, who have derived little benefit from immunotherapy in trials conducted to date.”
Further research is needed to understand why some patients receive the full spectrum of benefits from CDK4/6 inhibitors while others don’t, and to seek ways to expand these benefits to more patients. The results also should spur future studies of combined regimens of CDK4/6 inhibitors and different types of immunotherapy, the authors state.
- .American Cancer Society. Understanding Advanced Cancer, Metastatic Cancer and Bone Metastases. https://www.cancer.org/treatment/understanding-your-diagnosis/advanced-cancer/what-is.html.
- Benz CC. Impact of aging on the biology of breast cancer. Crit Rev Oncol Hematol. 2008;66:65-74
- World Health Organization. Women’s health fact sheet. September 2013. Available at . Accessed October 2017.
- Turner NC, Ro J, André F, et al. Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer. New England Journal of Medicine. June 1, 2015DOI: 10.1056/NEJMoa1505270.
- Tripathy D, Sohn J, Im S, et al. First-line ribociclib or placebo combined with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the randomized Phase III MONALEESA-7 trial. Presented at the San Antonio Breast Cancer Symposium (SABCS), December 6, 2017, San Antonio, Texas (abstract#S2-05).
- The data were presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #1000) and simultaneously published online in the Journal of Clinical Oncology.
- Patnaik A, Rosen LS, Tolaney SM, et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors [published ahead of print May 23, 2016]. Cancer Discov. 2016;6:740-753.