What Are CDK4/6 Inhibitors?
CDK4/6 inhibitors are a newer class of medicines used to treat certain types of metastatic breast cancer, which is cancer that has spread to other parts of the body, such as the bones or liver. These medicines interrupt the process through which breast cancer cells divide and multiply. To do this, they target specific proteins known as the cyclin-dependent kinases 4 and 6, abbreviated as CDK4/6. That's why you may hear them referred to as “targeted therapies.”
If a breast cancer is hormone-receptor-positive, it means the cancer’s growth is fueled by the hormones estrogen, progesterone, or both. HER2-negative cancers have tested negative for a protein called human epidermal growth factor receptor 2, or HER2, which promotes cancer cell growth. So HER2-negative cancers don’t respond to treatments that target the HER2 protein (such as Herceptin). More than two out of every three breast cancers are both hormone-receptor-positive and HER2-negative. 1
Currently there are three CDK4/6 inhibitors used to treat metastatic breast cancer:
How do CDK4/6 inhibitors work?
The CDK4/6 proteins, found both in healthy cells and cancer cells, control how quickly cells grow and divide. In metastatic breast cancer, these proteins can become overactive and cause the cells to grow and divide uncontrollably. CDK4/6 inhibitors interrupt these proteins in order to slow or even stop the cancer cells from growing.
All three CDK4/6 inhibitors are pills taken by mouth, but they are used a little bit differently. Verzenio is a pill that you take every day, either alone or with other treatments. It appears to affect the CDK4 protein more than the CDK6 protein. Ibrance and Kisqali affect both CDK4 and CDK6 and have to be taken along with hormonal therapy. They are also given in 4-week cycles that include a week-long break — so you would take the medication for 3 weeks and then take 1 week off.
Choosing a CDK4/6 inhibitor: Which one is right for you?
Ibrance, Kisqali, and Verzenio have not been directly compared to each other in a clinical trial. Still, doctors consider them to work equally well. Your treatment team can help you decide which one is right for your situation. This may depend on factors such as:
the stage of the breast cancer
what treatments you have had in the past, if any
how quickly the cancer progressed after previous treatment
if you are a woman, whether you are premenopausal or postmenopausal
the side effects associated with each CDK4/6 inhibitor
whether you and/or your treatment team prefer that you take medication continuously, as you would with Verzenio, or on a 3-week on/1-week off cycle (Ibrance and Kisqali)
whether your health insurance favors one of the medications over the others
Each CDK4/6 inhibitor is approved by the U.S. Food and Drug Administration (FDA) to treat certain stages of hormone-receptor-positive HER2-negative breast cancer in different groups of people. (If you live outside the United States, not all of these CDK4/6 inhibitors may have been approved yet, so check with your doctor.) Keep in mind that these approvals are likely to change over time, as clinical trials are still ongoing to figure out if CDK4/6 inhibitors can benefit additional groups.
All the CDK4/6 inhibitors are approved to treat advanced-stage and metastatic hormone-receptor-positive, HER2-negative breast cancer. Advanced-stage breast cancer is cancer that has come back (recurred) or spread beyond the breast to the chest wall below the breast. Metastatic breast cancer is advanced-stage cancer that has spread to parts of the body away from the breast, such as the bones or liver.
One CDK4/6 inhibitor — Verzenio — is also approved to be used after surgery to treat early-stage breast cancer with a high risk of recurrence.
For postmenopausal women and men: Ibrance can be used in combination with an aromatase inhibitor to treat patients who have not had hormonal therapy before. Aromatase inhibitors, which are a type of hormonal therapy, include Arimidex (chemical name: anastrozole), Aromasin (chemical name: exemestane), and Femara (chemical name: letrozole).
For all women and men: Ibrance can be used in combination with the hormonal therapy Faslodex (chemical name: fulvestrant) to treat cancer that has grown after previous hormonal therapy. Premenopausal and perimenopausal women who take Ibrance in combination with Faslodex also should be treated with a medicine to suppress ovarian function.
For premenopausal, perimenopausal, or postmenopausal women: Kisqali can be used with an aromatase inhibitor, such as Arimidex, Aromasin, or Femara, to treat patients who have not had previous hormonal therapy. Premenopausal and perimenopausal women who take Kisqali also should be treated with a medicine to suppress ovarian function.
For postmenopausal women: Kisqali can be used with Faslodex to treat patients who have not had hormonal therapy before, or whose cancer has progressed after previous treatment with another hormonal therapy.
For postmenopausal women: Verzenio is used in combination with an aromatase inhibitor (Arimidex, Aromasin, Femara) in patients who have not had hormonal therapy before.
For all women: Verzenio can be used in combination with Faslodex if the cancer has progressed after previous hormonal therapy. Premenopausal and perimenopausal women who take Verzenio in combination with Faslodex also should be treated with a medicine to suppress ovarian function.
For all women and men: Verzenio also is used by itself to treat women and men if the cancer progressed after hormonal therapy treatment and earlier chemotherapy for metastatic breast cancer. These are general guidelines for the use of CDK4/6 inhibitors. You and your treatment team can discuss the particulars of your situation and what makes the most sense for you.
For all women and men: Verzenio is used in combination with either tamoxifen or an aromatase inhibitor after surgery to treat early-stage hormone-receptor-positive, HER2-negative, node-positive breast cancer with a high risk of recurrence (the cancer coming back) and a Ki-67 score of 20% or higher. Node-positive means cancer cells have been found in one or more lymph nodes. Ki-67 is a protein in cells that increases as they prepare to divide into new cells. A staining process can measure the percentage of tumor cells that are positive for Ki-67. The more positive cells there are, the more quickly they are dividing and forming new cells.
Note that if you are pregnant or planning to get pregnant, you should not take any of the CDK4/6 inhibitors. These medications can harm the developing fetus. It is important to use effective birth control while you are taking a CDK4/6 inhibitor and for at least 3 weeks after your last dose. In addition, men who take the CDK4/6 inhibitor Ibrance are also advised to use contraception while on treatment and for 3 months after finishing the medication.
Side effects of CDK4/6 inhibitors
Like most cancer medicines, CDK4/6 inhibitors cause side effects, but they tend to be less intense than those caused by chemotherapy. The most common side effects of all three medicines are:
low platelet counts
If you are taking a CDK4/6 inhibitor, your doctor will monitor your blood counts before and during treatment. Your doctor also will order liver function tests, since these medications can sometimes affect the liver. Testing will usually take place every 2 weeks until your treatment team sees how your body responds to the CDK4/6 inhibitor. Some dose adjustments may need to be made during that time. After the first 2 months of treatment, testing usually can occur less frequently.
Even though every patient is different, doctors have observed that certain side effects tend to be more pronounced with some CDK4/6 inhibitors than others — and this might influence treatment decisions.
Verzenio, for example, is associated with a significant risk of gastrointestinal (GI) issues. Diarrhea is very common, and in about 10% of people it can be severe, leading to dehydration or infection. In most cases, it can be managed with an anti-diarrheal medicine such as Imodium (chemical name: loperamide), drinking more fluids, and diet changes. In some cases, your doctor may lower your dose of Verzenio or recommend that you take a break from treatment. If you already have GI issues — such as irritable bowel syndrome, colitis, diverticulitis, or frequent diarrhea, among others — your treatment team may recommend one of the other CDK4/6 inhibitors.
In rare cases, Kisqali can cause a heart problem known as QT interval prolongation. (The QT interval is a measurement made on an electrocardiogram, or EKG, used to evaluate some of your heart’s electrical properties.) This can lead to a fast or irregular heartbeat, which may be life-threatening. People taking Kisqali need to have an EKG every couple of weeks during the first few cycles of treatment. If you already have a heart condition, your treatment team may prefer one of the other CDK4/6 inhibitors.
These are not all of the potential side effects of CDK4/6 inhibitors. For more detailed information, visit our in-depth pages on Ibrance, Kisqali and Verzenio. Keep in mind that side effects can vary widely from person to person.
Switching between CDK4/6 inhibitors
Although Ibrance, Kisqali, and Verzenio have not been directly compared to each other in a clinical trial, doctors consider them to work equally well. So if you are on one CDK4/6 inhibitor and experience serious side effects over time, even after adjusting the dosage, you and your doctor can talk about switching you to a different one. In most cases, though, your doctor should be able to find a dose that improves your side effects while maintaining the medication’s benefits.
If you switch to a different CDK4/6 inhibitor, there will usually be a period of time where you do not take the medicine while the new one is ordered. This also gives your body a chance to recover from the side effects.
If the cancer progresses while you are taking a CDK4/6 inhibitor, there is no evidence from medical studies to suggest that another CDK4/6 inhibitor will be effective. Your doctor may wish to change the hormonal therapy you are taking in combination with the medication. In certain cases, though, a doctor may decide it is worth trying a different CDK4/6 inhibitor. Your treatment team can advise you based on the particulars of your situation.
These are not all of the potential side effects of CDK4/6 inhibitors. For more detailed information, visit our in-depth pages on Ibrance, Kisqali and Verzenio.
Tips for taking a CDK4/6 inhibitor
CDK4/6 inhibitors are pills taken by mouth and, in most cases, they are given along with hormonal therapy. If you’re prescribed one of these medications, some advance planning can help things go more smoothly. We asked Breastcancer.org Community members who have taken CDK4/6 inhibitors to weigh in with some of their top tips for those just getting started.
Know potential side effects, the time of the day to take the pill(s), whether they need to be taken with food, what to do if you miss a dose, and whether any other medications you’re taking might interact with the CDK4/6 inhibitor. Although each medication can cause a range of side effects, Verzenio is known for causing diarrhea, while all three are associated with low white blood cell counts, or neutropenia, which can increase infection risk.
You also may wish to investigate what your out-of-pocket costs will be, because even with insurance, they can be high. Depending on your income, you may qualify for financial assistance from the manufacturer, as Community member Bluegirlredstate did: “Ibrance is incredibly expensive. I do not know what my insurance would pay, because the doctor is using some sort of grant program that makes my out-of-pocket zero. Check the drug maker’s website for more information.” You also can ask your treatment team or the financial navigator at your hospital or cancer center.
Ask your treatment team how you will get your medication. Verzenio is taken daily, while Ibrance and Kisqali are taken for 3 weeks on, 1 week off. Often, CDK4/6 inhibitors are ordered through a specialty pharmacy (as opposed to your drugstore pharmacy) and mailed to your home. Work with your team to understand how the initial prescription and refills will be handled.
BLMike shares some advice: “Initially, when they were adjusting the dose, there were some disconnects between my wife’s medical oncologist and the mail pharmacy providing the Ibrance. This was frustrating as it caused a few-day delay in getting back on treatment. Be assertive to make sure there is coordination and communication between the doctor’s office and the pharmacy.”
In most cases, you’ll be taking hormonal therapy along with the CDK4/6 inhibitor. You may find it helpful to use a pill organizer or set reminders on your smartphone, computer, or watch to stay on track with your medication schedule.
You can expect to have frequent blood tests and liver function tests as you start on a CDK4/6 inhibitor. Based on those results and any symptoms you’re having (severe diarrhea, fatigue, low white blood cell counts), your team may recommend lowering the dose or taking breaks from treatment. This is fairly common and not a cause for alarm. Adjustments often have to be made to help you get the benefit of the treatment while minimizing side effects.
HopesFiercely shares her experience with Verzenio: “My main issue was with the fatigue that slowly became so bad over the first few months that I became unable to do more than a few tasks or errands in the morning then fell into exhausted sleep in the afternoon. It took careful planning to get to my appointments. My doctor lowered the dose to 100 mg two times a day and the fatigue slowly left. I didn't realize how bad it was until I started to feel better.”
Karenfizedbo15 of Scotland had to change her dosage of Ibrance and then the treatment cycle due to low blood cell counts: “Even after lowering the dose, my treatment cycle never managed to keep on track as my blood counts were too low. So I am on a 5-week cycle — 3 weeks on, 2 weeks off — in order for my cell count to recover. I still achieved no evidence of disease after 6 months, so we’ll see. The side effects are minimal compared with IV chemotherapy. Just don’t be afraid of dose reduction.”
About 80 percent of patients taking Verzenio experience some level of diarrhea, especially during the first months of treatment. Your doctor may give you a kit containing the anti-diarrheal medication Imodium (chemical name: loperamide) along with an action plan to follow if you experience diarrhea. You also can purchase Imodium over the counter in your local drugstore and have it on hand.
“The Verzenio starter kit came with a large box of lopermide and was much needed as the diarrhea was terrible,” HopesFiercely writes. “I learned to run at the slightest cramp, keep drinking to replace lost fluids, and carry a change of clothes. Thankfully my body adjusted and now I only need one lopermide each morning.”
In addition to drinking more fluids, making adjustments in your diet also can be helpful. Community member Mary in Spokane, WA, says: “Diarrhea does get better after the first 30 days. Also, I can almost eliminate all problems if I eat several small meals and avoid dairy.”
Find out who on your treatment team can help you manage diarrhea.
Because these medications lower white blood cell counts, they can increase your risk of infection. With Ibrance and Kisqali, these counts tend to be lowest during the third week of your treatment cycle (before the fourth week off). Wash your hands frequently or use hand sanitizer, avoid large crowds, and stay away from people who are sick. Thoroughly wash any raw fruits and vegetables before you eat them. Community members on Ibrance also report experiencing mouth sores.
TarheelMichelle shares: “I bought a lot of surgical masks in the beginning, because I was worried about low white blood cell counts, but didn’t wear the masks long. I found out about hydrogen peroxide wipes, which kill norovirus germs. I carry them with me all the time. At restaurants, I wipe off the table surface and wipe my hands after reading the menu. I wipe down airplane tray tables, doorknobs, my car. Yep, I’m that lady!”
“Although we’ve tried to keep a normal schedule,” BLMike writes, “we're careful not to travel and spend a lot of time in crowds and in close quarters with others when my wife’s immune system is the lowest (during the last week of her 3-week cycle). She rests when she's fatigued, and uses Biotene mouthwash for occasional mouth sores.”
In addition to using Biotene mouthwash and toothpaste, Simone80 of Arizona has some other tips: “I use a soft-bristle tooth brush and swish with baking soda throughout the day.”
With all of these medications, drinking lots of water can be helpful. Now’s a good time to invest in a water bottle you can refill and carry with you throughout the day, which is what Community member TarheelMichelle does while taking Ibrance:
“I subconsciously avoid hydration and have to force myself to drink water. I’ve found that icy cold water is best. A one-handed Contigo aluminum water bottle has been the winner for me. It has an extra cover to go over the opening, so it doesn’t spill in my purse. My mouth gets ‘hot,’ particularly during week 4, and popsicles help immensely.”
While you’re on a CDK4/6 inhibitor, you may find that you tire more easily. You might need to scale back on your activity level and work some break times into your day. Try to get help with tasks such as cleaning, cooking, childcare, and work obligations. That said, it’s important to remain physically active, even if that means taking a daily 15-minute walk — whatever you can manage.
Community member Vlnprh of Wisconsin shares her advice: “As far as fatigue, I pace myself by not overscheduling, allowing time to lie down as needed and doing a water exercise class two or three times each week. I feel better when hydrated. We have had to hire out jobs around the house which I would have attempted previously and have the funds for that by taking advantage of the Social Security disability allowance for those with metastatic disease.”
KangaRoo adds, “Exercise 15 minutes per day, even if it is a gentle walk to the end of your street and back, or a couple of laps of the mall.”
For nausea, DivineMrsM of Ohio finds certain foods better than others: “Cold foods are easier to eat than warm/hot food. Applesauce, popsicles, cold sandwiches, cottage cheese, and Jello are some foods that I keep around.” She also has found that Ibrance lowers her red blood cell counts, causing anemia, so she has adjusted her diet: “To help the red blood cells and boost iron, I have added foods such as peanut butter, dried prunes and other dried fruit, orange juice, fortified cereal, and a number of other foods I learned about when googling.”
If you’re a grapefruit fan, put it aside for now, as it can interact with CDK4/6 inhibitors.
Serious side effects of CDK4/6 inhibitors are rare but can happen. One such side effect is severe inflammation of the lungs — so if you have trouble breathing or chest discomfort, report this to your team. Another is liver function problems, which can cause yellowing of the skin and eyes, dark-colored urine, and pain in your right abdomen. In rare cases, Kisqali may cause a heart problem known as QT interval prolongation. (The QT interval is a measurement made on an electrocardiogram, or EKG, which is used to record the electrical activity of the heart.) Tell your doctor right away if you have a rapid or irregular heartbeat, or if you feel dizzy or like you might faint. Whatever medication you’re on, ask about possible serious side effects and what to watch out for.
It can take some persistence to get to a CDK4/6 inhibitor dose that works for you but doesn’t cause difficult side effects.
Community member Sadieservant of British Columbia writes, “To be honest, I have found Verzenio tough. Granted, I started at 200 mg twice daily which is a high dose. The diarrhea was manageable but I had severe nausea and quite a bit of fatigue. After two weeks my oncologist told me to pause. Then I started at a lower dose. My advice is to persevere and find the dose that works. Don’t feel you need to be at the highest dose to be effective. Drink lots of water, eat small meals, and stick close to home for the first few weeks.”
Karenfizedbo15 of Scotland, who takes Ibrance adds, “Use a decent mouthwash daily. Rest more but do the things you enjoy. Be mindful and grateful. Avoid kids with runny noses (I was a teacher for 32 years) and crowded places. And don't be afraid of dose reduction.”
National Cancer Institute. Cancer Stat Facts: Female Breast Cancer Subtypes. 2019. Available at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html.
Ibrance (palbociclib) prescribing information. Pfizer. New York, NY. 2018. Available at: https://labeling.pfizer.com/ShowLabeling.aspx?id=2191.
Kisqali (ribociclib) prescribing information. Novartis. East Hanover, NJ. 2018. Available at: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kisqali.pdf. (PDF)
Verzenio (abemaciclib) prescribing information. Eli Lilly and Company. Indianapolis, IN. 2018. Available at: https://pi.lilly.com/us/verzenio-uspi.pdf. (PDF)
— Last updated on April 1, 2022, 1:30 PM