Effects of CDK 4/6 inhibitors in early-stage breast cancer still unclear

Update: Abemaciclib (Verzenio) was FDA approved for early-stage breast cancer in October 2021. This content shares some of the research that supported the FDA approval. 

The benefits of giving CDK 4/6 inhibitors for early-stage, hormone receptor-positive breast cancer remain unclear after two studies, monarchE and PENELOPE-B, presented conflicting results during the San Antonio Breast Cancer Symposium on Wednesday.

The maker of abemaciclib (Verzenio) announced in June that monarchE is the first and, so far, only study to find that adding a CDK 4/6 inhibitor to early-stage breast cancer treatment lowered the risk of breast cancer coming back. But with the PENELOPE-B trial, also presented Wednesday, and the PALLAS trial, which came out earlier this year, showing no benefit to adding a CDK 4/6 inhibitor in a similar context, some doctors are cautioning that longer follow-up may be needed before changing current treatment plans.

Background

CDK 4/6 inhibitors are targeted therapies that block the function of certain proteins, cyclin-dependent kinases 4 and 6, in cancer cells. In 2015, the Food and Drug Administration approved the first medicine of this type to treat metastatic, hormone receptor-positive breast cancer. Since then, two other CDK 4/6 inhibitors have been approved and all three have become standard care for people with that diagnosis.

While an important treatment for people with metastatic, hormone receptor-positive breast cancer, researchers have not yet found a role for CDK 4/6 inhibitors in early-stage breast cancer treatment.

The monarchE trial

The monarchE trial included 5,637 people with early-stage, hormone receptor-positive, HER2-negative breast cancer that had spread to the lymph nodes and was found to be at high risk of returning. The trial included two cohorts. In each cohort, researchers used different criteria to determine the risk of cancer returning:

• Cohort 1 was found to be at high risk of recurrence based on cancer cells in at least four lymph nodes, or cancer cells in one to three lymph nodes and a tumor that is grade 3 or at least 5 centimeters
• Cohort 2 was found to be at high risk of recurrence based on cancer cells in one to three lymph nodes and the cancer having a Ki-67 score of at least 20 percent

The Ki-67 index is a measure of how many cells are making Ki-67, a protein made by cells in the process of reproducing, and is an indication of how fast the cancer is growing. High Ki-67 scores have been associated with a high risk of breast cancer returning. Ki67 scores in the monarchE trial were determined in a central lab to ensure consistency.

Participants were randomly assigned to get the CDK 4/6 inhibitor abemaciclib for up to 2 years alongside hormonal therapy, or to get hormonal therapy alone. In both groups hormonal therapy would continue for 5 to 10 years based on the recommendation of the participant’s doctor.

Results

The trial found that people taking abemaciclib had a higher invasive disease-free survival rate, meaning they were less likely to have breast cancer come back in the time studied. The results were statistically significant, meaning they were not likely the result of chance.

The invasive disease-free survival rate at 2 years was

• 92.3 percent in the abemaciclib and hormonal therapy group
• 89.3 percent in the hormonal therapy group

Looking specifically at people in the study who had Ki-67 scores of 20 percent or higher, the researchers found an even larger difference in 2 year invasive disease-free survival rates. The results for that subgroup were

• 91.6 percent for the abemaciclib and hormonal therapy group
• 87.1 percent for the hormonal therapy group

Researchers found the side effects were as expected for these medicines. The most common side effects in the abemaciclib group were diarrhea, fatigue, and neutropenia. In the abemaciclib group, 82 percent of participants experienced diarrhea, compared to 7.8 percent in the hormonal therapy only group. Grade 3 diarrhea, which is bad enough to be treated in the hospital, was experienced in

• 7.7 percent of the abemaciclib and hormonal therapy group
• 0.2 percent of the hormonal therapy group

In the study, 70.2 percent of people on abemaciclib had a dose delayed or reduced, in most cases because of side effects. Most of the dose changes happened early, within the first 5 months of treatment.

PENELOPE-B

The PENELOPE-B trial looked at adding the CDK 4/6 inhibitor palbociclib (Ibrance) to hormonal therapy for early-stage, hormone receptor-positive, HER2-negative breast cancer that showed a high risk of recurring.

In this study, all participants were treated with chemotherapy before getting breast surgery, called neoadjuvant chemotherapy. A person was considered to have a high risk of cancer returning if there were still cancer cells found during breast surgery (after completing chemotherapy) and they had a high CPS-EG score.

CPS-EG (clinical pathological stage-estrogen/grade) is a staging system that has been shown to identify people who have a high risk of cancer returning after neoadjuvant chemotherapy, according to the researchers. In this study a high CPS-EG score was a score of at least three, or a score of at least two and cancer cells found in the lymph nodes.

In the PENELOPE-B trial, 1,250 people were randomized to receive hormonal therapy alongside either

• palbociclib for a year
• placebo for a year

As in monarchE, the type and duration of hormonal therapy was at the discretion of the participant’s doctor.

Results

The primary endpoint of the study was invasive disease-free survival. While early results suggested that people in the palbociclib group had a lower risk of cancer returning, as time went on, the difference disappeared.

The 2-year invasive disease-free survival was

• 88.3 percent in the palbociclib and hormonal therapy group
• 84.0 percent in the placebo and hormonal therapy group

The 4.3 percent difference lessened as the study continued. The 4-year invasive disease-free survival was

• 73.0 percent in the palbociclib and hormonal therapy group
• 72.4 percent in the placebo and hormonal therapy group

With a median follow-up of 43 months, the researchers have determined that adding palbociclib to treatment did not change the risk of breast cancer returning and they did not find a difference in the risk of dying.

What does this mean for you?

The monarchE trial and the PENELOPE-B trial are similar in their basic structure. Researchers gave a CDK 4/6 inhibitor alongside hormonal therapy to people with early-stage, hormone receptor-positive breast cancer that had a high risk of returning. But there were many differences that may be important as doctors, researchers, and the FDA decide if there is a role for CDK 4/6 inhibitors in early-stage breast cancer and what that role is.

There are several important differences in these studies that doctors suspect may explain the conflicting results:

• Abemaciclib versus palbociclib. In metastatic breast cancer trials, the CDK 4/6 inhibitors behave very similarly, but it is possible that something about abemaciclib makes it more appropriate in treating early-stage breast cancer.
• Duration of treatment. PENELOPE-B studied palbociclib given for 1 year. MonarchE studied abemaciclib given for 2 years. NATALEE, an upcoming trial, is studying ribociclib (Kisqali), another CDK 4/6 inhibitor, given for 3 years. We don’t yet know if duration affects outcomes or what the best duration may be.
• Defining high risk. PENELOPE-B and monarchE used different measures to decide who is at high risk of cancer returning. If there is a group of people whose cancers respond to CDK 4/6 inhibitors, these measures will be important.
• Follow-up time. The PENELOPE-B trial saw significant differences in invasive disease-free survival at 2 years, but at 4 years both groups had the same rate of cases of recurrence. The monarchE trial only reported 2-year invasive disease-free survival, and doctors want to see if the benefit continues in the years after people stop taking abemaciclib.

In a discussion of these studies, Ruth O’Regan, MD, said that longer follow-up plus overall survival results showing that people taking abemaciclib were less likely to die in the years after treatment are needed.

With the upcoming NATALEE trial and future analyses of monarchE, we will learn a lot more about CDK 4/6 inhibitors in early-stage breast cancer, but it is not certain if they will have a role or what that role may be.