CDK4/6 Inhibitor Breast Cancer Clinical Trials


Dr Hart delves into the CDK4/6 inhibitor clinical trials for breast cancer, some that he’s even participated in.

Lowell Hart, MD, FACP: Well, CDK4/6 is 1 of the regulators of the cell cycle. This is something that we can use in patients that have intact cell cycle control mechanism to sort of suppress the cells.

I always tell the patients we’re sort of putting their cancer cells to sleep. We’re slowing them down, slowing down their growth rate.

There are 3 that are approved for use in women with advanced breast cancer. The first 1 out was Palbociclib [Ibrance]. There’s also ribociclib [Kisqali] and now abemaciclib [Verzenio] also.

These drugs have all been FDA [Food and Drug Administration]-approved and are very commonly used in the United States along with hormonal treatment for patients with advanced breast cancer and we’ve used them now for a number of years and almost all oncologists are very familiar with that so they’ve been a big advance.

Because of the fact that they seem to almost double the progression-free survival in patients who are receiving either an aromatase inhibitor or fulvestrant [Faslodex] for advanced breast cancer, of course, the next thing oncologists started to think about is will they improve the cure rate if we use these drugs in early breast cancer as an additional adjuvant maneuver?

The first 1 to be studied was palbociclib and there have been 2 studies, PENELOPE and PALLAS. Unfortunately, those studies did not seem to show a benefit. Those studies were both negative trials.

The third 1 to be studied, or the third trial, was the monarchE trial, which our group were investigators on. This used abemaciclib. In this trial, there were sort of 2 groups of patients.

There were patients who had 4 or more lymph nodes, and there was a second group of patients that had 1 to 3 lymph nodes and had at least 1 other high-risk feature, such as a T3 sized tumor [larger than 4 centimeters], 5 centimeters or bigger, high-grade histology like a grade 3 cancer, or a Ki-67 of more than 20%.

Now, Ki-67 is a stain that’s used to stain cancer cells that are in mitosis. It’s a way of telling what’s the growth fraction of the cancer cells. This was centrally reviewed. It wasn’t just something that anybody could do in their lab. This was a central review of this.

The monarchE trial has been presented and now published in the JCO [Journal of Clinical Oncology] recently. It did show about a 25% decreased risk in the group that took 2 years of abemaciclib in addition to their hormonal treatment.

They could either receive tamoxifen or an aromatase inhibitor. The majority of these patients did get adjuvant chemotherapy also. About two-thirds, actually, about 60%, got adjuvant chemotherapy also.

Some of these patients, about 60%, had 4 or more nodes, but the other 40% had 1 to 3 nodes and 1 of the other features that I mentioned at the start.

The FDA actually approved abemaciclib based on the results from the monarchE trial as adjuvant treatment for women with primary breast cancer who had 1 of these high-risk features and a Ki-67 read out at a central lab, an approved lab of over 20%.

This has been the case, and this treatment is now used widely, at least in the United States for these sorts of patients ever since the approval.

There’s also a trial, which I was an investigator on, called NATALEE which is a trial with ribociclib for a number of years. That trial has been completed. We don’t yet have the data. Perhaps, sometime in 2022 or ‘23, we may get the data on that trial and see whether that was a positive trial or not, but the trial is completed.

We’re awaiting the passage of time to determine whether it’s positive or not. The question does come up frequently about why was palbociclib a negative trial. Actually, why was the drug palbociclib in 2 trials negative and why was the abemaciclib trial positive?

Obviously, there are several reasons for that, potential reasons, we don’t know for sure, but potentially it could be a difference in the drugs. Obviously, they’re different drugs. Perhaps the 1 is more potent than the other. We don’t know that. However, in the advanced cancer setting, they look very similar.

Another possibility is that there are some differences in the schedule. Abemaciclib, as most of your viewers and listeners know, is given continuously, whereas with palbociclib and ribociclib, the drugs are given 3 weeks on and a week off. There is a break in there where the patients do not get the drug.

That’s necessary since abemaciclib has a little less of a suppressive effect on the bone marrow. You don’t need to have a week off each month for the bone marrow to recover. Whereas with the other drugs, there would be progressive neutropenia if you just continue it all the time.

It’s possible that in the adjuvant setting, you need to have this. It’s also another possibility that’s been brought up by many experts is that perhaps the patients in the monarchE trial were somewhat higher-risk patients. They perhaps learned from the prior negative trials with the other drug and chose a patient population that was a little bit higher risk.

Many folks do think that, so we will see how things play out. We don’t yet have overall survival data from the monarchE trial. We do have disease-free survival and distant disease-free survival data, which is quite positive. Certainly, hope for that eventually there will be overall survival data, but we do not have that yet.

This transcript has been edited for clarity.

Case: A 54-Year-Old Woman with ER+/PR+ Breast Cancer

Initial Presentation

  • A 54-year-old, postmenopausal woman presents with a newly diagnosed lump in her right breast
  • She has no family history of cancer and underwent menopause at age 50

Clinical work-up

  • Imaging demonstrated a 2.4-cm solid mass in the right upper quadrant with no suspicious lymphadenopathy identified
  • Core biopsy: positive for invasive ductal carcinoma, ER 100%, PR 97%; HER2 1+ and FISH negative; Ki-67 45%; modified Bloom-Richardson grade 3
  • Lumpectomy and sentinel lymph node biopsy performed
    • Tumor size is 2.4 cm, and 3 LNs are positive for metastatic disease
  • 21-gene assay recurrence score is 30
  • pT2N1M0, stage IIB
  • ECOG PS is 0


  • Patient underwent partial mastectomy with no residual disease
  • She is given radiation therapy to intact breast
  • She is started on adjuvant chemotherapy with cyclophosphamide and docetaxel

Followed by adjuvant therapy with AI + 2 years of abemaciclib

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