CDK4&6 Inhibitors Revolutionize Hormone-Positive Breast Cancer Care

Evolving ParadigmsBreast Cancer: Focus on CDK4&6 Inhibitors
Volume 1
Issue 1

Denise A. Yardley, MD, discusses the promise of CDK4&6 inhibitors in estrogen receptor (ER)-positive breast cancer, as well as the potential with immunotherapy agents. 

Denise A. Yardley, MD

CDK4&6 inhibitors have recently moved to the forefront of the treatment landscape when it comes to hormone-positive breast cancer, experts say.

“The CDK4&6 inhibitors have been exciting for the last 3 years, and 2015 welcomed the PALOMA-1 data that really took the clinical science of the CDK4&6 dysregulation in cancers and [worked to inhibit] that with the CDK4&6 inhibitor,” said Denise A. Yardley, MD.

In an interview with Targeted Oncology, Yardley, a senior investigator of breast cancer research at Sarah Cannon Research Institute, discussed the promise of CDK4&6 inhibitors in estrogen receptor (ER)-positive breast cancer, as well as the potential with immunotherapy agents.

TARGETED ONCOLOGY:Can you give an overview of the current state of ER-positive breast cancer?

Yardley: There are some changes in the management of hormone receptor [HR]-positive, HER2-negative breast cancer. There are all phases of treatment, such as going to early adjuvant breast cancer treatment recommendations and some of the recommendations with regard to extended adjuvant therapy.

Then, there is a changing standard now for the first-line HR-positive, HER2-negative patients with metastatic breast cancer; that really focused on the changing algorithm to incorporate CDK4&6 inhibitors in the first-line setting. Then, we looked at some data of later-line therapy with some of the recent [FDA] approvals of palbociclib [Ibrance] and abemaciclib [Verzenio]in combination with fulvestrant [Faslodex]. Then, from that, the next topic that was natural was looking at hormone resistance, so we really covered and focused a little bit more on different spectrums of hormone resistance.

TARGETED ONCOLOGY:What are the current recommendations for adjuvant endocrine therapy?

Yardley: The current recommendations for adjuvant endocrine therapy are still evolving. It takes a look at the premenopausal patients and the utilization of tamoxifen in that setting. If we look at the trials that are out there with axillary dissection with access min-imized [ADAM] and adjuvant tamoxifen longer against shorter [ATLAS], and then looking at extending the therapy from tamox-ifen from 5 to 10 years, the data are quite consistent. We have had the data there resonate very well throughout many of the trials. The problem is, is it a one-size-fits-all approach?

What we are learning is we’re still tailoring it to the patient and their risks, so we are trying to look at modifiers or even incorporate some of the genomic assays that help distinguish that. When we look at the aromatase inhibitors [AIs], the story is a little more muddy than challenging. We have some trials that are positive, like the MA17R study that looked at 10 years of letrozole after a 5-year backbone of tamoxifen. This showed that there was a disease-free survival [DFS] advantage, but again, it encompassed that patients did well in both groups of that trial, with outcomes of 90% disease-free overall survival. 

Now, the NSABP B-42 trial did not echo the same results of MA17R, but the design and the statistics were a little different; however, even though DFS was not overall statistically significant, [it showed that] breast cancer-free interval distance recurrence was a significant finding.

In some of the other trials, looking at the DATA trial and the IDEAL trial, in the subsets of the patients who had tumors that were ER-positive, those subsets who had prior chemotherapy for adjuvant therapy or had high-risk disease were groups who do seem to benefit when we look at subgroup analysis. For the AI, the challenge is to discuss that higher[-risk] patient tolerance—to ask, what is their risk of disease recurrence—to tailor that and pair that with the recommendation of extended adjuvant AI therapy.

TARGETED ONCOLOGY:What else are we seeing with CDK4&6 inhibitors?

Yardley: The initial [approval] was palbociclib; you could affect outcomes and show the doubling of the disease control rate or DFS. In February 2015, that opened the door for accelerated approval of palbociclib in that setting.

The confirmatory trial, PALOMA-2, resonated that the signal was real and reproducible; that went on to lead to an approval this year in March 2017. PALOMA-3 took on a different look—still wanting to test the role of CDK4&6 inhibitors in the patients with HR-positive metastatic breast cancer but [looking] at patients who have been on prior endocrine therapy, failed that, and then went on to receive fulvestrant with the CDK4&6 inhibitor. It showed that, while advantage wasn’t as statistically significant as what we saw in the first-line setting, the signal was clearly there and was statistically significant at 5 months. The margin of benefit was a little bit smaller, but there was a later-line therapy group of patients.

The MONALEESA-2 trial resulted with ribociclib [Kisqali]in combination with letrozole, again in that first-line setting. What’s so exciting there is that we saw a great benefit in show-ing that doubling of the progression-free survivals has essentially 1 year before patients are experiencing disease progres-sion with the addition of the ribociclib as the CDK4&6 inhibitor.

Abemaciclib is a little bit different as a CDK4&6 inhibitor in that it looked at a different patient population. [It was in] heavily pretreated patients who had prior chemotherapy and endocrine therapies, and those patients received abemaciclib, a CDK4&6 inhibitor as a single agent. Abemaciclib is a little bit different. It’s dosed continuously and not on a 3 weeks on/off schedule, such as palbociclib and ribociclib.

It’s continuous dosing and twice-daily dosing. As a single agent, we saw a nice signal in a later-line therapy group of patients. Of course, these patients were all CDK4&6-naïve patients. They also embarked on a trial with fulvestrant, as well. It showed benefit in a patient who had a prior line of endocrine therapy.

In September 2017, it received FDA approval in endocrine- and chemotherapy-pretreated patients as a single agent and then endocrine-pretreated patients with fulvestrant. The challenge now is looking at the market of CDK4&6 inhibitors. We have 3 that are FDA approved. Are they all a class of drugs or are there nuances that make each unique? That’s what we’re trying really sort through at this point. If you look at ribociclib, we see that it has a total 100% inhibition of CDK4 and CDK6, which makes it a little dfferent from palbociclib as well as abemaciclib.

The toxicity profile is what you would expect—largely neutropenia. The other interesting part [from preclinical studies] is that ribociclib does cross into the blood—brain barrier. Now, we’ll see how that evolved. We are waiting for other data, too, with ribociclib. It has also been looked at in the first-line setting in combination with tamoxifen. To this point, all of the other trials have only used the AIs or fulvestrant, so now we’re actu-ally going to see tamoxifen roll out. A lot of the patients aren’t eligible for the AI or can’t tolerate it, so we’ll get some exciting data as we move forward with that.

They also had a great quality of life that showed that pain control was apparent as a benefit reported by the patients at an 8-week first assessment. As we start learning how these roll out, how patients tolerate them, and what the administration schedule is, we’ll figure out abemaciclib, with those continu-ous dosing in different levels of CDK4&6 and some off-target effects with more gastrointestinal [GI] toxicity. It distinguishes itself with a little less neutropenia, but a little bit more GI toxic-ity. All of that will be a way of moving forward—of us exploring the patient populations a little bit more.

TARGETED ONCOLOGY:Can you talk about hormone resistance and how pathways are being looked at?

Yardley: Hormone resistance is an exploding arena in the HR-positive patients. We’ve welcomed the data for BOLERO-2 that put everolimus in combination with exemestane as a standard for patients who are failing endocrine therapy or a nonsteroidal AI. That was our first signal that doublet therapy with an endocrine agent backbone in combination with the targeted agent was effcacious and did improve the outcomes and DFS for patients.

The CDK4&6 inhibitors now have rolled out in advanced patients in the second-line setting. Now, what we’re learning is what the other patterns in pathways of resistance are. One of the most exciting [aspects] is ESR1 mutations and our ability to recognize them from even circulating tumor DNA. Some [analyses] that have looked at BOLERO-2 looked at the ESR1 prevalence as anywhere from 25% to 40% in AI-pretreated patients.

If you select a patient who failed on an AI, has an ESR1 mutation, and you have a choice of another steroidal, nonsteroidal AI, or fulvestrant, fulvestrant as a selective estrogen receptor degrade [SERD] has resulted in better outcomes from those patients. Understanding ESR1 mutations and being able to test for them is now helping us make better choices for those patients as the next line of endocrine therapy. It’s also opened the door now for a variety of oral SERDs, so while fulvestrant is sometimes a little bit more labor intensive because of the injections, now looking at the potential of having an oral SERD in the market for that population of patients is quite interesting.

As we look at adjuvant patients and recommendations of extended AI therapy, we’ll have to see the downstream effect of these patients if they relapse. Test them immediately for the consideration of an ESR1 mutation, and perhaps fulvestrant [combined with] a CDK4&6 inhibitor may be the ideal setting for that, so that’s what we’re looking for. PI3K has been great in terms of the science behind it.

Everolimus has led us to know that you can interrupt the mTOR/PI3/AKT pathway and improve outcomes in patients with HR-positive metastatic breast cancer. However, in the nearly 20 PI3K trials, none of them have really shown a benefit; there is clearly something different about the PI3K.

Then, there’s a class of [drugs] looking at the IGFR pathway, and some of those have been hit-or-miss. None have come to the market, but there’s a strong signal there if we can find the right way to interrupt that pathway—[it could be] that a ligand binder seems to be attacking the receptors associated with a lot of hyperglycemia. That just doesn’t seem to be a way to move forward.

Entinostat, which received a breakthrough designation from the FDA, has been a really exciting drug that we’ve also worked with and is currently out in a big phase III trial, hopefully for registration. It also seems to have a great signal with immunotherapy; there’s a lot of trials that are looking for that in patients, as well. We are partnering with our pharmaceutical industry to find drugs to attack those pathways, and it likely may be triplet drugs. I know we’re looking at ribociclib in combination with exemestane and everolimus, an actually very tolerable combination, and early signals seem to be promising.

TARGETED ONCOLOGY:What potential is there with immunotherapy in this population?

Yardley: The immunotherapy potential is something that we still struggle in the HR-positive arena. There have been a lot of trials looking at it, but none that have had a strong resonating signal as with some of the other so allenge for the HR-positive patients; however, we don’t know what these tumors are going to look like after CDK4&6 inhibition and failures, as well.

It’s something that’s continually being looked at. The signal is there. It’s been low—a 10% response rate as a single agent in a heavily pretreated group. HR-positive breast cancer is also very heterogenic. Some of the trials now are taking an approach of partnering the immunotherapy with another biologic target. Whether it would be a CDK4&6 or it’s going to be an AKT pathway, a MEK inhibitor, or PI3K, all of that are trials that are just now getting their foothold and then we’ll have to look for those results.

TARGETED ONCOLOGY:What else is important to highlight about this evolving field?

Yardley: One of the real excitements that has come from looking at the data and now 3 FDA-approved CDK4&6 inhibitors in the metastatic setting is now rolling these into the adjuvant setting. In that setting, we can potentially improve outcomes for more patients. Many of the trials have rolled out in the adjuvant setting looking at different features. We are still trying to identify the high-risk ER-positive adjuvant or early breast cancer patient. One of the trials that is rolling out, EarLEE-1, is looking at patients who either had neoadjuvant therapy or adjuvant therapy and embracing the new prognostic categories that are emerging now through the eighth edition of the American Joint Committee on Cancer [AJCC]. That will roll out for clinicians in January 2018. That’s a very interesting way of selecting patients for a trial and being able to select or predict outcomes.

The change in the AJCC is adding to the anatomic pathology that is the tumor, the nodes, or metastasis. Now, the ER or progesterone positivity, the grade of the tumor, and even incorporating some of the multigene assays in coming into a risk category. For the early EarLEE-1 adjuvant trial with ribociclib, which will be given for 2 years in HR-positive preEarLEE1 or postmenopausal patients. They’ll be randomized with an endocrine therapy and ribociclib versus endocrine therapy [alone]. Ribociclib is given for 2 years, so we’re going to see in a different patient population how that may improve the outcomes.

Abemaciclib is rolled out in the MONARCH 3 trial, and that’s looking at abemaciclib in early-stage breast cancer using a different definition and categories of inclusion criteria to select a high-risk patient population. However, we will also roll out with the 2-year plan of abemaciclib versus just standard endocrine therapy in patients who are given an adjuvant endocrine therapy.

Moving forward, seeing how that may totally alter how we treat early-stage breast cancer HR-positive patients, it’s going to be exciting, too. Now, we’ll still have to wait some time for those signals; however, at least by selecting the higher-risk population and then subsequent trials, we’ll get an intermediate group. Hopefully, we’ll get a signal or readout quite early from those trials. What we see now is a new standard in first-line HR-positive, HER2-negative metastatic breast cancer—perhaps an evolving standard for certain patients with early-stage HR-positive, HER2-negative breast cancer.

It is becoming so challenging in the management of HR-positive breast cancer because, up until a couple of years ago, we really didn’t have a host of trials or new data with regard to science or understanding resistance in those patients. All of it was monotherapy single-agent endocrine therapy. Now, the challenge is that the new standard seems to be combination endocrine therapy, so an endocrine therapy agent with a biologic targeted agent.

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