Expert Discusses Optimizing CDK 4/6 Inhibitors in Breast Cancer

Reshma Mahtani, DO

There are 3 approved CDK 4/6 inhibitors for the treatment of patients with metastatic breast cancer, and the decision of which one to use and when should be made on an individualized basis, explains Reshma Mahtani, DO.

The most recent of the 3, abemaciclib (Verzenio), was approved in February 2018 for use in combination with an aromatase inhibitor (AI) for the frontline treatment of postmenopausal women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer.

The first-line approval was based on data from the phase III MONARCH 3 trial, in which abemaciclib reduced the risk of progression or death by 46% when added to anastrozole or letrozole compared with a nonsteroidal AI alone.¹

Ribociclib (Kisqali), another CDK 4/6 inhibitor, was granted a breakthrough designation for use in combination with tamoxifen or an AI in patients with pre- or perimenopausal HR-positive, HER2-negative breast cancer in January 2018. This designation was based on data from the phase III MONALEESA-7 study, which showed a median progression-free survival (PFS) of 23.8 months for women treated with ribociclib in combination with either tamoxifen or a nonsteroidal AI and goserelin.² This was in comparison to a PFS of 13.0 months for patients who received the standard endocrine therapy plus placebo and goserelin (HR, 0.553; 95% CI, 0.441-0.694; P <.0001).

Ribociclib is currently approved by the FDA for use in combination with an AI for the frontline treatment of postmenopausal women with HR-positive, HER2-negative advanced breast cancer.

Palbociclib was granted an accelerated approval in February 2015 for use in combination with letrozole as a frontline treatment for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer. In March 2017, the FDA converted this accelerated approval to a full approval and also expanded the indication of palbociclib to include use in combination with other aromatase inhibitors in this setting.

Now, says Mahtani, the question is which patients should receive these agents, also emphasizing that use of CDK 4/6 inhibitors should not solely depend on age.

OncLive: Please give an overview of your presentation.

Mahtani discussed the use of CDK 4/6 inhibitors in older and younger populations in a presentation during the 2018 OncLive^® State of the Science Summit™ on Breast Cancer. In an interview during the meeting, Mahtani, assistant professor of clinical medicine, Sylvester Comprehensive Cancer Care, University of Miami Health System, discussed the tolerability of these agents, and how to best select the patients to receive them.Mahtani: I focused on the use of CDK 4/6 inhibitors in 2 different populations: older patients and younger patients. There was a very important presentation on an FDA pooled analysis of the registration trials that led to the approval of CDK 4/6 inhibitors, and the investigators looked at these studies with respect to age and treatment effect for CDK 4/6 inhibitors. This is a common issue that comes up quite a bit when we have an older patient in our clinic. We know that these drugs are highly efficacious and pretty well tolerated, but should we give them to everyone? Do older patients tolerate the therapies as well as younger patients?

Practicing here in South Florida, where we see an older population quite frequently, these questions are quite relevant to the audience at this particular meeting. I hope they understood that the use of CDK 4/6 inhibitors is something that we should consider in older patients, and that we should not use age as a reason to not offer these therapies. There is an increased incidence of treatment discontinuation, but when looking at select adverse events that are associated with the use of these agents, the differences were not that large. This highlights the point that we need to individualize treatment for older patients.

In the younger patient population, I reviewed the MONALEESA-7 trial, which was an eagerly awaited trial. We have known that patients with ER-positive metastatic breast cancer who are pre- and perimenopausal tend to have more aggressive disease. We tend to look at these patients a bit differently in terms of chemotherapy.

Frontline abemaciclib was approved not too long ago. What has the impact been so far?

There is a general perception that maybe we should give these patients chemotherapy. In this setting, it was reassuring to see that the use of the CDK 4/6 inhibitor ribociclib in combination with ovarian suppression and either a nonsteroidal AI or tamoxifen is a very efficacious and well-tolerated treatment for these patients. It is important for the audience to know that we have a CDK 4/6 inhibitor that has now been looked at in an exclusive pre- and perimenopausal patient population. The other takeaway is the use of tamoxifen. Some patients who are premenopausal don't do as well with ovarian suppression and an AI, and now we have data with tamoxifen.This just happened very recently, so I haven't even had the opportunity to consider using abemaciclib in the first-line setting. We may have to talk about some patients with pre-existing neutropenia or issues with their blood counts where abemaciclib may be a better choice because of the decreased risk of blood count issues. I do have some concern with regard to the diarrhea, especially in the first-line setting.

Anecdotally, how have you seen some of your older patients tolerate CDK 4/6 inhibitors?

Even though it seems quite manageable, we have to remember that palliation and quality of life (QoL) is one of the important goals in metastatic disease. This is the first treatment that patients are receiving for metastatic disease, so they are supposed to maintain a good QoL and not make the treatment worse than the disease. I do not have enough experience with abemaciclib to know how the diarrhea will play out, but it is certainly something I would consider for the appropriate patient.I have seen some older patients do very well with CDK 4/6 inhibitors. Conversely, I have seen younger patients have a tough time with them. Therefore, we can’t use age alone as a deciding factor. We must have that physician-patient relationship where we can take into account patient preference and all of the other factors to make an individual decision for the patient in front of us.

What factors would deter you from putting an older patient on a CDK 4/6 inhibitor?

It’s very hard to predict, and it can be dependent on things other than age. We talk about comorbidities, patient preference, and compliance, and all of these things factor in when you have the individual patient in front of you. It is hard to predict how certain patients may respond just based on their age.This is something that we have started to look at. For example, in 1 of the MONARCH trials there was an analysis of patients who had a very long disease-free interval and maybe didn't benefit from the use of a CDK 4/6 inhibitor. However, it being an exploratory analysis, it is possible that we just need to follow these patients longer to see a benefit with a CDK 4/6 inhibitor.

We all, anecdotally, have case reports in our practice of patients who have these prolonged responses to AI monotherapy. It is definitely tempting to consider an AI as monotherapy, but unfortunately, we do not have a crystal ball. Sometimes you think a patient is going to do very well; meanwhile, they fall right into that average of about 14 months before they have to go onto the next therapy. Without the availability of a biomarker, I have a tough time identifying a patient in whom I am not using a CDK 4/6 inhibitor up front.

Looking at the available CDK 4/6 inhibitors, are there any discernible differences between them?

I guess the only real issue would be if I was concerned about compliance. That would be a deciding factor for me.First, I will start off by saying this is a great problem to have; we have choices. This tells us that we have made significant progress for these patients with ER-positive disease. Palbociclib was the first approved CDK 4/6 inhibitor; it is given on a 3-week-on/1-week-off schedule. Ribociclib is given the same way. We see neutropenia quite a bit with this class of therapy, and perhaps a little bit less with abemaciclib—there is a continuous dosing with that agent. However, there is more diarrhea with abemaciclib.

What other research are you particularly excited about?

The efficacy data with all of these agents, especially in the first-line setting, is remarkably similar. When we talk about how to make a choice between these therapies, there are a lot of other factors such as cost, convenience, or insurance coverage. For example, with palbociclib, you have to write a new prescription for a dose reduction so the patient may need to wait. With ribociclib, the patient can just take 1 less pill, which is more convenient, but you have to perform ECG/EKG monitoring. You also need to consider the drug-drug interactions that ribociclib has. Again, it is an individualized decision with each patient, and it’s a good problem to have. We are very interested in mechanisms of resistance and mechanisms of response. Who is going to respond? How does resistance develop? Looking at trials that are investigating the continuation of CDK 4/6 inhibitors beyond progression, studies that incorporate other targeted therapies with CDK 4/6 inhibitors are eagerly awaited.

Any final thoughts on CDK 4/6 inhibition in this space?

One of the patient subtypes that I am particularly interested in are the HER2-positive, ER-positive patients. For example, we have the MONARCHER study that is looking at abemaciclib, fulvestrant (Faslodex), and trastuzumab (Herceptin) in that population. Identifying the use of these agents in other subtypes of breast cancer is something that we are eagerly awaiting data on. The main issue for metastatic patients is keeping quality of life in mind, and recognizing that sometimes quality of life is not just physical—but emotional as well. One thing that I don't hear discussed frequently is the psychological benefit that we are able to afford patients when we give them a treatment that will work for 2 years in the metastatic setting. This is especially true for a newly diagnosed patient who is coming to terms with the fact that she has an incurable illness. The ability to tell a patient that they are doing well on their first-line therapy for up to 2 years needs to be emphasized more as we discuss whether CDK 4/6 inhibitors are needed upfront, or whether they should be saved for use in later lines of therapy.

References

1. Di Leo A, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for patients with HR+/HER2- advanced breast cancer. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 236O_PR.
2. Tripathy D, Sohn J, Im SA, et al. First-line ribociclib vs placebo 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. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Abstract GS2-05.