McAndrew: No Reason Not to Start With CDK4/6 Inhibitors in Metastatic HR+ HER2-Negative Breast Cancer

The American Journal of Managed Care® (AJMC®) recently spoke with Nicholas McAndrew, MD, MSCE, an assistant clinical professor of medicine at the University of California, Los Angeles (UCLA) in the Division of Hematology/Oncology and a medical oncologist and breast cancer specialist at UCLA Health. AJMC® asked McAndrew about the arrival of CDK4/6 inhibitors in the treatment landscape.

AJMC®: What is HR-positive HER2-negative breast cancer?

McAndrew: HR-positive [means] hormone receptor positive. HER2-negative means the breast cancer does not overexpress the HER2 protein. Hormone receptor positive means positive for either the estrogen receptor or the progesterone receptor. HER2-negative metastatic breast cancer is the most common subtype of breast cancer. Hormone-positive, HER2-negative metastatic breast cancer represents [approximately] 60% to 80% of all cancer diagnoses, with HER2-positive breast cancer being [approximately] 20% and triple-negative breast cancer—meaning it’s negative for estrogen, progesterone, and HER2—representing [approximately] 10% of breast cancers.

AJMC®: What are the goals of therapy in treating patients with this type of breast cancer?

McAndrew: The main goal of therapy for anybody with metastatic breast cancer—but in particular, hormone-positive, HER2-negative breast cancer—is to control the progression of their cancer. Unfortunately, with metastatic breast cancer, once cancer cells have left the breast and spread to distant organs in the body, or just in lymph nodes in the body not within the regional lymph node chain of the breast tissue, it’s no longer curable. Now, of course, the minority of patients develop that. Most patients who have been diagnosed with breast cancer are [diagnosed] at an early stage, but [some] patients either recur or present with de novo metastatic disease. When a breast cancer is not curable, the main goal is to try [to] control the growth of the cancer to try to delay or avoid any kind of complications that could arise from where metastasis can develop. Also, that’s in conjunction with helping maintain somebody’s quality of life. The main goal of therapy is to prolong someone’s life, but also to prolong a good quality of life. That takes into account trying to control the disease, but also especially for hormone-positive, HER2-negative breast cancer, trying to give treatments that will achieve that goal with a minimum amount of toxicity. That’s the most important part for hormone-positive, HER2-negative breast cancer.

AJMC®: Could you give us a brief overview of the current treatment landscape for HR-positive, HER2-negative breast cancer? give us a brief overview of the current treatment landscape for HR-positive, HER2-negative breast cancer?

McAndrew: In advanced or metastatic hormone-positive, HER2-negative breast cancer, the broad overview is that, because we’re trying to help patients feel as well as possible for as long as possible, you want to start with therapies that are going to be well tolerated and maximally effective. So we prioritize giving hormone-based therapies or hormone-blocking therapies that are usually in conjunction with a molecular therapy. We do that first to try to extinguish those options, because oftentimes, those drugs can be tolerated for a longer period of time and have a better [adverse] effect profile. With chemotherapy, which is traditionally prior to the advent of all these amazing hormone-blocking therapies, we try to use those prior to having to give chemotherapy. In terms of a brief overview, we start off by trying to control the cancer with the less toxic hormone-blocking therapies before moving on to trying to control it with chemotherapy, which is oftentimes more toxic and less effective.

AJMC®: How has the arrival of the CDK4/6 inhibitors changed the treatment landscape?

McAndrew: It’s been game changing. They’ve been incredible drugs that have drastically improved survival in patients with metastatic breast cancer—even in the first-line setting. [Traditionally], patients who have first-line metastatic disease for hormone-positive, HER2-negative breast cancer have initially been started on single-agent endocrine therapy. What Dr [Richard] Finn and Dr [Dennis] Slamon [had shown] in their labs is that it was hormone-positive, HER2-negative breast cancer cell lines that seemed to be especially sensitive in a synergistic fashion, with a different therapy to CDK4/6 inhibitors.1 [This] launched the first of many trials that showed that when we add these compounds to first-line and second-line endocrine therapy, it significantly improves progression-free survival, and importantly, with some CDK4/6 inhibitors, overall survival in both the first- and second-line settings. We have a couple studies now showing that when ribociclib [Kisqali] is added to a first-line endocrine therapy for both premenopausal patients and postmenopausal patients, it significantly improves overall survival.

AJMC®: What are your preferred treatment regimens for treating patients with HR-positive, HER2- negative advanced breast cancer?

McAndrew: I take certain things into consideration when I’m trying to select a treatment for patients. The CDK4/6 inhibitors do have different toxicities. For instance, abemaciclib [Verzenio] has more gastrointestinal [GI] toxicity and more diarrhea associated with it, but less neutropenia. It’s given on a daily basis rather than a 1 week on 1 week off basis. Ribociclib has less GI toxicity and has [a] more overlapping toxicity profile with palbociclib [Ibrance], with the exception that ribociclib additionally does carry the risk of QT prolongation. For patients whom I’m worried that they’re not going to be able to reliably come in [for] electrocardiograms [EKGs] during the first 4 weeks of treatment, I sometimes consider not prescribing that one because I want to make sure they’re safe and monitored on therapy.

With palbociclib, there’s nothing of concern for QT prolongation. However, some of the overall survival data with palbociclib has not been positive. So I generally don’t prefer that one when I’m considering between ribociclib and abemaciclib, because the survival data in those drugs has been consistently positive. Those are some of the factors I take into account.

AJMC®: In addition to concerns about patients coming in for an EKG, has the pandemic affected treatment choices? We know cancer screenings dropped during the early months of the pandemic. Was there any impact on the treatment of metastatic breast cancer?

McAndrew: In my practice, it hasn’t impacted the treatment of metastatic breast cancer. I certainly think many of the patients who were concerned about coming in for regular follow-ups in regular chemotherapy—especially for patients who were getting treatment for early-stage disease—in the end, I did see some patients concerned about coming in for their chemotherapy, and even in some rare cases, decide not to do chemotherapy. [This was] because of the concern for leaving the home during the pandemic, but that’s a minority of patients. I would say most patients were able to come in. [With metastatic breast cancer], these patients are highly motivated to remain in close contact with their oncologist to continue to receive care, so I haven’t seen a major impact when it comes to the availability of treatment and the treatment decisions during the pandemic.

One of the major things, especially early in the pandemic, in the early-stage setting, was that [a lot of] patients who were diagnosed with low-risk hormone-positive or negative early-stage breast cancer—back when the operating rooms were not running at full capacity—were [being] managed with neoadjuvant endocrine therapy until they were able to book their surgery, [which was] usually months down the line. Typically, these patients will go right to surgery, but because of the institutional decision to try and preserve ventilators for the intensive care unit, and to minimize the number of nonemergent surgeries and elective surgeries, a lot of patients were managed with neoadjuvant endocrine therapy until the operating rooms opened back up at full capacity. That was pretty successful. We didn’t see any delay or anyone’s care be compromised from a cancer perspective. We didn’t see any progressions because of that decision, so that was good.

AJMC®: Your earlier response about using CDK4/6 inhibitors in first-line treatment is consistent with responses we are hearing from oncologists who treat several types of cancers—that the trend in the first-line setting is to use the best drugs available. Is this true across the board with CDK4/6 inhibitors?

McAndrew: Yes, absolutely. Often, these drugs are very well tolerated. In many of these studies, patients would have gone on to receive a subsequent CDK4/6 inhibitor. Despite that potential source of confounding in the studies, we still see a maintained overall survival benefit when [we] start by giving them the CDK4/6 inhibitor plus the endocrine therapy. At this point, unless there are patient-specific comorbidities or tolerability [that] preclude the physician from being able to prescribe the CDK4/6 inhibitor, there’s no reason not to start with the CDK4/6 inhibitor. Because when cancers become resistant to a line of therapy, it’s not the same type of cancer, and we don’t know whether delaying the addition of the CDK4/6 inhibitor [is the right thing to do] until they progress on endocrine therapy. Because you’re now dealing with a different type that has already become an acute resistance. So if you capture the opportunity to try to control the disease when it’s as endocrine sensitive as possible with the strongest tools possible, you’re likely offering the patient the maximum amount of benefit.

AJMC®: Is there anything we haven’t covered that you would like to add?

McAndrew: The main focus at this point, in terms of where the field is headed, is trying to understand the mechanisms behind CDK4/6 resistance and trying to tailor subsequent therapies to the different ways patients may become resistant to these drugs. I think next-generation sequencing with both liquid biopsies and solid tumor biopsies is going to be a huge part of where we see this field moving in the future. Hopefully we’ll be able to tailor subsequent lines of therapy specifically to patients’ mutations as they arise throughout the course of treatment to stay one step ahead of the cancer. 

Reference
Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cell lines in vitro. Breast Cancer Res. 2009;11(5):R77. doi:10.1186/bcr2419