The American Journal of Managed Care (AJMC) recently spoke with Nicholas McAndrew, MD, MSCE, a medical oncologist and breast cancer specialist at UCLA Health and assistant clinical professor of Medicine at UCLA in the Division of Hematology/Oncology. 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 stands for hormone receptor positive, and HER2-negative means that the breast cancer is 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 about 60% to 80% of all cancer diagnoses, with HER2-positive breast cancer being about 20% and triple negative breast cancermeaning it's negative for estrogen, progesterone, and negative for HER2, representing about 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 have 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, its no longer curable. Now, of course, the minority of patients develop thatmost patients who have been diagnosed with breast cancer are found at an early stage. But [some] patients either recur or present with de novo metastatic disease. And so, when a breast cancer is not curable, the main goal is to try and control the growth of the cancer in order to try and 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. So, the main goal of therapy is really to prolong someone's life, but also to prolong a good quality of life. And 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. Thats really 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?

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 off with therapies that are going to be well-tolerated and maximally effective. And so, we prioritize giving hormone-based therapies or hormone-blocking therapies that are usually in conjunction with some kind of 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 side effect profile. Then with chemotherapy, which is traditionally prior to the advent of all these amazing hormone-blocking therapieswe 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 change the treatment landscape?

McAndrew: It's really been game changing. They've been incredible drugs that have drastically improved survival in patients with metastatic breast cancereven in the first-line setting. In patients who have first-line metastatic disease, for hormone-positive HER2 negative breast cancer, traditionally, patients 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 that when ribociclib 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. So, these drugs 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 (Kisquali) is has less GI toxicity and has more overlapping toxicity profile with palbociclib (Ibrance), with the exception that ribociclib additionally does carry the risk of QT prolongation. So, for patients whom I'm worried that they're not going to be able to reliably come in 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.

And then with palbociclib, theres nothing of concern for QT prolongation; however, some of the overall survival data with palbociclib has not been positive. And so, I generally dont prefer that one when I'm considering between ribociclib and abemaciclib because the survival data in those drugs has been consistently positive. So, those are some of the factors that I take into account.

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

McAndrew: In my practice it really hasn't impacted the treatment of metastatic breast cancer. I certainly think that many of the patients who were concerned about coming in for regular follow-ups in regular chemotherapyespecially for patients who were getting treatment for early-stage diseasein the end, I did see some patients concerned about coming in for their chemo 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. And I would say that 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 actually haven't seen a major impact when it comes to the availability of treatment and the treatment decisions during the pandemic.

But certainly, one of the major things, especially early in the pandemic, in the early-stage setting was that patients who were diagnosed with low-risk hormone-positive or negative early-stage breast cancerback when the operating rooms were not running at full capacitywe were managing a lot of these patients with neoadjuvant endocrine therapy until they were able to book their surgery, 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 ICU, 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 open back up at full capacity. And 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 cancersthat 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, very well-tolerated. And in many of these studies, patients would have gone on to receive a subsequent CDK4/6 inhibitor. And despite that potential source of confounding in the studies, we still see a maintained overall survival benefit when you 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 really not a 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 until they progress on endocrine therapy is really the right thing to do. Because you're now dealing with a different type of cancer that was resistantthat 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, youre likely offering the patient the maximum amount of benefit.

AJMC: Is there's anything we haven't covered that you'd 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 really tailor subsequent therapies to the different ways that patients may become resistant to these drugs. I think that that next-generation sequencing with both liquid biopsies and with solid tumor biopsies is going to be a huge part of where we see this field moving in the future. And hopefully, we'll be able to tailor subsequent lines of therapy specifically to patients mutations as they 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-postive human breast cell lines in vitro. Breast Cancer Res. 2009;11(5):R77 doi: 10.1186/bcr2419.

Original post:
McAndrew: No Reason Not to Start With CDK4/6 Inhibitors in Metastatic HR+ HER2-Negative Breast Cancer - AJMC.com Managed Markets Network

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