Breast Cancer : Episode 3

Hurvitz: CDK4/6 Inhibitors With Endocrine Therapy Is the “Gold Standard” in the First Line for HR+/HER2-Negative Advanced Breast Cancer

Sara A. Hurvitz, MD, of UCLA Health spoke with The American Journal of Managed Care® (AJMC®) about advanced hormone receptor–positive (HR+), HER2-negative breast cancer and the emergence of CDK4/6 inhibitors with endocrine therapy as the “gold standard” for first-line treatment.

Sara A. Hurvitz, MD, is a medical oncologist and breast cancer specialist with UCLA Health. She practices in the Santa Monica Parkside location, which is home to the integrative breast cancer practice and high-risk breast cancer clinic. Hurvitz leads the Translation Oncology Research Laboratory at UCLA in preclinical evaluation of novel breast cancer targets and has won numerous awards for her research. She is associate professor at the David Geffen School of Medicine at UCLA and medical director of the Jonsson Comprehensive Cancer Center Clinical Research Unit, co-director of the Santa Monica-UCLA Outpatient Oncology Practice, and director of Breast Cancer Clinical Trials at UCLA. Hurvitz is also a member of the National Comprehensive Cancer Network committee for clinical practice guidelines in breast cancer.

Recently, Hurvitz spoke with The American Journal of Managed Care® (AJMC®) about advanced hormone receptor–positive (HR+), HER2-negative breast cancer and the emergence of cyclin dependent kinase 4/6 (CDK4/6) inhibitors with endocrine therapy as the “gold standard” for first-line treatment.

This interview has been edited lightly for clarity.

AJMC®: For those who are unfamiliar, could you tell us what is advanced breast cancer?

Hurvitz: Advanced breast cancer is breast cancer that has spread outside the breast and lymph nodes, the regional lymph nodes in the axilla, or armpit region, and has been detected elsewhere in the body—for example the bone, the liver, or the lungs.

AJMC®:How are patients screened and diagnosed with advanced breast cancer? Does this occur with a patient who starts with a more localized form of breast cancer and progresses, or do we find patients who come into the clinic and present with metastatic or advanced breast cancer?

Hurvitz: In general, patients are diagnosed first with early stage breast cancer. And then at some point after treatment for early stage breast cancer, they may develop advanced disease. In the United States, only about 10% of patients diagnosed with advanced breast cancer or incurable metastatic breast cancer are diagnosed [at that stage] when first diagnosed with breast cancer. That's called de novo metastatic breast cancer. It's relatively uncommon, in part because we implement very strict screening guidelines in the United States, where patients generally are undergoing screening mammography to detect breast cancer at an earlier stage.

AJMC®:We'll be talking today about HR+, HER2-negative breast cancer. Could you explain how these terms that tell us the status of a patient are defined in breast cancer? How do we learn that a patient is HR+, HER2-negative during diagnosis?

Hurvitz: When a patient is initially diagnosed with breast cancer, and then when a recurrence happens, the patient's tumor is tested by a staining mechanism, in essence called immunohistochemistry, to look for the presence or absence of certain proteins. These proteins include the estrogen receptor and the progesterone receptor. Collectively, they are called hormone receptors, and the immunohistochemical assay tests for that. And they're also tested for something called HER2, which is human epidermal growth factor receptor number 2—it’s easier to say HER2—which in about 15% to 20% of patients is amplified at the gene level, leading to overexpression that can be detected by the protein stain or immunohistochemical stain.

It is critical that we know a patient's tumor’s hormone receptor status and HER2 status because these weigh heavily in treatment decision-making. We have therapies available that target HER2, and they are very effective at managing HER2-amplified or -positive [HER2+] breast cancer. And we have therapies that are very effective for HR+ breast cancer.

There is a class of breast cancer about 15% of patients have that's called triple-negative breast cancer. That’s a class that is based more on what the cancer is not expressing rather than what the cancer is distinguished by on a molecular level. Triple-negative breast cancer currently doesn't have targeted therapies available—although we are seeing the use of immunotherapy and antibody drug conjugates now making their way into the clinical setting—but it tends to be a more challenging type of breast cancer. So, it's important for clinicians to know what [type] of breast cancer a patient has when developing a treatment strategy to manage the disease.

AJMC®:One last question to frame our conversation here, and I think you touched on it: Metastatic or advanced breast cancer is generally considered incurable. Could you elaborate on that? Why is this so? Do you think this is something that might change—is this something we're just living with at the moment?

Hurvitz: In general, advanced breast cancer is considered incurable. There are select patients that may have a prolonged survival in HER2+ breast cancer; for example, I do have patients in my own practice who've had no evidence of disease progression and no evidence of disease on their scans for many years. Now, we don't know if they're truly cured, and we don't know whether we can stop treatment to control the disease. But this is an area that is of interest and a lot of investigators are studying right now to better understand how frequently that occurs for each of the subtypes of breast cancer.

In general, we treat patients for a lifetime with medicine or systemic therapy to control disease, because it's impossible to know who's going to have a durable remission that lasts forever—otherwise known as a cure—from a patient who would have a prolonged control of their disease and then have progression later.

So, in general, we treat patients palliatively and to control the disease, not expecting them to be free of the disease ever. But I do think that there are exceptions to that rule. And my hope is with better and better systemic therapy approaches, that perhaps we'll see a greater fraction of patients who truly can overcome the disease and be so-called cured.

AJMC®:Today we are discussing HR+, HER2-negative breast cancer. Can you walk us through what the treatment landscape looks like now for standard of care, for patients who have HR+, HER2-negative advanced breast cancer?

Hurvitz: Currently, the gold standard therapy in the frontline setting for patients with HR+, HER2-negative advanced breast cancer is the use of endocrine therapy, which is essentially either fulvestrant or an aromatase inhibitor, in combination with a CDK4/6 inhibitor. This is the gold standard doublet regimen. That is based on a number of phase 3 clinical trials that have now established that CDK4/6 inhibitors, when added to endocrine therapy in the firstline setting, significantly prolong progression-free survival—they roughly double it. This is consistent across the different clinical trials with different endocrine partners and different CDK4/6 inhibitors. And now, we have data emerging, at least related to ribociclib (Kisqali) of the CDK4/6 inhibitors, that overall survival is also significantly prolonged in patients who take this in the frontline setting. So, except for very unusual situations where a patient, for example, couldn't tolerate oral therapy or had a contraindication to receiving one of these agents, this would be considered the gold standard of care.

AJMC®:It sounds like a CDK4/6 inhibitor is incredibly important up front in a patient's care. With that in mind, have you ever encountered any barriers to up-front use? You mentioned some clinical characteristics that might harm a patient, perhaps if they're taking it? Are there any other barriers you've run into, or in your practice, with trying to start a CDK4/6 inhibitor up front?

Hurvitz: Well, there are some barriers to taking CDK4/6 inhibitor–based therapy that I've run into [during] the COVID pandemic. [The pandemic] has certainly created its own set of barriers, and each of the CDK4/6 inhibitors does require that patients come into clinic at least twice monthly for the first 2 months to have blood checks and in some cases, EKGs checked, and then monthly thereafter. I think we've become a little bit better at managing these lab draws. Sometimes, we’re able to use home health visits or a local laboratory rather than making patient come into clinic, and we're utilizing video visits to check in with patients to make they're tolerating [the therapy] well. But that certainly can be a barrier, especially with the current pandemic.

In addition, there are some patients who have very bad comorbidities; breast cancer isn't their only issue. [They may have] out of control diabetes or other immune issues that put them at high risk of infection if they were to develop neutropenia. All the CDK4/6 inhibitors are associated with neutropenia, which is typically asymptomatic and not a problem. But if you have a patient who has a lot of comorbidities and other risk factors for infection, it would certainly be prudent to think carefully about whether adding this in will benefit them.

And then taking oral therapy can be challenging. There are some patients who struggle with remembering to take pills, remembering when to call; ribociclib and palbociclib (Ibrance) are given 3 weeks on, 1 week off. So sometimes that gets a bit confusing to patients. So, I think it's important to help patients with compliance by utilizing frequent visits the first 2 months to make sure they're keeping up with how the medicine should be taken, and so that we can be notified if any problems come up with tolerating it.

AJMC®:There are a few options in the CDK4/6 inhibitor space right now. What factors do you consider when selecting one of these inhibitors? How do you select among those that are currently available?

Hurvitz: There are 3 CDK4/6 inhibitors that are commercially available to our patients: palbociclib, ribociclib, and abemaciclib (Verzenio). They all have very similar hazard ratios in terms of benefits within progression-free survival, be it in the first- or second-line setting. Ribociclib and abemaciclib are also associated with an improved overall survival; we still don't have data yet with palbociclib to indicate an overall survival benefit, but we are awaiting some phase 3 results to come out.

So, when deciding among the 3 inhibitors, you can keep in mind the overall survival benefits for a given indication, and that certainly sometimes influences me in what I'm recommending for a patient. We also can consider the side effect profile and monitoring profile; ribociclib and palbociclib are associated with grade 3/4 neutropenia on the order of 65% to 75%, so that's something to keep in mind, whereas abemaciclib is only about 25%. On the other hand, abemaciclib has more gastrointestinal toxicity that patients need to contend with. And patients need to take abemaciclib twice daily continuously. So, these are factors that can play into shared decision making—talking to a patient about the different side effect profiles and deciding with her which one to start.

Ribociclib comes with a requirement to follow the EKGs the first 2 months, especially every 2 weeks, given the risk of QT prolongation. So, looking at a patient's concomitant medications to make sure there's not going to be any drug-drug interaction is an important component of decision-making. All other things being equal—side effect profile, etc—I will choose ribociclib for my premenopausal women given Level 1 evidence in that setting with ribociclib. And I think ribociclib and abemaciclib tend to be my choice for postmenopausal women based on the overall survival benefits we're seeing, although palbociclib is well tolerated and we don't know yet if there will be overall survival benefit associated with it.

AJMC®:You touched on the overall survival benefit of ribociclib. You were recently a co-author on the updated MONALEESA-7 trial results, in the premenopausal/perimenopausal subset of patients with this type of breast cancer. Can you tell us about this trial, and these results that came out recently?

Hurvitz: The MONALEESA-7 clinical trial was a very uniquely designed study. It's the only study of a CDK4/6 inhibitor that’s phase 3 and was conducted solely in pre- or perimenopausal women—so really focusing on the younger patient population to interrogate whether a CDK4/6 inhibitor, in this case ribociclib, improves outcomes for young women with HR+ metastatic disease. And indeed, ribociclib when added to endocrine therapy did significantly improve not only progression-free survival, but it was the first clinical trial of a CDK4/6 inhibitor to demonstrate an improvement in overall survival as well. Which is why I feel that for pre- and perimenopausal women, the use of ribociclib is supported by the best level of evidence in phase 3 clinical trials. Patients can receive ribociclib in combination with an aromatase inhibitor and, of course, ovarian function suppression is required. We would not want to give ribociclib with tamoxifen, given that tamoxifen itself can add to QT prolongation. So, although it was studied with tamoxifen by investigators’ choice in MONALEESA-7, that would not be my clinical choice to use ribociclib with tamoxifen in in the clinical setting.

AJMC®:To focus on this a little more, this patient population is unique. Do you suspect we'll see more trials in a pre- or perimenopausal population following the results of this trial? Will this become the FDA standard for new agents coming to market—making sure that these agents are tested in this population?

Hurvitz: I'm not sure that we're going to see phase 3 trials that specifically home in on pre- or perimenopausal women. However, my hope is that we will see studies [that do] not exclude these patients. The first clinical trial to lead to the FDA approval of a CDK4/6 inhibitor in PALOMA-2 was conducted only in postmenopausal women, and to exclude premenopausal women who are placed on ovarian suppression I think is not the right answer. These patients do have serious illness, and their outcomes may be worse than a patient diagnosed with metastatic disease at an older age. And so, I think it's important to include them in our clinical trials, which does appear to be the trend moving forward. More and more clinical trials in HR+ disease, at least, are allowing women regardless of menopausal status.

AJMC®:Let’s talk about patients who continue to have their disease progress despite CDK4/6 inhibitor use. What's your approach to this, for a patient with HR+, HER2-negative advanced breast cancer?

Hurvitz: Unfortunately, the majority of patients treated with the CDK4/6 inhibitor in the first- or second-line setting will develop disease progression, indicating resistance has developed [to] this agent. A number of groups have modeled CDK4/6 inhibitor resistance, and there are no real good data from a preclinical perspective that continuing a CDK4/6 inhibitor or swapping for a different CDK4/6 inhibitor will benefit patients, at least not based on the in vitro and in vivo assays that have been done. However, there are a number of clinical trials ongoing that are interrogating this question where patients whose disease is progressing on a CDK4/6 inhibitor are randomly assigned to a different independent therapy or a different CDK4/6 inhibitor or having a PI3K pathway inhibitor added in. And so, I think in the next few years, we will have some clinical data to guide our treatment decisions.

At this point, I am not giving a patient a CDK4/6 inhibitor after progression outside of a clinical trial. The one exception may be with the use of single-agent abemaciclib in a patient who's run out of all endocrine therapy options, and previously did well on a CDK4/6 inhibitor, because abemaciclib is a less specific inhibitor, meaning it targets other cyclin dependent kinases besides 4 and 6. It may have a broader efficacy across tumors that have developed resistance to CDK4/6, but I would prefer to do that in a clinical trial setting. In the clinic setting, what I am typically doing is giving patients endocrine therapy with a PI3 kinase pathway inhibitor, which would be everolimus (Afinitor) if the patient does not have a tumor with PIK3CA mutations or alpelisib (Piqray) if they have PIK3CA mutations.

AJMC®:Would you like to provide any closing thoughts on this type of breast cancer?

Hurvitz: This is an exciting time for us as clinicians and investigators treating HR+ metastatic disease. Keeping in mind this disease subtype reflects about 70% of all breast cancer, it is critical for us to continue to support clinical trials and clinical Investigation of novel therapies to target this disease subtype. Although patients can do very well for many years, they will ultimately develop disease resistance, so novel therapies are going to be very important for us to continue improving outcomes for patients. I'm really excited about oral SERDS [selective estrogen receptor degraders], elacestrant, oral PROTAC [proteolysis-targeting chimera] molecules, other agents that target ERs [estrogen receptors], and really excited to see combination strategies with these oral ER degraders. I think it's going to be potentially practice changing in the long term.

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