Debra Patt, MD, PhD, MBA 

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How have you changed your practice to accommodate patients on targeted therapy in terms of patient care?

 We frequently see these patients in intervals when they receive treatment. So, if we see these patients every 3 weeks, frequently they require regular follow-up with echocardiograms to evaluate their cardiac function, as many HER2 [human epithelial growth factor receptor 2] targeted agents have an infrequent side effect of cardiac toxicity. Other toxicities need to be managed if they’re just on a nonchemotherapy-based regimen that has HER2 blockade and endocrine therapy. Frequently, they have to be seen even less by providers, once doctors or advanced practice providers that work with us can establish that they’re tolerating their treatment without significant side effects.

 What have been some of the challenges, and can you include both clinical and nonclinical factors?

 Some challenges in this patient population are some of the adverse events that we see. If you see that someone has cardiac morbidity related to infusion of HER2 targeted therapy, that needs to be managed appropriately. We’re very fortunate here to work with a cardiologist that really is an onco-cardiology expert. We’ve been very successful in referring patients, treating them on cardiac remodeling drugs like carvedilol, and then retreating them with HER2 blockade safely and effectively. So, while that’s an infrequent complication, because I have many patients with HER2-positive metastatic breast cancer I have seen some of it and have been very successful in patients continuing their remission despite these toxicities, because we can manage them well in collaboration with our cardiology partners and get patients back on effective therapy. So that’s been really encouraging. The other complication that’s challenging for providers and patients is that this patient population has a higher predilection for brain metastasis and managing brain metastases is complex. It used to be, 15 years ago, that frequently we would have these patients undergo whole brain radiation therapy whenever they had brain metastasis, because the long-term supply of whole brain radiation therapy wouldn’t manifest for many years. Generally, patients with breast cancer that had metastasized to the brain did not survive long enough to realize some of those long-term toxicities. That’s no longer the case in this patient population because we’ve had tremendous positive disruption because of innovation, and therapeutic interventions that cross the blood brain barrier. We’re very effective at controlling this patient population. I personally have many patients in my practice who had brain metastases more than a decade ago. They continue to live well, without any progression of their disease. They continue to work in their jobs. So, figuring out how frequently to look in the brain is always tricky in this patient population. The standard of care would suggest that we only look when patients have symptoms. But in my experience, patients can have some mild symptoms of mild lethargy, or could have focal neurologic deficits that leads you to image their brain. Imaging the brain is important because HER2 disease has such a predilection for the central nervous system that you need to work in collaboration with a multidisciplinary team to understand what exactly the best way is to manage this for the patient. Sometimes it might require surgery for the patient, which would involve a neurosurgeon. Frequently, it involves collaboration with a radiation oncologist that can give targeted therapy to the patient. Usually, it is combined with some sort of systemic treatment change to make sure that we’re giving a therapy that’s highly effective in controlling disease and the central nervous system. Many of these patients will go on later to develop other central nervous system metastasis. How we approach this each time is really a multidisciplinary treatment decision. So having a good multidisciplinary team can be really important in helping you navigate this complicated space.

 What have been the implications of these changes or challenges for your practice in terms of resource utilization?

 Frequently, when we have patients with cardiac complications or brain metastasis, we have weekly multidisciplinary tumor boards where we discuss these patients just for breast cancer. We frequently can benefit from multidisciplinary treatment planning. Well, we don’t bill for that service. Of course, it’s just sort of volunteer time on our part, but we think it’s a good part of patient care. So, it doesn’t directly impact health care resource utilization for the patient, the fact that we have to go through these additional steps, but patients undergoing additional steps of surgery and/or radiation and/or changes to new or novel therapies that may have better penetration of the central nervous system does impact health care resource utilization. Let’s say for example, I had a patient that was on an endocrine blockade and trastuzumab alone, and they had brain metastasis, and I chose to transition them either to ado-trastuzumab or tucatinib in combination with trastuzumab and capecitabine; that would be a higher cost choice, that would increase health care resource utilization, but it would be effective therapy for the patient.

 Can you share how you have had to educate staff or patients in light of changes in practice, due to the use of targeted therapies?

 We have to provide a lot of education. The pace of change in oncology is unprecedented. We have newer drugs all the time, and the advent of targeted therapies and immunotherapies has dramatically changed the field. So, we have to provide a lot of education. We have a lot of informational webinars for our nurses and for our physicians. I do an update here locally after our major conferences, and there are a lot of updates in general from various sources. There are many different ways in which people can sort of ingest the new oncology content. But I feel like once I finished school, I still have homework every night, because cancer care is continuously changing. Again, at a pace that’s unprecedented.

Videos

Debra Patt, MD, PhD, MBA, explains how clinical practice has adapted to the use of targeted therapies to treat HER2-positive metastatic breast cancer.

How HER2+ mBC Targeted Therapies Impact Clinical Practice

For this next segment, we’ll be looking at the regimen-specific costs and cost drivers. How do cost considerations factor into your treatment decision-making?

 I think for every therapy that we administer, we want to consider efficacy, toxicity, and cost or value. But specifically, about this population, I think the most important value-based initiative is that patients go on to live disease-free. You can’t discount that, because I think superior efforts and the best possible evidence for disease control is the most appropriate value-based choice. Really, it’s in the patient’s best interest to give the most effective therapy first. That’s the value-based care decision. Because, if you look at outcomes over cost, having a patient that goes years without disease progression, living their life on their standard where they continue to be in the workforce, continuing to interact in meaningful ways with their families; that’s really the most effective way to approach this patient population. We want to keep them on effective treatment. Aside from that, I will say that there are some HER2 [human epidermal growth factor receptor 2]-targeted therapies that are of higher toxicity and higher cost that do require special consideration. We may use them less frequently because of that consideration.

 Could you share what other kinds of costs need to be considered with these regimens?

 I think most of these regimens are relatively low toxicity. Putting patients on effective therapy keeps them in the workforce and their lives in a meaningful way that adds value to them. When you consider the burden of having poor disease control—disease progression, disability, leaving the workforce—those are really expensive choices that aren’t often factored in when we consider our choices about the value-of-care delivery. In addition, there are some therapies that have particular toxicities that can be quality-of-life limiting. For example, if you initiate a patient on treatment with nilotinib, it can cause a lot of diarrhea. That can be a challenge as you think about their costs, because if they are not well-managing that diarrhea, it can diminish the ability to work or participate in their life. In my opinion, there is a real opportunity here for oncologists to shine, because we have the ability to start them on a lower dose and gradually escalate them to accompany their therapy that could potentially be toxic with medications to try to mitigate those toxicities. I think there is an opportunity there for oncologists to act; to reduce some of those toxicities on the patient. That provides a high value care.

Thank you. Are you able to share what the primary drivers are of the cost associated with these regimens?

 I think a lot of innovator products do have a higher price point. We have a lot of new products in HER2+ [human epidermal growth factor receptor 2-positive] metastatic breast cancer over the last year. Many of them come with a higher price point. I think that’s true even when there is a higher price point when there is a biosimilar on the market. As you know, trastuzumab now has biosimilars. They are also at a high price point because these are therapies that are not chemically made but grown. They are monoclonal antibodies. Some of the innovator and biosimilar products in this space I think do have a higher price point. Again, they are effective therapy, so you need to give them. That’s the high value choice, but they drive costs in this space.

 Thank you. What is the impact of using HER2-targeted therapies, including dual HER2-targeted regimens, on costs to providers and patients?

 So, using dual HER2-targeted therapies does increase the total cost of care. But again, in frontline metastatic HER2 amplified breast cancer it is the most effective therapy that you can provide. Using chemotherapy in combination with dual-targeted HER2 blockade is the frontline regimen that most people use. It does increase the cost of care for patients. But again, I think that in the bigger picture, and certainly in conversations between doctors and patients, patients desire the therapy that is going to give them the best possible outcome. It’s going to keep them living their lives on their terms—whether that’s being teachers, or attorneys, or doctors in the workforce picking up their kids from soccer, at the dinner table with their families—I think that we can’t discount the benefit of having long-term disease control. So, while it does drive cost in this space, it’s really important because it provides tremendous value to patients.

 What else drives these cost differences?

 Chemotherapy that is no longer on patent, like docetaxel for example, is relatively inexpensive in comparison to HER2 blockade, whether it’s an innovator product or its biosimilar equivalent. Those are expensive therapies. But I don’t see that changing in the near term, and it adds so tremendously to the efficacy of the therapeutic intervention. I think it’s necessary to provide high value care.

 What would the cost implications be of using newer approaches in earlier lines?

 If you use newer approaches in earlier lines, you’re unlikely to have biosimilar equivalent to the innovator product. They’re likely to still have patent protection. So, it’s likely that their costs are going to be higher. We are seeing some of our newly approved agents being tested in earlier lines of therapy. We think that if they are approved in that setting, it likely will drive up costs to some degree. Again, I would say that while it is never a trivial issue, the cost of therapeutic intervention is always important to discuss; that the most effective way you can provide good-value, high-value care to patients is to control their cancer.

Debra Patt, MD, PhD, MBA, discusses the cost considerations of conventional and novel therapies for HER2-positive metastatic breast cancer.

Cost Considerations for HER2+ mBC Therapies

 Next, we’ll be looking beyond chemotherapy in HER2+ [human epidermal growth factor receptor 2 positive] metastatic breast cancer. For the first question, what are some of the newer targeted approaches that you have incorporated into practice?

 It’s actually been a year of discovery in HER2+ metastatic breast cancer. We’ve had a lot of different therapeutic innovations that have been incredibly useful. You can think of them categorically as sort of your antibody drug conjugates, and then your targeted therapies that have been really useful. We’ve seen tucatinib in combination with trastuzumab and capecitabine enter into the market with the HER2CLIMB [trial]. That study has been incredibly beneficial, especially for women with brain metastases. [It is] very encouraging in this patient population that has a higher predilection for central nervous system metastases. We’ve seen neratinib move forward as a viable therapeutic target to target the HER2 family; that’s been effective. We’ve seen T-DXd, or trastuzumab deruxtecan, evolve as an appropriate therapeutic intervention that is highly efficacious. We’ve seen margetuximab enter the market. We’ve seen more therapeutic interventions in the HER2+ space this year than in any other year. I think that it doesn’t alter frontline choices at this moment, though it may because some of these agents are really effective. Putting them as frontline treatment may be an option that is currently under investigation. But it does make it more complicated to make treatment decisions after first-and-second-line therapy when you look to subsequent line of therapy choices because there are many innovator products in that space.

 When should targeted approaches be used in the metastatic setting?

 I think targeted approaches should be used in every line of therapy when they can be. We know that chemotherapy and endocrine therapy act best when they are in combination with HER2 blockade. In my opinion, always combining those strategies with HER2 blockade, when that’s felt to be safe, is a more effective treatment strategy. It’s interesting that you bring this up, because I have been on peer-to-peer reviews of prior authorization where other doctors that are not oncologists have come on the phone, and said if the patient has progressed on trastuzumab, they shouldn’t have trastuzumab again. Obviously, it was not an oncologist, because that’s an indicator that the patient should always have a backbone of HER2 blockade as long as that backbone of HER2 blockade can be given safely in combination with the other therapeutic intervention. For example, you would not combine doxorubicin with a HER2 blockade, because we don’t believe that that’s a safe strategy. But when it’s a safe strategy, we always believe that either endocrine [therapy] or chemotherapy should be accompanied by a HER2 blockade backbone.

 What are the considerations for deciding which targeted therapy is appropriate for a given patient?

 I think it’s very patient-specific. What have they seen? What have they progressed on? How long they were on it? Are there brain metastases? What do we know about penetration into the central nervous system? That’s a nuanced decision, each time you make it, for each subsequent line of therapy.

 Thank you. What is the rationale for the use of dual HER2-targeted monoclonal antibody therapy?

 That’s a great question. I would say upfront, the regimen of docetaxel, pertuzumab, and trastuzumab is highly efficacious. We generally always use that in combination with dual HER2-targeted therapy. In other regimens, when we are looking at multiple targets, such as the HER2CLIMB regimen, for example, those are also beneficial when they are given in combination. I would say in the absence of those 2 examples generally speaking, people are using HER2 blockade as single agents in combination with another treatment strategy or alone.

 Thank you. What are the data that led to the incorporation of dual HER2-targeted therapy as part of the current treatment landscape for metastatic disease?

 Really looking at the efficacy of docetaxel in combination with trastuzumab and pertuzumab. This is a highly effective strategy. Not only is the trial data compelling, but I think now that we have had these drugs in this space for such a long period of time, many of us in our own practice have many patients that are more than 5 years into their initial therapy on docetaxel in combination with trastuzumab and pertuzumab. When they had some toxicity with docetaxel, the oncologist sunsetted the docetaxel and continued the patient on trastuzumab and pertuzumab, which they have continued on targeted therapy with or without endocrine therapy depending upon the patient and the doctor’s choice. But they have enjoyed prolonged disease-free intervals of many years; I think that that’s incredibly compelling.

 Thank you. Can you please describe some of the issues surrounding administration of dual HER2 therapy in the metastatic setting and the need for convenient and effective approaches? For example, treatment schedules, COVID-19, and patient concerns.

 I would say that many of these therapies, especially as it pertains to trastuzumab and pertuzumab, can be given at 21-day intervals and that’s really useful. Generally speaking, that’s convenient for patients. When you are also cycling other therapies that may be pertinent to patients with metastatic breast cancer, like for example, bone health agents, like zoledronic acid or estrogen blockade with fulvestrant, or ovarian suppression, sometimes people do consider alternate schedules of these therapeutic interventions to try to keep treatment more convenient for the patient. Understanding the half-life of some of these therapies; I think that many of us can make those informed choices in reasonable ways. For example, I always treat patients on a 3-week schedule of trastuzumab and pertuzumab when I’m treating them in the metastatic setting. However, I have a patient that fell into my practice who was on, for 9 years now, a combination of fulvestrant in combination with trastuzumab. She’s taken on a 4-week schedule for 9 years and continues to be in complete remission for 9 years. Obviously, that’s an effective strategy which combines a reasonable way to block HER2 in combination with estrogen blockade that’s been incredibly convenient for the patient. She has continued to work and travel and do all the wonderful things in her life. Again, I think that the guidelines about how we administer treatment are incredibly important, but it doesn’t supplant the need for clinical decision-making about what’s right for a patient. Those are choices really made between doctors and patients.

An expert in HER2-positive metastatic breast cancer discusses the new targeted treatment regimens for patients.

New Targeted Therapies for HER2+ mBC

 program titled “Value-Based Decision-Making in Metastatic Breast Cancer.” My name is Briana Contreras, and I am an associate editor of 

. Joining me today is Dr. Debra Patt, executive vice president at Texas Oncology. Dr. Patt, in our first series of questions, we’ll be reviewing the standards of care for frontline treatment of metastatic HER2+ [human epidermal growth factor receptor 2 positive] breast cancer. For my first question, can you share what the historical frontline standards of care have been for HER2+ metastatic breast cancer?

 That’s a great question, Briana. I think that there is a simple answer, and then there are multiple nuances to that simple answer. Most patients who have metastatic HER2 amplified breast cancer benefit frontline from a combination of chemotherapy with docetaxel in combination with HER2 targeted therapy like trastuzumab and pertuzumab. The easy answer is that this frontline strategy has been incredibly effective at maintaining disease control in this population of women. Many of them have benefited from having that strategy implemented, and it has controlled their disease for many years. The more complicated answer is that we always need to think about certain patient specific factors as we consider what treatment is right for which patient. When you look at patients with metastatic breast cancer in general, breast cancer only metastasizes to the brain an average of about 10% of the time. But in patients with metastatic breast cancer, brain metastases are much more common and can happen maybe as much as 50% of the time. If you have a patient that has brain metastases at the time of their presentation, then possibly giving them a more central nervous system-directed type of treatment makes a lot of sense. There are a couple of strategies which we implement that are more favorable for penetration of the central nervous system with the efficacy of disease control in the central nervous system, such as the HER2CLIMB data like tucatinib, trastuzumab in combination with capecitabine or with ado-trastuzumab. In addition, sometimes patients who have highly endocrine sensitive cancers may benefit from treatment with endocrine blockade in combination with HER2 blockade as an upfront treatment strategy. That may be a good answer for some patients. I will say even a consideration for some patients, which is not yet FDA [Food and Drug Administration] approved in this space, is the combination of endocrine therapy HER2 blockade and CDK 4/6 inhibition like in monoclonal [antibodies]. Those are reasonable considerations in this patient population.

 Thank you. What is the current role of chemotherapy in the frontline management of metastatic breast cancer?

Generally speaking, HER2-directed therapy is more effective given in combination with chemotherapy. We favor giving the 2 in combination. I think for most breast medical oncologists, the frontline regimen which we tend to favor is docetaxel in combination with trastuzumab and pertuzumab. That’s a very effective frontline regimen of treatment.

 Thank you. How do you decide which patients are appropriate for chemotherapy in this setting? What do the NCCN [National Comprehensive Cancer Network] guidelines recommend?

That’s a great question. Again, each patient has an individualized decision based on their age, their performance status, their comorbid illnesses, and their ability and desire to have certain treatment interventions. I think that guidelines put you down a certain path. Doctors make individualized treatments in the rooms of patients when they are able to make informed decisions. I think that’s always a complicated factor. For example, in a patient that is much older, has substantial comorbid illness, and has an ER+ [estrogen receptor-positive] and HER2 amplified cancer, I might favor giving that patient endocrine blockade in combination with HER2 blockade as opposed to chemotherapy in combination with HER2 blockade. I think that it would be more tolerable for the patient. Patient factors are always taken into account as we make these treatment decisions. In addition, as I already mentioned, brain metastases can influence your choice of upfront treatment strategies. All of those are important. NCCN guidelines recommend either chemotherapy combined with HER2 blockade or endocrine therapy combined with HER2 blockade as frontline treatment choices. Again, you can think of guidelines like a map that aspires to get you to a particular destination, but there may be patient-specific factors, like you would have route-specific factors along a map. As you go along that journey, they would cause detours or deviations from a guideline based on informed clinical decision-making.

 Thank you. What are some of the challenges associated with available frontline therapies for providers and for patients?

Well, we all face challenges in the prior authorization environment that limit patient care. That is always the limitation, even for very straightforward, guideline-based treatment. Frequently, prior authorization management is a delay, and sometimes a detour, to patients getting the appropriate care that they need. That’s a challenge to manage. Then, in this era where we are burdened by a global pandemic, all of the workup patients need in the metastatic setting is a little delayed. It’s taking longer. There are capacity limitations with biopsies, additional imaging, and with staff that causes delays and appropriate care delivery. Things that used to happen more quickly now takes longer.

Debra Patt, MD, PhD, MBA, describes the frontline standards of care and the factors involved in deciding on a treatment for human epidermal growth factor receptor 2-positive metastatic breast cancer.

Debra Patt, MD, PhD, MBA

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How HER2+ mBC Targeted Therapies Impact Clinical Practice

Cost Considerations for HER2+ mBC Therapies

New Targeted Therapies for HER2+ mBC

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