Debra Patt, MD, PhD, MBA 

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HER2-Positive mBC Standard of Care: Chemotherapy Plus HER2-targeted Therapy

For patients with newly diagnosed HER2-positive mBC, Krop and Patt explained that the current standard-of-care regimen includes both chemotherapy and HER2-targeted therapy, as the combination has been demonstrated to be more efficacious than using either alone. They added that treatment typically involves a taxane, such as Taxol (paclitaxel) or Taxotere (docetaxel), combined with the monoclonal antibody Herceptin (trastuzumab), but recently, chemotherapy combined with dual HER2-directed therapies, Herceptin and Perjeta (pertuzumab) has demonstrated increased survival benefit.

There have been several advancements in the therapeutic landscape of HER2-positive mBC, many of which have created additional treatment options in later lines of therapy. Nerlynx (neratinib) in combination with Xeloda (capecitabine) was approved by the FDA in February 2020 for adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

 Soon after, in April 2020, the FDA approved Tukysa (tucatinib) in combination with Herceptin and Xeloda for the treatment of adults with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

 Later that same year in December, the FDA approved Margenza (margetuximab-cmkb) in combination with chemotherapy for adults with HER2-positive mBC who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease.

Additional combinations are being explored in ongoing clinical trials in patients with HER2-positive mBC. The phase 3 DESTINY-Breast09 trial aims to evaluate Enhertu (trastuzumab deruxtecan) with or without Perjeta versus the standard-of-care regimen (taxane, Herceptin and Perjeta) in the first-line metastatic setting. The primary end point of the study is progression-free survival (PFS; assessed by blinded independent central review); some of the secondary end points include investigator-assessed PFS, overall survival, objective response rate, duration of response, time to second progression or death and health-related quality of life.

 Previously, Enhertu was granted accelerated approval by the FDA in December 2019 for patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

Although the therapeutic landscape for HER2-positive mBC has experienced recent innovations, numerous challenges have the potential to affect the overall delivery of care.

Challenges With Current Treatment Approaches

Most patients with HER2-positive mBC will be treated with chemotherapy in combination with HER2-directed therapy, but clinicians must still make treatment decisions that consider patient-specific factors, as well as systemic obstacles that may affect the delivery of appropriate care.

Krop and Patt agreed that therapeutic approaches in HER2-positive mBC can be associated with treatment toxicity, which can have lasting effects on the patient’s quality of life. Numerous patient-driven factors can influence how therapy is tolerated, including patient age, performance status, comorbidities and location of metastases, according to Patt. She added that when patients are overburdened with toxicity from treatment, they may be less able to maintain productivity in the workforce, compounding the financial burden of treatment.

The financial burden of treatment can be an obstacle to care. "These drugs are all incredibly expensive, and it’s a big challenge for the healthcare industry and for our society," Krop noted. "It’s a societal problem that we’re going to have to deal with.” Patients with HER2-positive mBC are typically treated using combination regimens, which can compound the overall cost of therapy. Many of the available HER2-targeting agents are costly, with those entering the treatment landscape more recently being particularly expensive. However, treatment may still be cost prohibitive even when biosimilars enter the market, Patt added. Additionally, she indicated that the overall cost of treatment is also likely to increase as HER2-directed agents have the potential to receive FDA approval for use in earlier lines of treatment.

Both Krop and Patt emphasized that it is critical for clinicians to recognize that there may be challenges associated with insurance coverage when it comes to treating HER2-positive mBC. Among patients with commercially available insurance, prior authorization can pose a significant challenge, delaying appropriate therapy and imaging. Patients with Medicare may encounter unique obstacles to care related to formulary choice, reimbursement and single-dose vials. Patt further explained that patients who are uninsured are likely to encounter significant barriers to appropriate treatment; there may be charitable care pathways available, but these are highly variable by region and other factors.

According to Krop and Patt, the use of chemotherapy in combination with HER2-directed agents can increase the overall treatment burden for patients with HER2-positive mBC. When on combination therapy, patients may have medications with multiple routes of administration and dosing cycles. This can be challenging for patients to keep track of, so they sometimes require additional coaching about when to take their medication at home and when to come into the clinic for infusion, Krop explained. To accommodate the difficulty of managing complex treatment regimens, Patt noted, “When you use those other agents at different cycles, sometimes people do consider alternative schedules of these therapeutic interventions to try to keep treatment more convenient for the patient.”

Patients with HER2-positive mBC may also encounter obstacles associated with their overall healthcare system utilization, particularly because disease management typically involves monitoring and treating potential side effects of therapy. Patt described how patients require follow-up echocardiograms to evaluate their cardiac function, for example. Managing this side effect of treatment involves numerous added touch points with the healthcare system. Even without side effects complicating treatment, additional steps such as surgical or radiological intervention may complicate already challenging cost and access issues, Patt added. She explained that the scope of healthcare utilization required by patients with HER2-positive mBC can exacerbate problems associated with overburdened and understaffed healthcare systems. This can result in critical delays to receiving lab results, scheduling imaging and performing biopsies, she noted.

Patt described how, in the era of COVID-19, there have been pervasive decreases in cancer screening, biopsies, diagnoses and subsequent therapeutic intervention. In addition to these reductions in cancer care diagnoses, she said, there have been challenges with managing patients with metastatic disease: “We have been burdened by a global pandemic, (so) all the work-up (that) patients need in the metastatic setting is a little delayed. It’s taking longer. There are capacity limitations in the ability to do biopsies or additional imaging.”

Physicians have needed to adjust their treatment strategy to accommodate existing patients. According to Krop, some healthcare providers have reconsidered the use of immunosuppressive regimens or started using longer-acting therapies to minimize the number of clinic visits necessary. Visiting nurse services and phone- or internet-based forms of communication have also been used, but Krop indicated that the degree to which these will remain cost-effective or feasible at scale post-pandemic is unclear.

National Comprehensive Cancer Network (NCCN) Guidelines

Krop commented on the value of current treatment guidelines for HER2-positive mBC by stating, “If you look at the NCCN Guidelines, they’re not very directive.” He explained that this can make it challenging to navigate patient-specific factors when deciding whether to use upfront chemotherapy versus an alternative therapy. Current guidelines do not specify which patients may derive benefit; they provide helpful guardrails, but there are many reasons why a patient’s treatment plan may deviate from the guideline-directed approach.

Taking a value-based approach to the care of HER2-positive mBC requires an analysis of the potential benefits and costs of treatment to provide appropriate care for patients. For the future management of patients with HER2-positive mBC, both Krop and Patt agreed that the healthcare system should provide patients with treatment that is both medically effective and cost effective to maximize disease control without causing undue burden on patients and the healthcare system.

Patt addressed value-based care in HER2-positive mBC: “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 [are] the most appropriate value-based choices," she said. “Patients with HER-2 positive metastatic breast cancer can benefit from these long disease-free intervals (for) more than a decade. And so I think a question remains: 'How can we give the most effective therapy upfront, and then keep them on some chronic therapy in perpetuity to keep their disease controlled, and (do this in) the most cost-efficient way?' And with so many innovator products in this space, I think we're going to have better answers there in the next years to come.”

1. Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study.

. 2020;21(4):519-530. doi:10.1016/S1470-2045(19)30863-0

2. FDA approves neratinib for metastatic HER2-positive breast cancer. FDA. February 26, 2020. Accessed August 5, 2021. https:// 

www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neratinib-metastatic-her2-positive-breast-cancer

3. Nerlynx. Prescribing information. Puma Biotechnology; 2021. Accessed August 5, 2021. 

https://nerlynxhcp.com/pdf/full-prescribing-information.pdf

4. Tukysa. Prescribing information. Seagen; 2020. Accessed August 5, 2021. 

https://seagendocs.com/TUKYSA_Full_Ltr_Master.pdf

5. FDA approves margetuximab for metastatic HER2-positive breast cancer. FDA. December 17, 2020. Accessed August 5, 2021. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-margetuximab-metastatic-her2-positive-breast-cancer

6. Margenza. Prescribing information. MacroGenics; 2020. Accessed August 5, 2021. 

https://www.margenza.com/pdf/prescribing-information.pdf

7. DESTINY-Breast09 head-to-head first-line phase 3 trial of Enhertu initiated in patients with HER2 positive metastatic breast cancer. News release. Daiichi Sankyo. June 14, 2021. Accessed August 5, 2021. 

https://www.daiichisankyo.com/files/news/pressrelease/pdf/202106/20210614_E_ver2.pdf

8. Trastuzumab deruxtecan (T-DXd) with or without pertuzumab versus taxane, trastuzumab and pertuzumab in HER2-positive metastatic breast cancer (DESTINY-Breast09). ClinicalTrials.gov. Updated August 2, 2021. Accessed August 3, 2021. 

https://clinicaltrials.gov/ct2/show/NCT04784715

9. FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer. FDA. December 20, 2019. Accessed August 5, 2021. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2-positive-breast-cancer

10. Enhertu. Prescribing information. Daiichi Sankyo; 2021. Accessed August 5, 2021. 

https://dsi.com/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true

Articles

In this Managed Healthcare Executive® KCast, Ian Krop, M.D., Ph.D., oncologist and associate professor of medicine at Dana-Farber Cancer Institute in Boston, and Debra Patt, M.D., Ph.D., MBA, executive vice president at Texas Oncology in Austin, provide key insights into the value-based care model for patients with HER2-positive metastatic breast cancer (mBC). This article summarizes the highlights of the discussion.

Value-Based Decision-Making in Metastatic Breast Cancer

 Now for our last series of questions, we’ll be looking at value-based care models in precision oncology in HER2-positive metastatic breast cancer. What are some of the challenges with HER2-directed therapy in a value-based care model?

Well, when you have a higher percentage of patients that’s HER2-positive, I think that your total health care resource utilization is going to be higher because you’re using more novel therapies like trastuzumab, pertuzumab, trastuzumab deruxtecan [DS-8201], and tucatinib therapies that are on average, more expensive. In contrast to if you were to look at other types of breast cancer, though I will say for other types of breast cancer for triple-negative breast cancer that is amenable to immunotherapy. Immunotherapy is also expensive. And for ER [estrogen receptor]-positive breast cancer that’s HER2-negative, frontline treatments with estrogen blockade and CDK4/6 inhibition also add cost. Because of the innovation in breast cancer and HER2-positive breast cancer in the last year, I think those therapies in general are more expensive. But I think that all of cancer care is experiencing tremendous innovation, and that does drive up the total cost of care. As we think about value, again value being outcomes over cost, I think you can’t question these incredible outcomes that patients have had, and their improvements in progression-free and overall survival as a natural consequence of these innovator, therapeutic interventions.

 How does total cost compare with that of standard chemotherapy approaches and how does the cost breakdown vary?

When you’re using chemotherapy in combination with HER2-directed therapy, it is substantially more expensive than chemotherapy alone. But I would argue that chemotherapy alone, unless HER2 therapy is truly contraindicated, really isn’t a reasonable treatment choice for patients with HER2-amplified metastatic breast cancer because it doesn’t give them an optimal outcome.

 How do guidelines and pathways influence your treatment decisions in value-based care delivery?

I think of guidelines and pathways as a map. For many oncologists, pathways can exist in a clinical decision support system like a nudge for appropriate guideline-based care delivery that’s in the best interest of patients, just like Google Maps is going to get me to my destination in the most efficient possible way. So, I think in general, patients do better when they’re treated in accordance with guidelines and pathways. Those strongly influenced our choices around care delivery. However, just like when I sit, and I drive, and I’m in the driver’s seat of my car, really therapy choices belong in a room with individual patients and their doctors. There may be really reasonable reasons why patients vary from guideline-based choices that are individualized. So, what I would say is, while guidelines and pathways are incredible facilitators of evidence-based decision-making, they don’t supplant the need for clinical decision-making. That still remains an important component of care delivery plans, and patients have a say in how they move forward. I think that they’re really useful tools to try to make sure that most patients are treated in accordance with guidelines and evidence that makes a lot of sense and is in the best interest of patients. But at the end of the day, those are still individualized choices between doctors and patients that can depend on many patient-specific factors.

 Lastly, what are other considerations regarding HER2-targeted therapy from a value-based care perspective?

Well, again in patients with HER2-positive metastatic breast cancer, they can benefit from these long disease-free intervals more than a decade. I think the question remains, how can we give the most effective therapy upfront, and then keep them on some chronic therapy in perpetuity to keep their disease controlled, and in the most cost-efficient way. With so many innovator products in this space, I think we’re going to have better answers there in the next years to come.

Videos

Debra Patt, MD, PhD, MBA, highlights how value-based care models affect treatment decisions for patients with HER2-positive metastatic breast cancer.

Value-Based Care Models for the Treatment of HER2+ mBC

 What are some of the most common HCP [health care provider] barriers related to getting access for their patients, especially for novel targeted approaches, such as dual HER2-targeted regimens?

Among the commercially insured patients, prior authorization barriers are present. That limitation usually is a delay from appropriate therapy, but it can be a detour. Actually, even getting appropriate imaging can be a challenge. In patients with metastatic breast cancer, we do need appropriate imaging prior to the initiation of treatment, [so] managing the prior authorization and scheduling can be a barrier that frequently delays treatment. That’s a challenge. Among Medicare beneficiaries, it’s much more straightforward. The Medicaid program has some novel challenges around formulary choice, around reimbursement and single dose vials, which remains a challenge to patients getting the appropriate therapy that they need. Among the uninsured patient population, there’s a whole hurdle of new challenges to try to get patients the care that they need. I would say that that’s very region specific. I come to you from Texas where we have [a population of] 30 million, and a high percentage of the population is uninsured. It’s about 17% of the general population, but 25% of the population between 18 and 64. So that poses a challenge. Many manufacturers can be generous with indigent patients by donating drugs. Many of our cancer centers have indigent programs that allow patients to receive care. But this is a problem that’s highly variable based on the region of the state and region of the country. So, I talk about the challenges that we have in Texas, but I practice in West Austin, which is very different from the Rio Grande Valley. And so, I would say that more broadly as you think about this conversation in a national audience, is that those are regional specific concerns that can be highly variable.

 Can you share some of the access challenges patients have faced getting targeted treatments for metastatic breast cancer? Could it be related to cost, physical access, or coverage?

Where I practice in Texas, the major challenge is patients not having access to insurance products, so there’s a high burden of uninsured patients. My own organization has employed social workers to get patients enrolled in the breast cancer Medicaid program—we call it “pink Medicaid”—there are different criteria for breast and cervical cancer than there are for traditional Medicaid for adults. So, we’ve been more successful at getting patients on the “pink Medicaid” program. But it takes some time. Eligibility has to be verified frequently with more aggressive cancers like HER2-positive cancers, but you want to start patients on treatment right away. That can be a challenge. So, navigating the issue of insurance is a challenge. Understanding when you can get drugs donated is a challenge. Then even for Medicare beneficiaries, when some of these involve oral oncolytics, like tucatinib or capecitabine, you have to manage their Part D benefits. Some Medicare beneficiaries have Part D benefits because they’re participants in the Part D program. Some have commercial counterparts. Some do not. So, managing their therapies to manage their out-of-pocket costs becomes a real consideration. In some patients that don’t have a Part D plan, it can be cost prohibitive for them to have a strategy of oral oncolytics because it’s not covered under the traditional program.

 How does the use of HER2-targeted therapies impact site of care considerations?

Well, I would say that I don’t think that patients make a choice about site of care based on HER2-targeted therapies. But when patients receive outpatient infusion in a hospital setting, particularly a 340B hospital setting, the hospitals are able to purchase those drugs at a substantial discount. So somewhere between a 25% and 50% discount on trastuzumab, pertuzumab, and other oral and IV [intravenous] therapeutic interventions, in contrast to say a community oncology or private practice clinic, that does not purchase them at a discount.

 Now did your use of HER2-targeted therapies for patients with metastatic breast cancer change during the COVID-19 pandemic? And if so, how do you think these changes will continue now that COVID-19 vaccines are available?

 It’s a great question. I will say that has been very regional. If you look broadly across the Medicare population, we did a study with Community Oncology Alliance and Avalere Health that we published in [JCO] 

 this last year and we understand that there was a great impact in cancer care from the COVID-19 pandemic. We saw decreases in cancer screening, biopsies, new cancer diagnoses, and subsequent therapeutic interventions. So, we know that it was pervasive; in April and May of 2020 it was down by 80% in comparison to 2019. I would say more broadly over the year, it’s probably about 30%. It’s difficult because we know of course that those cancers are happening, they’re just being diagnosed later. So yes, cancer care was absolutely impacted. I think it’s highly variable though. Because in places like West Austin, where I practice, our radiology centers stopped screening during that time, whereas our practices in West Texas sort of operated business as usual. I’m sure that if you lived in Queens, New York, which was greatly impacted by the pandemic, if you were receiving your care at the hospital setting, you probably didn’t go in for it whenever they had high rates of COVID-19. So, I think those are very regional stories. But if you look at global population health impact, generally speaking, there were substantial reductions in cancer care delivery and cancer care diagnoses during the pandemic. I anticipate that those will return to more normal rates after the pandemic, as people are vaccinated, and our rates appear to be improving. But I suspect that with regards to screening and new cancer diagnosis and delayed cancer diagnosis, that those will be changes that we will continue to appreciate for the next years to come. I think it’s true for all of us. And I think each one of us has our list of things that have had deferred maintenance during the pandemic, whether it’s our haircuts or dentist visits or screening mammograms, and we just simply can’t address them all at once. Some of them will take priority. If you lost your job during the pandemic, that’s probably the priority that’s going to demand your time for several months before you ever get to the hairstylist or the dentist or the imaging center to get your breast cancer screening, and that is a shame. So, I think that if we can have efforts to heighten awareness about the importance of screening, we have better opportunities to reduce morbidity and mortality of cancers, because we’re able to catch them early. In the words of Ben Franklin, “An ounce of prevention is a pound of cure.” That’s certainly true of cancer. We want to see people screened, and screened early, but I suspect that we’re going to see the ramifications of those delays for many years to come.

A key opinion leader describes treatment access considerations among patient with HER2-positive metastatic breast cancer.

Challenges of Patient Access to HER2+ mBC Therapies

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.

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.