Ian E. Krop, MD, PhD

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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

I have a couple of questions that will be highlighting the ways in which the availability of HER2-targeted therapy has required adaptations to clinical practice. For my first question, how do you incorporate patient preference in treatment selection?

 I think we touched on that a little before. The advantage of having multiple options now for HER2-directed therapies is that we can tailor our therapies for individual patients. We certainly take into account things, as I mentioned, like hair loss. There are regimens like T-DM1 [trastuzumab emtansine] and the HER2CLIMB regimen, which don’t cause any significant alopecia; and we use those if patients are averse to losing their hair. Drugs like trastuzumab deruxtecan cause hair loss in about half of patients. Those are some of the considerations; also whether patients are able to travel to your infusion center easily, or an every-3-week infusion drug versus a weekly drug. There are big medical issues, like brain metastases, which I think would steer us more toward drugs like tucatinib-based treatment. Other inpatients who don’t have brain metastases can use this very effective agent trastuzumab deruxtecan, which has about a 97% disease control rate. Those are the medical issues, layering on top of patient preferences. The good thing is we have lots of options; most patients are going to get all of these drugs at one point or another, and it’s a matter of sequence.

How have you changed your practice to accommodate patients on targeted therapy in terms of patient care, and what are some of the challenges that may have come about?

 In the COVID-19 era, those kinds of practical issues have to be thought of even more than in the past. There is not a big difference between giving an infusion of trastuzumab versus an infusion of vinorelbine, or chemotherapy versus targeted therapy. In other words, there’s not a huge difference in terms of practical infusion issues. Particularly during the COVID-19 pandemic, we’ve been trying to minimize the number of visits patients have to have; using longer-acting therapies is helpful there. We’ve been trying to avoid using immunosuppressive regimens; that’s a reason to try to avoid immunosuppressive chemotherapy for patients, especially when COVID-19 was flaring in each of our areas. Those are some of the things we’ve been thinking about to try to make it easier for patients, cutting down visits, avoiding immunosuppression. I think those are the main things. The other issue is some of these are oral regimens, meaning you need to have nurses be able to call patients to make sure they’re taking the drugs appropriately at home, and they’re not having real problems managing things like diarrhea or mucositis. It helps to have more outreach to patients now that they’re taking more medications at home versus getting infusions in the infusion room.

As you mentioned the pandemic, 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 the COVID-19 vaccines are available?

 Yes, particularly when COVID-19 was really surging, we did our best to try to minimize the number of trips patients had to make, and used therapies that only required once-every-3-week visits or therapies that patients could take largely at home. There has been a push to try to use fewer infusions. There’s an interest in subcutaneous formulations of antibodies, which we now have with trastuzumab and pertuzumab. That’s been helpful because it means that if they have to come in [to the infusion room], it can be for a short time. There are people who are investigating whether you can get these drugs at home as subcutaneous formulations, and have nurses go to people’s homes to give them their subcutaneous injection, so they don’t have to come in at all. That’s going to require a whole new set of infrastructure if it scales, but it’s worth thinking about that. COVID-19 gave us a nudge that we needed to try to explore some of those things. Whether they’ll prove to be cost-effective and feasible for everybody post–COVID-19, we’ll have to find out. But it certainly made us think creatively, and we’ll probably come up with some kind of happy medium where we’re requiring patients to come in fewer times, and for shorter amounts of time, as much as possible.

Thank you so much, Dr. Krop, for your time. This has been an excellent discussion, and we hope you found the information to be valuable to your clinical practice. Thank you all for watching this 

Videos

The impact of the COVID-19 pandemic on the utilization of newer targeted therapies for HER2-positive metastatic breast cancer and considerations regarding their adoption into clinical practice based on the availability of vaccines.

COVID-19 and the Use of HER2-Targeted Therapy for MBC 

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

: There are now several different ways to do dual HER2 therapies. The one we first figured out was the combination of trastuzumab with pertuzumab, as you asked about, 2 different antibodies. That’s based on the fact that even though they both target HER2, they target different spots on the molecule, different epitopes on the HER2 molecule. That allows them to block the different types of signaling of HER2, and different methods of dimerization. That’s relevant because it looks like one of the ways cancers were getting around the effects of trastuzumab was activating a pathway, whereas HER2 would bind to other similar molecules that trastuzumab doesn’t block, but pertuzumab does. By combining trastuzumab and pertuzumab, you can block both of those signaling pathways and overcome resistance. That was shown in clinical trials to be advantageous with a big survival benefit compared to either one alone. There are also data combining antibodies like trastuzumab with tyrosine kinase inhibitors, like lapatinib or tucatinib. That’s a part of the rationale for the HER2CLIMB regimen, using both trastuzumab and tucatinib along with capecitabine. Because of synergistic effects on HER2 signaling, you get better efficacy than using one of those alone.

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

 That’s the data we were talking about. In the first line, we had this CLEOPATRA trial that compared chemotherapy and trastuzumab versus chemotherapy and dual therapy of trastuzumab and pertuzumab. There was a 16-month survival benefit by adding pertuzumab, showing unequivocally more efficacy when you use those dual approaches. There have been smaller studies looking at combining antibodies with tyrosine kinase inhibitors, including this HER2CLIMB trial, which used trastuzumab and chemotherapy with or without the tyrosine kinase inhibitor tucatinib. It showed a benefit in terms of survival by adding 2 HER2 therapies versus 1 alone.

Can you please describe some of the issues surrounding administration of dual HER2 therapy in the metastatic setting?

 There are some practical things. When you’re combining an oral therapy with an antibody, it’s more complicated for patients. They have to come in to get their infusions, and have to take oral medications at home. They need a lot of coaching for that to make sure they are taking their oral regimen correctly, and having to come in as well. There is a problem with using 2 different antibodies, each with its own infusion time, leading to longer times that patients have to stay in the infusion room. That’s being addressed in part by products combining trastuzumab and pertuzumab into 1 drug, which cuts down the infusion time. There are also subcutaneous versions of the combination, which completely get rid of the infusion time. The market is working to get around some of the hassles of using multiple HER2-targeted therapies. But until that problem is completely solved, it is more complicated, both for patients and providers, to use multiple HER2 therapies as opposed to 1; there is a cost.

As you mentioned cost, how do cost considerations factor into your treatment decision-making?

 Fortunately, I’m an academic oncologist, and I work in a state that has a relatively high number of patients who have good health insurance. But at least in the HER2 therapy world, cost hasn’t been much of a direct challenge for patients. It’s been a long time since I’ve had a patient have a problem with out-of-pocket payment for these drugs. Even the oral agent tucatinib, I haven’t had that issue so far. That’s what patients are experiencing; it hasn’t been a problem. These drugs are incredibly expensive, and it’s a big challenge for the health care industry and our society. We are combining more than 1 of them; obviously, that’s more expensive than using 1 drug alone. It is a societal problem that we’re going to have to deal with. But at least at the individual patient level right now, cost, in my experience, has not been a real problem in this particular arena.

The rationale for treating metastatic breast cancer with a dual HER2-targeted therapy approach. 

Dual HER2-Targeted Therapy for MBC

I know some of these targeted approaches may be used at different times. You mentioned a few examples. In general, when should target approaches be used in the metastatic setting?

: That’s a great question. I think unlike most other areas of breast cancer, in which sometimes we use target therapy, sometimes we use conventional therapies, in HER2-positive disease, it’s not really a question of when to use it. Because we’ve now shown in multiple studies that when you use a HER2-directed therapy, it’s always better than not using HER2 therapy. In every line of therapy we’ve looked at, using a HER2 therapy either by itself or with chemotherapy or endocrine therapy is always better than using the chemotherapy or endocrine therapy alone. In practice, what happens is, at least in the United States where fortunately these drugs are all available, we always have at least 1 HER2 therapy in everybody’s regimen. I think the data really support that. As we talked about, there are lots of different options, and how you sequence them can differ depending on patient preference and other factors. But I think the general sense is you should always have at least 1 HER2-directed therapy in your regimen, be it an antibody or a tyrosine kinase inhibitor, or a combination, or an antibody-drug conjugate.

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

 I think that’s where things are evolving and where clearly a one-size-fits-all approach doesn’t make sense anymore. As I was talking about earlier, I think whether a patient has brain metastases at least helps me decide whether you’re going to use trastuzumab deruxtecan versus tucatinib-based therapy. We didn’t talk about neratinib, which also seems to have some effectiveness in the brain. My opinion about this is that we should probably use tucatinib in most of those patients first, along with capecitabine and trastuzumab, and then you could consider using neratinib after that if they have progression. But with the caveat that we really don’t have any data yet on whether neratinib does work after the use of another tyrosine kinase inhibitor like tucatinib. I’m hoping we get some data on that.

Those are the kind of things that we should think about, whether they have brain metastases. Somebody who has prior significant pneumonitis probably would like to avoid using trastuzumab deruxtecan, at least until you’ve tried other regimens. People who have problems with their GI [gastrointestinal] tract would like to avoid the drugs that cause significant diarrhea. I think those are things that should be considered. Some of these drugs cause less hair loss than others. For a patient who’s averse to hair loss, trying to use a regimen that doesn’t cause hair loss first would make sense. It’s definitely something where you have to consider lots of different variables. But it’s nice that we have all these different options.

Ian E Krop, MD, PhD, elaborates on which treatment settings are most appropriate to use HER2-targeted therapies in to manage metastatic breast cancer.

Sequencing HER2-Targeted Therapies in MBC

 We have 4 new drugs, all of which are now approved, mostly in these patients who have had at least 2 lines of prior HER2-directed therapy. The question would be, how do you decide which one to use? For first-line and second-line therapy, we still use the tried-and-true standard of taxane, trastuzumab, pertuzumab in the first line, and T-DM1 [trastuzumab emtansine] in the second line. In the third line, we have these 4 new drugs. How do we decide which ones to use? I think different oncologists probably have different views. There’s no right answer here.

In my mind, it makes sense to use trastuzumab deruxtecan in patients who do not have brain metastases, or who had brain metastases treated a long time ago and never had another problem. The reason I think it makes the most sense to use that drug is because the efficacy of trastuzumab deruxtecan, which we really haven’t talked about yet, appears markedly more active than any of the other drugs we’ve had so far. The response rate in heavily pretreated patients is over 60%, and progression-free survival is approaching 20 months, which is roughly 3 times longer than what we’ve seen with other drugs in the pretreated setting. It works very effectively, very uniformly, and it tends to have very durable responses. I think it’s very nice to be able to tell a patient that you have a drug that’s going to work in the vast majority of people to some extent, and it’s going to likely work for a long time. One [adverse] effect of trastuzumab deruxtecan that we have to pay attention to is that in about 15% of people, you can get pneumonitis or interstitial lung disease, which can be serious and can be fatal in a small number of patients. That has to be monitored when you use that drug.

For patients who have significant brain metastases, using tucatinib-based therapy in the third line, to me, makes the most sense because the drug clearly shows activity in that setting. In the fourth line, you can switch to whichever one the patient didn’t get. After that, you can use this new drug margetuximab along with chemotherapy to take advantage of its immune effects. That’s in my mind how we integrate all of these new drugs, at least one approach for patients now that they’re all available.

Considerations regarding how to best integrate newer targeted therapies available for HER2-positive metastatic breast cancer [MBC] into clinical practice.

HER2+ MBC: Integrating Newer Targeted Therapies Into Practice

 For our next series of questions, we’ll be reviewing the newer treatment regimens for HER2-positive metastatic breast cancer. For my first question, what are some of the newer targeted approaches that have been incorporated into practice?

 This field has exploded in the last year and a half or so with 4 new drugs approved by the FDA in that time frame. It’s unprecedented to see that growth in a field. Prior to a year and a half ago, our standard treatments included the drugs we’ve already talked about, which are trastuzumab, pertuzumab, the tyrosine kinase inhibitor [TKI] lapatinib, and one drug we haven’t spoken about yet is T-DM1 [trastuzumab emtansine], which is an antibody-drug conjugate consisting of trastuzumab linked to a potent microtubule inhibitor. Those were the drugs that we had been using for multiple years in the HER2+ metastatic space. We typically used the trastuzumab, pertuzumab, and taxane regimen in the first line, as I mentioned. Then we would use T-DM1 [trastuzumab emtansine] in the second line because that had been shown in a randomized trial to have better efficacy than capecitabine and lapatinib.

Where things have changed a lot is in the third and later lines of treatment. Previously in that setting, we would typically use some type of chemotherapy along with trastuzumab, and rotate the chemotherapies as patients progressed. There were a lot of options, but they didn’t tend to work all that well. Typically, patients would have a response rate of less than 20% in that setting, and progression-free survival was typically 4 to 5 months. There were a lot of different options you could use for those later-line patients, but we clearly needed better options because the ones we had were pretty limited. That’s where things have changed is in this third- and later-line settings. The new drugs we have include another antibody-drug conjugate. This one’s called trastuzumab deruxtecan. It differs from T-DM1 [trastuzumab emtansine] in the payload connected to the antibody. The antibody is pretty much the same. It’s essentially trastuzumab, or at least it has the same amino acid sequences as trastuzumab. But it’s linked to a different class of chemotherapy. With trastuzumab deruxtecan, the payload is a topoisomerase 1 inhibitor.

This is a type of chemotherapy we typically don’t use in HER2-directed therapy. It’s unlikely that cancers would have developed resistance to this class of drug by the time they see trastuzumab deruxtecan. In addition, there are more payload molecules per antibody. Theoretically at least, it can deliver more chemotherapy to the cancer cell. The payload has what’s called bystander effect, meaning that once the conjugate binds to the cancer cell, the payload gets released into the cytoplasm of that cancer cell, but it can then diffuse out of that cancer cell and kill neighboring cancer cells, regardless of whether they make HER2. In a cancer that is heterogeneous for HER2, meaning that there may be a mixture of cancer cells that are highly HER2+, and maybe some that only have low or no HER2 levels, a drug with bystander effect may be more effective than a drug without. T-DM1 [trastuzumab emtansine] does not have that bystander effect, whereas trastuzumab deruxtecan does. That’s a new antibody-drug conjugate.

We have 2 new tyrosine kinase inhibitors. As I mentioned, lapatinib was the first TKI approved. There are now 2 more. One of them is neratinib, which is a very potent HER2 kinase inhibitor. It also blocks a related kinase called EGFR, or HER1, and HER4. That’s relevant because inhibition of EGFR results in toxicities like rash and diarrhea. This drug is very active and potent. But again, it does carry this liability of causing diarrhea and rash because of its effects on EGFR. Neratinib was approved after 2 lines of therapy based on a trial comparing neratinib and capecitabine versus lapatinib and capecitabine, showing that neratinib and capecitabine were more effective in terms of progression-free survival and prevention of need for interventions in the brain. Neratinib was approved in the setting in combination with capecitabine.

The second tyrosine kinase inhibitor that was approved recently is tucatinib. Tucatinib is a little different from neratinib and lapatinib in that it’s very specific for HER2. It doesn’t inhibit EGFR much at all, so it doesn’t have as much of that problem with diarrhea as these other agents do. Tucatinib was approved in combination with capecitabine and trastuzumab based on a trial called HER2CLIMB, which compared that regimen to capecitabine and trastuzumab and placebo. The addition of tucatinib led to significant improvements in progression-free and overall survival, as well as showing substantial activity in the brain, not only in improving survival in patients who had active brain metastases, but also showing response rates in the 40% range in the brain when treated with that combination of tucatinib, capecitabine, and trastuzumab.

The last agent that has been approved, which is the most recent approval, is an interesting new antibody called margetuximab. Margetuximab is essentially the same as trastuzumab, but it’s modified to have more immune effects. We’ve known for a long time that trastuzumab works at least in part by activating the immune system to attack the cancer cells. It does this by activating something called ADCC, or antibody-dependent cellular cytotoxicity. That happens by binding of the antibody to something called an Fc receptor on natural killer cells. The problem is that many patients, in fact about 85% of patients, have Fc receptors that don’t bind to these antibodies as well as the 15% of patients who have the high-affinity Fc receptors.

Margetuximab is modified so that it binds really tightly to these Fc receptors, even if you’re one of the 85% of people who have these low-affinity receptors. By doing this, it should increase the immune effect of these antibodies. It was compared to chemotherapy and trastuzumab in a trial called SOPHIA, which randomized patients to chemotherapy and trastuzumab or chemotherapy and margetuximab, showing that margetuximab had improved progression-free survival, and a trend toward overall survival superiority in those patients who had these low-affinity Fc receptors. Again, 85% of patients have these low-affinity Fc receptors. Margetuximab is an interesting molecule; it doesn’t have much in the way of added [adverse] effects compared to trastuzumab because it’s so similar. But it does appear to be better than trastuzumab, particularly in these patients with low-affinity Fc receptors.

Ian E. Krop, MD, PhD, of Dana-Faber Cancer Institute, highlights more recent targeted therapy approvals for HER2-positive metastatic breast cancer and describes how each therapy is designed to work.