Soliman Details Testing for and Treating HER2+ Breast Cancer

Hatem Soliman, MD

Over recent years, patients with HER2-positive metastatic breast cancer now have new therapies which have changed the treatment landscape in this space based on the completed and ongoing trials.

The phase 3 CLEOPATRA study (NCT00567190), the efficacy and safety of pertuzumab (Perjeta), trastuzumab (Herceptin), and docetaxel was compared with placebo, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. Data from the trial were positive, showing significantly improved progression-free survival (PFS) and overall survival (OS) rates with pertuzumab vs placebo.¹

These findings have solidified the role of pertuzumab plus trastuzumab as a frontline standard treatment for this patient population.

Then, while fam-trastuzumab deruxtecan-nxki (Enhertu) was once only useful for a fraction of patients with high HER2 expression, findings from the DESTINY-Breast04 trial (NCT03734029) have shown different results, creating a new second- and third-line option for patients.²

DESTINY-Breast04 trial evaluated the use of an antibody-drug conjugate (ADC), trastuzumab deruxtecan, in patients with HER2-low, unresectable and/or metastatic breast cancer. Patients were randomized 1:1 or receive either trastuzumab deruxtecan or physician’s choice of therapy.

Findings from the trial showed that PFS and OS significantly improved in patients with low HER2 expression, regardless of hormone receptor status vs standard. Now, using this ADC, patients with low HER2 expression are candidates for this effective therapy.

“The landscape of drug development right now has accelerated quite dramatically because of these enabling technologies, like antibody drug conjugates, that are a way that you can in essence, select a given target on a cell to have it preferentially attacked by the therapy while trying to avoid the delivery of the payload to the normal tissue. By combining different antibodies that go after different targets with different payloads, there's a possibility that we can develop new drugs,” said Hatem Soliman, MD, in an interview with Targeted Oncology^TM.

In the interview, Soliman, an associate member of the breast oncology program, and medical director of the clinical trials office, Moffitt Cancer Center, provides an overview on testing for HER2-positive breast cancer and the available therapies in the first-, second-, and third-line settings.

Targeted Oncology: How do you currently test for HER2 status?

Soliman: The clinical standard to test for HER2 status, in most cases, involves a combination of immunohistochemistry, testing for overexpression of the HER2 protein, and the other method that we use as well is based on a either a fluorescence or a chromogenic dye in situ hybridization test, to check to see if there are amplifications of the HER2 gene that are detected within the nucleus of the cells that are counted. So, either by having that amplification of HER2 on the [in situ hybridization] tests or overexpression of the protein on the immunohistochemistry test, then we would classify those patients as HER2-positive for targeted therapy.

Can you explain some of the current treatments for patients used in the first-line?

Many of the treatments that we use in the first-line setting for patients with metastatic HER2+ positive breast cancer are based off of the data from the CLEOPATRA trial, which was published in the New England Journal of Medicine a number of years ago. It involved using a taxane-based chemotherapy, in addition to 2 antibodies, pertuzumab and trastuzumab, which cooperate in order to more fully suppress HER2 signaling. Based on the results of the CLEOPATRA trial, that is still considered the current preferred standard of care for first-line HER2-positive metastatic patients.

Often though, what we can do is treat them initially with the taxane plus [pertuzumab] and [trastuzumab] for about 6 cycles or until we get a good response. Then, sometimes we can peel the chemo off and just maintain them on the [pertuzumab and trastuzumab] for a period to give them a break from chemotherapy and potentially improve their quality-of-life while maintaining control of their disease over time.

What is important to note about the use of trastuzumab deruxtecan among patients with HER2+ breast cancer?

Trastuzumab deruxtecan is a game changer for us in the field. This is a very active drug, which showed its promise quite early on in its development based on some of the early DESTINY trials that were conducted. This drug is highly active, and it's an antibody drug conjugate. As opposed to the pertuzumab and trastuzumab-based treatments, which are just monoclonal antibodies, the antibody drug conjugate is a different way to deliver targeted chemotherapy payloads to the cells preferentially that overexpress or have a particular target while trying to spare the toxicity from normal tissues that don't express as much of the target. Trastuzumab deruxtecan tries to exploit that by taking those patients who are HER2-positive and delivering a highly potent payload known as SN-38, which is attached to the antibody. It's conjugated and gets sucked into the cells that overexpress HER2. Although nowadays, we use it for tumors that may have lower levels of HER2 expression as well with quite a bit of success. But the idea is still the same. The antibody gets sucked in, and then the chemical payload that's attached to the antibody gets cleaved off within the cell, and then it can go about doing its business of trying to knock off the target cell. That's what makes it so active and effective is the combination of that targeted delivery of a potent payload that allows it to have such a great level of activity in HER2-expressing cancers.

What second- and third-line strategies are being used for these patients?

Based on the DESTINY-BREAST03 data, showed that the current standard of care that was looked at at the time was the use of basically another antibody drug conjugate called [trastuzumab emtansine (Kadcyla)], which had a different payload. It was a different chemical payload than what is on trastuzumab deruxtecan and that was the standard of care for a number of years following the combination of taxane, pertuzumab, and [trastuzumab]. However, as a result of the head-to-head trial in which trastuzumab emtansine was a control, the activity was superior dramatically in the HER2 comparator arm of [trastuzumab deruxtecan]. That became now the preferred second-line therapy for most patients with HER2-positive breast cancer in the metastatic setting and displaced the use of [trastuzumab emtansine] going forward.

Now in our guidelines, we will use trastuzumab deruxtecan in the second-line setting, and then basically also have a consideration for another combination, as well as for a specific group of patients, either in the second-line or in the third-line setting. That triple combination of capecitabine [Xeloda] plus trastuzumab plus tucatinib [Tukysa], which was studied in the HER2CLIMB [NCT02614794] is another one of the options that we look at in that second- and third-line space.

Has any ongoing research caught your eye in this space?

A lot of the research now that's exciting is in looking at potentially with trastuzumab deruxtecan in HER2 being moved up further in the treatment paradigm in order to see if it can deliver a more potent benefit for patients, particularly like those that may have a specific amount of HER2 expression across the board, and for patients that are not just HER2-positive or overexpressing, but those with lower levels of HER2. We want to see if we can broaden that use over time. Also, there's some exciting data looking at its ability to potentially salvage patients with residual disease following neoadjuvant chemotherapy that are HER2-positive. We know that those patients can be at a little bit higher risk of relapse, and eventually develop metastatic disease. They're looking at whether the use of trastuzumab deruxtecan in those patients provides a superior cure rate. For those patients, I think that would be very exciting. At the end of the day, that would be the most bang for our buck. If we can cure more patients upfront with the most active drugs that we have in our arsenal, that will lead to the largest gain and improvement in outcomes for that population. I think there'll be exciting results in the months and years to come as the drugs are looked at in some of these different scenarios, to see where we can best apply them to get maximum effect.

Are there any other future directions that you anticipate the landscape moving towards?

The landscape of drug development right now has accelerated quite dramatically because of these enabling technologies, like antibody drug conjugates, that are a way that you can in essence, select a given target on a cell to have it preferentially attacked by the therapy while trying to avoid the delivery of the payload to the normal tissue. By combining different antibodies that go after different targets with different payloads, there's a possibility that we can develop new drugs in a way that can target metastatic cell populations within the patient based on the levels or expressions of some of these targets, in addition to exposing them to novel drug agents that may be too difficult to give on their own. But when attached to an antibody, it may allow them to be used in a safe manner to provide a significant benefit. I think the field is moving towards looking at how we can best utilize this platform or technology to provide a larger number of treatment options for patients over time, and keep their disease under control, or even potentially in the future, use them in such a way that we could even conceivably eradicate metastatic disease, which would be the dream of all of us. That's a major direction.

The other direction is looking at how we can better use targeted agents or molecular therapies in combination, even with some of these antibody drug conjugates. This is being done, and they're looking at combining tyrosine kinase inhibitors that target HER2 alongside with antibody drug conjugates, as well, to see if you can have a potent 1/2 combination that can better eradicate the cells. Those types of approaches are also going to be exciting for us to be able to see if we can deliver that maximal combinatorial effect safely, and eradicate disease more effectively over time, and in particularly, it may help patients that are at risk of developing brain metastases, which we know is a significant problem in the HER2 population. Some of these smaller drugs can get into the brain tissue with a higher level of drug penetration, that may eradicate some of those cells before they have the ability to start trouble in the brain. I think those are some of the things that we're looking at going forward in order to help our patients with HER2-positive breast cancer.

What unmet needs still have to be addressed in this space?

I think the unmet need for this space, in particular, is the brain metastases issue. It is a significant challenge because a lot of the drugs that we do use in that space may not entirely be able to overcome the sanctuary that the brain represents. Finding those improved combinations that can have sufficient activity to ward off the disease from going into the brain is going to be critically important, because we do tend to see more CNS escape over time, the longer the patients go on their systemic therapy. In a way, it's 1 of those kinds of things that can happen as an escape event when they've been on treatment for a long period of time. That is an important unmet need for sure.

The other thing as well is in trying to understand how we can best pick patients for the right therapy upfront as opposed to right now, where it's a bit more of a trial-and-error type of situation. I think the more these therapies can be targeted or applied in the right setting or paradigm that would help us spare patients unnecessarily from toxicities while applying the best drugs that give them their optimal chance for getting good disease control and durable disease control over time. I think those are going to be unmet needs going forward for medical oncologists, and figuring out how we best apply the available treatments in order to get the best outcome for our patients.

What advice do you have for community oncologists who are treating patients with HER2-positive breast cancer?

My main advice would be, the HER2 gene remains the dominant target to try to afford the best chance of controlling disease and improving [patient] outcomes. It's critical for a community oncologist to think about how they can incorporate HER2 targeting in whatever treatment plan they come up with for the patient. They do have to be cognizant of the fact that many of these agents will have slightly different toxicity profiles that they have to pay attention to. For example, with trastuzumab deruxtecan, it's been well publicized and known that this can sometimes cause some lung toxicities that have to be monitored carefully, in order to avoid the toxicity from becoming excessive or potentially life threatening. They have to involve their colleagues, their subspecialty colleagues, such as pulmonary doctors, as well when managing these patients alongside them so that they can provide the highest level of care while also maintaining that level of safety for the patients while they're getting treated with these new agents. As new agents come online, it's going to be important for community oncologists to reach out to subject matter experts to educators to look at these programs that may be available to educate them on how to best handle these new drugs coming online, and, what toxicities they need to anticipate so that they can again provide the optimal care for their patients in clinic going forward.

REFERENCES:

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

2. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690