HER2+ Breast Cancer Treatment Arsenal Expands With ADCs

Sara A. Hurvitz, MD

Therapeutic options for patients with HER2-positive breast cancer have expanded over the last decade, leading to improved outcomes across patient subgroups and transitioning the malignancy to a more chronic disease, experts say.

“HER2-positive breast cancer comprises about 15% to 20% of all metastatic breast cancers, but HER2-positive breast cancer isn't 1 disease. We're beginning to see that there are subtypes even within that subtype,” explained Sara A. Hurvitz, MD, an associate professor at the David Geffen School of Medicine and medical director of the Jonsson Comprehensive Cancer Center Clinical Research Unit at the University of California, Los Angeles (UCLA).

Antibody-drug conjugates (ADCs) have been garnering interest in HER2-positive disease for some time. Ado-trastuzumab emtansine (T-DM1; Kadcyla), for example, is approved as an adjuvant treatment for patients with HER2-positive early breast cancer who have residual invasive disease following neoadjuvant trastuzumab (Herceptin) and chemotherapy. It is also indicated for patients with metastatic disease who previously received treatment with trastuzumab and a taxane.

Most recently, fam-trastuzumab deruxtecan-nxki (Enhertu; DS-8201) received an accelerated approval from the FDA in December 2019 for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received ≥2 prior anti—HER2-based regimens in the metastatic setting.

The approval was based on findings from the phase II DESTINY-Breast01 trial, which showed that trastuzumab deruxtecan had an objective response rate (ORR) of 60.3% per independent central review in heavily pretreated patients with advanced HER2-positive breast cancer.

Additionally, the median duration of response was 14.8 months (95% CI, 13.8-16.9), and the disease control rate was 97.3% (95% CI, 93.8-99.1). At a median follow-up of 11.1 months, the median progression-free survival (PFS) was 16.4 months; in the 24 patients with brain metastases, the median PFS was 18.1 months. The median overall survival (OS) was not reached.

Neelima Denduluri, MD

“The reason that [ADCs] work well is that if a tumor is driven by HER2, you're guiding a missile to the HER2-positive breast cancer cell,” added Neelima Denduluri, MD, a medical oncologist at Virginia Cancer Specialists.

In interviews with OncLive^®, Hurvitz, Denduluri, and Madelaine Kuiper, MSN, RN, an advanced nurse practitioner at Ronald Reagan UCLA Medical Center and Santa Monica UCLA Medical Center, discussed the rise of HER2-targeted therapies and their implications on the field.

OncLive: How has HER2-positive breast cancer treatment evolved over the past few years?

Hurvitz: HER2-positive metastatic breast cancer has seen a revolution in the way that it's treated, especially in the last decade. In the last several years, we have seen the introduction of novel agents that have moved the needle over to extending OS. The introduction of pertuzumab (Perjeta) when added to trastuzumab and a taxane from the CLEOPATRA study saw a median OS of [nearly] 5 years. When I was in training, we were excited if a patient survived 2 years. To see that the median OS had moved by several years was really impressive. Now, because we know the HER2 target is so important to go after in HER2-driven disease, there have been multiple agents that have been developed for this breast cancer, including selective HER2 TKIs such as tucatinib, novel ADCs, such as T-DM1, and now trastuzumab deruxtecan.

Madelaine Kuiper, MSN, RN

Denduluri: In the past, we always knew that the HER2 oncogene conferred a poor prognosis for patients, but we didn't have a good way to target it. About 20 years ago, trastuzumab started being incorporated into patient care. For the last 14 years, we've been using it routinely to reduce the risk of early breast cancer coming back. We also knew that those who had stage IV or metastatic breast cancer had a poor prognosis when it was HER2-positive. In the advent of HER2-positive targeted therapy, including trastuzumab and pertuzumab, HER2-positive breast cancer has truly become a chronic disease where the median survival is about 5 years and about 40% of patients are alive 8 or more years later—but by no means is a “home run.” At the same time, the progress has been dramatic. We have more targeted molecules.Kuiper: [The paradigm has] changed rapidly. I remember in the 1980s when [these drugs were] new and we started actually treating patients. Even in the last 6 years that I've been working in breast cancer, there has been a rapid development of HER2-targeting therapies, including T-DM1, pertuzumab, neratinib (Nerlynx), and tucatinib. Now, we have trastuzumab deruxtecan. It's amazing how many drugs are looking very positive in this setting and expanding treatment options for patients.

How are ADCs utilized in HER2-positive treatment?

Hurvitz: We previously had 1 approved ADC for breast cancer: T-DM1. T-DM1 causes the HER2 antibodies to stably link to a cytotoxic payload, which is a derivative of maitansine; this is a microtubule poison. T-DM1 was approved for [patients with] metastatic breast cancer in 2013. Results from the EMILIA study showed that T-DM1 improved PFS and OS compared with lapatinib (Tykerb)/capecitabine (Xeloda). [T-DM1] is now the gold standard for second-line therapy. First-line therapy is taxane, trastuzumab, and pertuzumab, and when a patient’s disease progresses, they move to T-DM1.

We have recent results relating to trastuzumab deruxtecan, which received accelerated approval in December 2019. There was a phase II, single-arm study called DESTINY-Breast01, which demonstrated an impressive ORR and median PFS in very heavily pretreated patients.

Denduluri: The most commonly used ADC [in HER2-positive breast cancer] is T-DM1. However, trastuzumab deruxtecan was recently approved after showing significant activity in a heavily pretreated population. There are also several [ADCs] that are being developed. One agent in the pipeline is called SYD985.

Kuiper: It's a new and great opportunity to look at how we can utilize therapies and perhaps combine them. One of the first ADCs was T-DM1, with a true smart bomb effect, which gave an opportunity to use a drug that was not too toxic. Now, looking at trastuzumab deruxtecan, it's a great opportunity for patients in further lines of therapy.

Could you explain the mechanism of action of ADCs and what makes them so effective?

Hurvitz: ADCs are a very exciting modality of treatment because it pairs with a very specifically targeted antibody, which targets the tumor cells more specifically than normal cells. It combines a cytotoxic payload with that antibody, or links to that antibody, which is a very potent type of chemotherapy. This allows the chemotherapy to be directed to the antigen overexpressing T cell. The thought is, if you can specifically direct the chemotherapy to the antigen overexpressing T cell, you're going to limit toxicity to the normal cells. We see that with drugs such as T-DM1, where patients are getting a very toxic type of chemotherapy, but because it is specifically targeting the HER2 antigen, patients don't even have hair loss and generally feel quite well on it. They don't have the typical adverse events (AEs) of a naked, cytotoxic chemotherapy.

Denduluri: ADCs are kind of like smart bombs. While that sounds like a very simple analogy, we know, for example, that trastuzumab has dramatically improved outcomes in patients with HER2-positive breast cancer. Trastuzumab goes after HER2; the payload goes into the cell and it only goes into the cells that have HER2 overexpression, which trastuzumab guides them to. It goes inside the cell, explodes, and leads to cell death. The reason that they work well is that if a tumor is driven by HER2, you're guiding a missile to the HER2-positive breast cancer cell.

Could you review the DESTINY-Breast01 trial results with trastuzumab deruxtecan?

Hurvitz: The DESTINY-Breast01 trial was a single-arm, phase II study evaluating patients with HER2-positive metastatic breast cancer, all of whom had received trastuzumab and T-DM1 in the metastatic setting. The patients had a median of 6 prior lines of therapy, making this an incredibly heavily pretreated patient population with metastatic breast cancer.

In this study, they showed that using trastuzumab deruxtecan yielded an ORR of over 60%. This is unheard of. This is an ORR we get excited about in a first-line metastatic study, so to see this in the third-line setting and beyond is pretty phenomenal. The median PFS was more than 16 months. Again, these are very impressive data in a setting where you expect patients to have a quick progression. However, ongoing phase III randomized trials will be important in defining where we should be utilizing this drug.

Denduluri: The DESTINY-Breast01 trial was a phase II trial in a heavily pretreated population where patients received trastuzumab and T-DM1; many patients had several lines of prior HER2-targeted therapy and chemotherapy. These patients were given trastuzumab deruxtecan and we saw that there was an over 60% ORR, which is unheard of in a population that is heavily pretreated.

It was extremely promising, and there was a group of patients that didn't have to change therapy for about 10 months. The median PFS was over 16 months, which was extremely promising and very exciting. The toxicities associated with the drug are nausea; there was some alopecia. The most significant concern was something called interstitial lung disease (ILD). We know now that we must be on the lookout for it. We're developing guidelines to manage ILD and manage the drug toxicity. We are looking forward to taking it to the next step of phase III studies and compare [this drug with] the current standard of care.

Kuiper: Trastuzumab deruxtecan seems to be very, very promising and exciting for patients. A lot of my patients are heavily pretreated and may not have so many options left now. This looks like a great option for these patients. I definitely think the DESTINY-Breast01 study shows very positive results, and it's a drug that we will start to use more frequently now. I'm not sure where it will fit within the lines of therapy. I still have to talk to my physician about all of that. The safety profile is worrisome, but it is something that we're all very aware of. We have to monitor and work with patients. I definitely think this is going to be good for us, and good for patients.

How can early detection of ILD be improved? How can it be best managed?

Hurvitz: A number of different anti-cancer therapies are associated with ILD or pneumonitis. This is an AE that is potentially serious and life-threatening, so it needs to be recognized and managed early in order to prevent a severe outcome. Trastuzumab deruxtecan has been associated with pneumonitis, with some patient deaths in the early-phase clinical trials. Therefore, for patients who have a preexisting history of pneumonitis or ILD, we aren't going to recommend this therapy for them.

When we evaluate patient scans while they are on therapy, if we begin to note ground glass opacities or other findings that are suggestive of pneumonitis, or if a patient develops a dry cough, fever, or shortness of breath, those things would lead us to hold therapy while we evaluate. If a patient is shown to have more severe clinical symptomatic pneumonitis, we would use steroids and stop therapy. It is an important AE for us all to be aware of, not only with trastuzumab deruxtecan, but with immune-based therapies and other therapies that are being investigated in breast cancer.

Denduluri: Unfortunately, 4 patients died due to ILD and it is definitely a concern. The most important thing that we can do to prevent and/or manage it is communicate with our patients, listen to them, and listen for respiratory issues, such as cough and shortness of breath. When we listen to them with our stethoscope, are we hearing anything? Physical exams are very important. What are we seeing on their scans? Once we recognize it, then image it, hold the drug, implement steroids early, and work in a multidisciplinary fashion with our pulmonologist. If it's very severe, then the drug needs to be stopped.

Kuiper: I educate my patients. ILD tends to present as a dry cough that's persistent—it doesn't get better with whatever you do for it—and shortness of breath. One of my discussions with the patient is if you develop these symptoms, let us know immediately. I explain to my patients that it's inflammation in the lungs. If we can catch it early, then usually we can treat it easily. If I have a patient complaining of the symptoms, I tend to stop the drug and work it up with a CT of the chest.

If there is evidence of ILD, then depending on how significant the symptoms are, use steroids and keep the patient off therapy until you can get them back to a baseline again. Then, do you consider reattempting the drug? Do you have to look for another treatment option? However, [ILD] is not common. I don't see it all the time. We do a lot of therapy [with trastuzumab deruxtecan] and it's the same risk that you have with some of the other therapies we already have, such as everolimus (Afinitor). It's important to be aware and educate the patients to be aware, too.

Krop IE, Saura C, Yamashita T, et al. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: a phase 2, multicenter, open-label study (DESTINY-Breast01) [published online ahead of print December 11, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1914510.