Trastuzumab Deruxtecan Shows “Remarkable” Responses in HER2+ Breast Cancer, Requires Monitoring of Respiratory Symptoms

Charles E. Geyer, Jr, MD

Fam-trastuzumab deruxtecan-nxki (Enhertu) has shown impressive response rates and progression-free survival (PFS) outcomes in patients with heavily pretreated metastatic HER2-positive breast cancer, explained Charles E. Geyer, Jr, MD, who added that the potential for interstitial lung disease (ILD) does not have to be a prohibitive factor—even in the era of coronavirus disease 2019 (COVID-19).

Rather, with careful monitoring of new respiratory symptoms, routine chest imaging, and increasing access to COVID-19 testing, providers can distinguish between ILD and COVID-19 and prevent the development of more severe symptoms.

“ILD is an important [toxicity] that clinicians will need to pay attention to, but we do that all the time with other drugs. I don’t think it should be a barrier to using the drug in the appropriate patient populations,” said Geyer.

Currently, the drug is indicated for the treatment of patients with unresectable or metastatic HER2-positive breast cancer who have received at least 2 prior anti–HER2-based regimens in the metastatic setting.

The drug received regulatory approval in December 2019, based on findings from the phase 2 DESTINY-Breast01 trial, which showed clinical activity in patients with or without stable brain metastases and a median PFS in excess of 1 year.

“Right now, it’s approved kind of in the last-line setting,” said Geyer. “How do we work it in earlier? Can we get more benefit? The trials that need to be done have been set up. Then of course, there is the obvious question of whether it has a role in early breast cancer. Can we push our cure rates up even higher? There is a lot of excitement about the drug, but a lot of work [needs] to be done.”

In an interview with OncLive, Geyer, the Lois E. and Carl A. Davis Centennial Chair in Cancer Research, and the Deputy Director of the Cancer Center at Houston Methodist, discussed the state of HER2-positive breast cancer, the significance of the results of the DESTINY-Breast01 trial, and symptoms that could be an early indicator of ILD.

OncLive: Could you shed light on the findings that were first reported from the DESTINY-Breast-01 trial?

Geyer: The DESTINY-Breast01 study was a very impressive trial when you consider the patient population that was studied. These patients had heavily pretreated HER2-positive breast cancer. All patients had received prior ado-trastuzumab emtansine (T-DM1; Kadcyla). The

response rate was really remarkable. The waterfall plot is really one of the most dramatic plots we have seen in the field of medical oncology. We saw a very high response rate. The PFS is out to 16 months and overall survival (OS) is extraordinary in that it’s nowhere near reaching a median. Trastuzumab deruxtecan is a very active drug, without question, in patients with heavily pretreated HER2-positive breast cancer.

An issue we’re going to have to manage is the lung toxicity that was evident in a subset of patients. All in all, it’s a very important drug that’s going to be of clear benefit to women with metastatic HER2-positive breast cancer. The challenge will be working it in.

Have you had any experience using the drug since the approval?

I recently moved to a new hospital, so my practice volume is still relatively small. My colleagues have been very active in the DESTINY studies, including the DESTINY-Breast02 and DESTINY-Breast03 studies, so we’ve had a lot of collective experience with the drug here. There is a sense of being quite impressed with the activity we are seeing in those patient populations. Personally, I’ve only given it to 1 patient so far since it has been approved.

With the approval came the Blackbox warning for ILD. Are there certain symptoms to be aware of that can be an early indicator of ILD?

You want to query your patient about any new cough or dyspnea, and you want to be very attentive to that. In patients with metastatic disease, you’re getting regular scans that may or may not include the chest. You certainly want to be very attentive [to those]. It’s very important to assess any sense of dyspnea or cough. [You’ll want to assess] oxygen saturation, all the things that you can do easily. You want to get imaging. If patients have new respiratory symptoms, they need to be listened to. If they haven’t had chest imaging, you want to get that done and be very attentive to onset of pneumonitis. We want to be able to identify pneumonitis at grade 1, or at the most grade 2, and hold therapy and initiate interventions with steroids to try to avoid the more severe cases.

In the DESTINY-Breast01 trial, 4 patients died with lung pathology that the independent adjudication committee determined didn’t need to be classified as a death related to the lung toxicity.

A lot of the symptoms you described overlap with symptoms of COVID-19. Has there been an increasing concern of distinguishing the symptoms of ILD from COVID-19–related symptoms?

It will make it a definite challenge. Patients receiving the drug who have those symptoms, if there are other associated symptoms, such as fever and if they act like they have a viral illness, that would of course [indicate] COVID-19. However, early COVID-19 may just result in some cough without a lot of strong systemic symptoms. These patients will need to be evaluated for interstitial pneumonitis and then you have to determine whether patients are COVID-19 positive or not. Until you do that, you’re going to hold therapy.

However, we have a number of drugs that can cause ILD. Those symptoms already present some additional challenges. Fortunately, now testing is available with faster turnaround. If you have a patient who is on therapy and may be getting hospitalized, you can find out quickly if COVID-19 is a confounding factor or if the patient does have a drug-related toxicity.

Given the subgroup analyses we saw from the ESMO Breast Cancer Virtual Meeting 2020, are you more inclined to use the drug in patients with stable brain metastases?

The brain metastases data are interesting. The data tell me that if I have a patient who has stable brain metastases, where I think that this drug would be good for their systemic disease, there’s no reason not to use it. Right now, we’re challenged, in a very positive way, in our management of patients with metastatic HER2-positive breast cancer in terms of what agents to use in patients with brain metastases.

The HER2CLIMB data with tucatinib (Tukysa) was very impressive. HER2CLIMB was a randomized phase 3 study, in which nearly half of the patients had brain metastases. We saw very impressive data [with tucatinib] in patients with brain metastases. We saw improved survival [in those patients] at the 2020 ASCO Virtual Scientific Program. If I have a patient with metastatic disease with brain metastases, I will generally and preferentially go to the HER2CLIMB regimen. However, that is not to say that if you have a patient who has had stable brain metastases, and they have disease progression, you can’t go for trastuzumab deruxtecan. It’s comforting to see that the PFS is approximately 18 months, which very similar to the PFS in the overall patient population. I don’t think stable brain metastases are a contraindication for trastuzumab deruxtecan.

Would you like to highlight ongoing research with trastuzumab deruxtecan?

It’s really great that the company is doing a study with trastuzumab deruxtecan versus physician’s choice in the third-line setting; that will give us the randomized data. An interesting study that we all want to see is the head-to-head data versus ado-trastuzumab emtansine (T-DM1) at the point patients would normally receive T-DM1. Those will be really important data in terms of how we might bring the drug up earlier in the metastatic treatment algorithm.

Right now, I’m using trastuzumab deruxtecan where it’s approved—in that third-line setting. A lot of [where it’s used] relates to the challenge of the ILD in some patients. It’s clearly a very active drug, and we know that we need to figure out how to manage the interstitial pneumonitis so patients can benefit from a great drug. The waterfall plots were amazing in the DESTINY-Breast01 trial. As the OS curves mature, they may become equally as impressive, if not more impressive than the waterfall plots, which is a remarkable statement.

What is the biggest challenge in the HER2-positive arena?

Other antibody-drug conjugates are being developed. We’re also seeing new [approvals]. We just had the subcutaneous combination of pertuzumab (Perjeta) and trastuzumab (Herceptin) approved by the FDA. Although that’s not introducing a new therapeutic, it is introducing a method of administration that has significant potential for improving patient lifestyle and quality of life. It’s very exciting that patients can get the subcutaneous [administration] and shorter infusions, possibly at home.

The challenge is we have really active drugs. In getting those sorted out, [we have to ask whether] margetuximab is going to be approved. How will we use tucatinib with the monoclonal antibodies? We have such active therapies, but how do we incorporate them and optimize them to get as much benefit as possible for our patients with metastatic disease?

We’re getting close to where we expect cure in a large majority of our patients with early-stage HER2-positive breast cancer, which is just remarkable. In KATHERINE, the really high-risk patients had a significant reduction in their risk [of invasive disease] with T-DM1, but there was still some residual risk [for] brain metastases. Now that we have tucatinib and trastuzumab deruxtecan, it looks like we have agents to step into the breach [according to the data from KATHERINE].

I’m particularly excited about getting to the point where we have almost an expectation of cure now for our patients with early-stage HER2-positive breast cancer. That is a remarkable change from where we were back in the early 2000s before we got the approval for trastuzumab.