Successes With T-DXd and the Need for Continued Research in Brain Metastasis


In an interview with Targeted Oncology, Sarah Sammons, MD, discussed an analysis of the DESTINY-Breast03 trial, highlighting the need for further research on trastuzumab deruxtecan in other breast cancer subtypes and solid tumors with brain metastases.

Sarah Sammons, MD

Sarah Sammons, MD

Trastuzumab deruxtecan (Enhertu; T-DXd) has become a top-tier antibody drug conjugate (ADC) in the treatment of HER2-positive breast cancer with baseline brain metastases. However, according to an exploratory analysis of the DESTINY-Breast03 trial (NCT03529110), the need to evaluate T-DXd for the treatment of patients with HER2-low breast cancer, active HER2-positive breast cancer, and other solid tumors expressing brain metastases remains an unmet need.

While the trial showed promising results for T-DXd in treating brain metastases in patients with HER2-positive breast cancer, Sarah Sammons, MD, highlighted the significance of brain metastasis in this subtype of breast cancer and the need for further effective treatment options.

In an interview with Targeted OncologyTM, Sammons, medical oncologist, clinical investigator in the Breast Oncology Center, associate director of the Metastatic Breast Cancer Program, Dana-Farber Cancer Institute, discussed the analysis of the DESTINY-Breast03 trial, highlighting the need for further research on T-DXd in other breast cancer subtypes and solid tumors with brain metastases.

Targeted Oncology: Could you provide an overview of the DESTINY-Breast03 trial and the purpose behind your analysis?

Sammons: I was not a primary investigator, but I am very aware of the data and happy to talk about the trial because it has had major implications for our patients with HER2-positive metastatic breast cancer. The DESTINY-Breast03 clinical trial was a randomized, multicenter, phase 3 clinical trial that looked at comparing trastuzumab deruxtecan, or T-DXd, with an older antibody-drug conjugates called T-DM1, or trastuzumab emtansine [Kadcyla]. This was an important trial that established the new standard-of-care treatment for our patients with metastatic HER2-positive breast cancer in the second-line setting after treatment with a taxane and trastuzumab [Herceptin]/pertuzumab [Perjeta]. Patients in this clinical trial who had already received first-line therapy were randomized to either T-DXd, which is a new antibody-drug conjugate, or T-DM1, which is an older antibody-drug conjugate.

We have seen the primary results of this clinical trial a while ago, and it was a dramatically positive clinical trial. That patients that got T-DXd had a progression-free survival of almost 29 months, which is really just unprecedented in the first- or second-line HER2-positive metastatic setting vs about 7 months with T-DM1, so almost a 4-fold improvement in progression-free survival. We have also seen overall survival benefits in the second-line overall population.

Breast Cancer Image: © Giovanni Cancemi-

Breast Cancer Image: © Giovanni Cancemi-

What are some of the problems seen with brain metastasis in HER2-positive metastatic breast cancer?

Breast cancer spreading to the brain for this particular subtype is a real problem. Depending on the trial, about one-third to one-half of patients with metastatic or HER-positive disease will develop brain metastasis, and the risk seems to go up per line of therapy. Brain metastasis has been historically difficult to treat. Prior therapies did not penetrate the brain very well. Patients that develop brain metastasis had inferior survival compared with those patients who did not develop brain metastasis, and so trying to figure out the best ways and to use the best medications to treat these patients has been an overall challenge.

In the context of HER2-positive breast cancer with brain metastases, how significant are the findings from this analysis regarding T-DXd vs T-DM1?

In the DESTINY-Breast03 clinical trial, they did allow patients who had a history of stable brain metastasis on the trial. Stable means that they had had prior radiation, and their brain metastasis were not progressing. There are a handful of patients in DESTINY-Breast03 with active brain metastasis that were enrolled, and they did look and see how both the stable and active [patients with] brain metastasis did on the trial with T-DXd vs T-DM1. We recently saw those results that were published in [European Society for Medical Oncology (ESMO) Open]. Essentially, what we saw was that the patients with a history of brain metastasis did incredibly well with T-DXd, and they did better with T-DXd than with T-DM1. In terms of progression-free survival, the patients with a history of brain metastases had a progression-free survival of 15 months with T-DXd vs 3 months with T-DM1, so a dramatic benefit.

The authors and [principal investigators] of the study also retrospectively looked at the MRIs of the patients that had a history of brain metastasis in DESTINY-Breast03, and they looked to see what the intracranial response rate was, so what was the number of patients who had their brain metastasis either go away completely, a complete response, or shrink by about 30% in the brain, and they reported an intracranial response rate of almost 66% with T-DXd vs 34% with T-DM1. So, 66% in terms of an intracranial response rate is very high and really the highest that we have ever seen for an antibody-drug conjugate, or really any therapy in HER2-positive [breast cancer with] brain metastasis. That is exciting news for these patients, and it makes T-DXd an excellent option for patients with either stable or active HER2-positive brain metastasis.

Another thing that I want to point out is that T-DM1, which is kind of our older antibody-drug conjugate, still had an intracranial response rate of 34%, which is pretty high too. Just to put it all in context, in metastatic breast cancer with standard chemotherapies, we are used to intracranial response rates around 10%. So, what this has shown us is that antibody-drug conjugates, both T-DM1 and trastuzumab deruxtecan, do seem to get into the brain quite well, which opens up future research in this hot category of drugs called antibody-drug conjugates for the treatment of really all [patients with] metastatic breast cancer with brain metastasis. Even in other solid tumors, I think ADCs are a promising strategy.

Based on this research, how would you approach treatment decisions for patients with HER2-positive breast cancer with brain metastases?

Historically, we thought that for patients that had this brain predominant [disease], or a problem with brain metastasis, that tyrosine kinase inhibitors, which are much smaller molecules and get into the brain like tucatinib [Tukysa], we always thought that they should be 1 of the first lines of therapies that we should use for these patients. Historically, for patients with active brain metastasis, brain predominant disease, we have preferred tucatinib, capecitabine, and trastuzumab. That regimen also works well for patients with HER2-positive brain metastasis and has intracranial response rates around 50% in a more pretreated population. But this study, as well as other supportive studies that are now showing intracranial response rates of around 60%, tells us that in the second-line, trastuzumab deruxtecan or this tucatinib/capecitabine/trastuzumab regimen can both be options. I think for the vast majority of patients, those certainly without brain metastases, T-DXd is the standard of care. For those with brain metastases, either stable or active, I do think T-DXd is a very good second-line option for nearly all patients, and that the tucatinib-containing regimen also has great efficacy and could be considered in the second-line, or certainly the third-line if you chose T-DXd in the second-line.

Are there any challenges with the tucatinib-containing regimen?

There are challenges with any regimen that we use in metastatic breast cancer. All therapies have [adverse] effects. With trastuzumab deruxtecan, that is a regimen that is given [intravenously] once every 3 weeks. There is about a 15% risk of pneumonitis, which is inflammation of the lungs. There is hair loss for the majority of patients, and so that is the real risk. Then there has been nausea, and we manage that with antiemetics. For the tucatinib, capecitabine, trastuzumab regimen, 2 of the drugs are oral, and trastuzumab is given either by injection or intravenously. There is not any hair loss which is nice, but there are a lot of pills, there is still a risk of diarrhea, still a bit of a risk of nausea, fatigue, and we have to monitor liver enzymes as well. With the capecitabine, sometimes people can get a rash on their hands and feet, but most breast oncologists are becoming pretty familiar with managing both regimens at this point. I think most of our patients with HER2-positive metastatic breast cancer will receive both of those therapies, both T-DXd and the tucatinib-containing regimen. It is nice to have 2 good options for these patients that we did not have a couple of years ago.

This study also highlights the need for further investigation into T-DXd. What are some areas for future research based on these findings?

T-DXd is also FDA-approved in patients with metastatic breast cancer that have low expression, so now we are investigating whether or not T-DXd works for patients with low levels of HER2 and brain metastasis. We have a small amount of data in HER2-low brain metastasis so far. The patients with brain metastasis were analyzed retrospectively from the DESTINY-Breast04 clinical trial [NCT03734029], and it is looking like there is an intracranial response rate around 25% in those patients, which actually for HER2-low or historically, HER2-negative brain metastasis is respectable. It is promising and I think we are awaiting more data on how T-DXd performs in HER2-low brain metastasis, but I think that is a promising area.

I would also say that HER2 is expressed in other types of solid tumors, [including in] some [gastrointestinal] tumors, some endometrial cancer, and we just got an approval for T-DXd in all solid tumors that are HER2-overexpressed with an [immunohistochemistry] score of 3+. Those tumors also have a higher propensity that is high HER2-expressing to go to the brain. This could be an option for patients that are HER2-expressing with brain metastasis in other solid tumors, which is exciting.

Sammons S, Lin NU. Antibody-drug conjugates are active in patients with HER2-positive breast cancer brain metastases: where do we go from here?. ESMO Open. 2024;9(5):102990. doi:10.1016/j.esmoop.2024.102990
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