Progression-Free Survival Associated With Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer

In an interview exploring the progression-free survival and overall survival associated with trastuzumab deruxtecan (T-DXd) in patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy, Naoto Ueno, MD, the University of Texas MD Anderson Cancer Center, Houston, TX, discussed the impact that the study’s findings may have on the future of breast cancer care.

Transcript

Hi, my name is Naoto Ueno, I'm from the University of Texas MD Anderson Cancer Center. Today I'm here to have a chance to speak about DESTINY-Breast04 with Journal of Clinical Pathways, so hopefully I could answer many of your questions.

Can you provide some background about the DESTINY-Breast04 trial, what were the aims?

DESTINY-Breast04 is a clinical phase 3 study. It's a multicenter phase 3 study, and it's a comparison of T-DXd, which is known as trastuzumab deruxtecan. And it is an antibody conjugate-targeting HER2, comparing two treatment physician choices in the low-HER2 positive metastatic breast cancer. The primary endpoint was progression-free survival and the secondary endpoint was overall survival, and they also looked into health economic and patient-reported outcome in this study.

Can you talk a little bit more about the study’s design and endpoints?

As I mentioned, this is a randomized clinical study. The patient that we enrolled is what we call the low-HER2 metastatic breast cancer. It’s important to remember what does the “low-HER2” means. And in this study, it means that by doing immunohistochemical staining, it's either 1+ or 2+, and the in situ hybridization known commonly as FISH is negative. They have to be treated with one to two prior chemotherapies, and many of the patient included their hormone receptor positive dominantly, so they were refractory to endocrine therapy.

So once they are enrolled in the study, they were randomized into two groups. And this is a 2:1 randomization between T-DXd vs TPC, treatment of physician choices, which include a variety of chemotherapy such as capecitabine, eribulin, gemcitabine paclitaxel. So that's where the study, as I said, the primary endpoint is progression-free survival.

What were the results of this study, and the significance of these results?

The primary results of the DESTINY-Breast04 is a comparison of T-DXd to the treatment physician choices. And we looked at the median progression-free survival, and it was 10.1 months vs 5.4 with a hazard ratio of 0.5. The secondary endpoint, overall survival, also was significant with T-DXd showing 23.9 months and TPC around 18 months and hazard ratio was 0.64. So basically, in terms of efficacy, T-DXd was more favorable than just giving standard chemotherapy. That was the primary outcome. And they also looked into safety, the safety was well known already. And more than Grade 3 toxicity, T-DXd was about 52%, and TPC was 70%. This is not about statistics, but little bit favoring T-DXd in this study.

How might this trial influence the way pathology laboratories report HER2 results moving forward?

That's a really good question. And HER2 has been classified as positive or negative. And positive was defined by immunohistochemical staining, and immunohistochemical staining has 3+, 2+, 1+ and 0. So, if it's 3+, it was considered positive. And if you have 2+ and 1+ they would do in situ hybridization. And if that was negative, then they would classify as negative. So, what's happening now is you have to do this immunohistochemical staining to really quantify the 3+ and 2+ and 1+. So now we have high-HER2; low-HER2, which is 1+ and 2+; and the 0. So we're having three different classifications.

The other impact, which is really, sometimes the community physician will only order the in situ hybridization, and just by this they'll call it positive or negative and they don't do immunohistochemical staining. What I'm trying to say here is, the practice is now that all patients with breast cancer will require immunohistochemical staining, and they actually need to read the positivity of the study so that they know it's high or low. The other thing you have to remember is that the companion diagnostic tool that was used for this study was Ventana antibody. So it's really important to make sure that similar antibody is used to define the positivity of the tumor tissue for the HER2.

As T-DXd has now been established as a new standard of care for HER2-low metastatic breast cancer, how can we integrate T-DXd within the currently available treatment landscape among patients?

This study was focused on hormone receptor-positive population, but the actual study contains the hormone receptor-positive and triple-negative breast cancer. So, for the hormone receptor-positive metastatic breast cancer with the low-HER2, this study will help to guide those patients who received a CDK4/6 inhibitor with endocrine therapy, and after they progress, they have a choice of this treatment coming more toward upfront. And they could obviously try different endocrine therapy, but now you have a choice of giving this treatment, comparing to other forms of endocrine therapy or oral chemotherapy such as capecitabine.

Now, for triple-negative breast cancer this study was never designed to show the difference. However, we know that there is a similar type of hazard ratio for the progression-free survival and overall survival, And it is FDA label indicated at this moment. So the context is going to be that they will initially check the PDL1 status for the first line, and they'll determine combination with chemotherapy with checkpoint immunotherapy, yes or no. And after that second line and third line, there is an opportunity of bringing in the ENHERTU trastuzumab deruxtecan as potential treatment choices.

Is there anything else that is important for health care providers or those with breast cancer to know about the therapy?

I think, the treatment indication is quite clear. What we really need to remember is about the toxicity of this treatment. One is, when we reported our patient-reported outcome at ESMO, there is a more prominence of nausea with this regimen. And particularly the first several early cycles, it is worse comparing to a standard treatment. So they consider this treatment as moderately nauseating, but just, I think we all need to remember that you need to be very aggressive about controlling the nausea. It's really nice to know that it does sustain the quality of life. However, being nauseated is…none of the patients will like this. So aggressive management of nausea is very important.

The other thing is pneumonitis. And we all know T-DXd could cause pneumonitis, and if you let it go it could be fatal. So any early sign of pneumonitis, you should be stopping the drug and wait for this drug to really make sure that it normalizes completely before any kind of rechallenge is considered. What's really important? That it's effective and it's reasonably safe, but there are certain things that you have to pay attention to.

Thank you very much for listening to my interview. And we truly appreciate the patients and their family who participate in the clinical trials. And we also appreciate all the people who contributed to the study. And we thank you all the investigators for working together to bring this very successful clinical trial. So thank you again, everybody.