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Dr. Debu Tripathy breaks down the FDA approval of Enhertu in unresectable or metastatic HR-positive, HER2-low or -ultralow breast cancer.
On Jan. 27, the Food and Drug Administration (FDA) granted approval to Enhertu (fam-trastuzumab deruxtecan-nxki) for patients with unresectable or metastatic HR-positive, HER2-low or -ultralow breast cancer, according to the agency, who added that this approval includes patients whose disease progressed on one or more endocrine therapies in the metastatic setting.
Progression-free survival: the time during and after treatment that a patient with cancer lives without the disease worsening.
Objective response rate: the percentage of patients whose cancer disappears or shrinks from treatment.
Complete response: when there are no detectable signs of cancer in the body after treatment.
The approval of was based on findings from the DESTINY-Breast06 trial. In 866 chemotherapy-naïve patients with HR-positive, HER2-low or -ultralow metastatic breast cancer, Enhertu reduced the risk of disease progression or death by 36% versus chemotherapy. Median progression-free survival was 13.2 months with Enhertu compared with 8.1 months with chemotherapy.
“The recent approval for Enhertu in patients that have HR-positive, and HER2-low or -ultralow breast cancers expands the number of patients that can benefit from treatment,” Dr. Debu Tripathy explained
In an interview with CURE®, Tripathy sat down to discuss the regulatory approval of Enhertu in this patient population, what it could mean for eligible patients with HER2-low and -ultralow breast cancer, as well highlights the side effects associated with this treatment route. Notably, he is a professor and chairman of the Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, in Houston, and the editor-in-chief of CURE®.
Tripathy: We've [seen] from some of the earlier trials, like the DAISY trial — which was a small phase 2 trial that enrolled some patients with totally HER2-negative breast cancers — that some responses [have been] seen. It's difficult to quantify very low HER2 since most assays are based on declaring patients to be truly HER2-positive by the conventional [criteria], where you have either amplification of the gene or overexpression. The very low levels of detection are ultimately, I think, going to require special techniques. However, those who are experts at reading it can do this with a normal, generally approved assay for HER2 determination.
In some of the early observations, this was formally studied in a large phase 3 randomized trial, the DESTINEY-Breast06 trial, which enrolled HER2-low patients, but it also enrolled a cohort of patients that were HER2-ultralow. This is defined as very weak staining in less than 10% of cells, and anything more than that is considered HER2-low. Ultralow states that there has to be some epithelial staining. It can even be partial staining of a part of the cell, but the ones that are truly totally negative are true zeros. That is the distinction to be made; we're now expanding it to this ultralow group.
The DESTINEY-Breast06 trial was a randomized trial comparing standard of care treatment versus Enhertu in patients who had progressed on endocrine therapies and had low or ultralow [disease]. That study was overall positive, including a subset of patients with ultralow, although that subset was small and didn't have the statistical power on its own to show that, but as time goes on, there may be more power as we get more events in that overall cohort.
The first thing is to make sure that their tumor is being tested for HER2 content, everybody's tumor who may be a candidate for antibody-drug conjugate therapy should be tested because it leaves open the possibility of using Enhertu. We know that, in general, the data has shown that patients can get durable responses to this agent, and it is better than the standard-of-care chemotherapy. [However], we don't know how it may stand up against targeted therapies; this is an area that needs further study.
We do use certain targeted therapies, like PI3K-targeted therapy in patients that have alterations in that pathway and so on. But when it comes to shifting over to chemotherapy, we do know from the DESTINY-Breast series of trials that this really remains a viable and strong possibility to use this antibody-drug conjugate. That's why it's important that we know that we at least need to do HER2 testing.
Secondly, it's important that the pathologists that are doing the testing are equipped, knowledgeable and able to report to you the level of HER2-positive versus -negative. Within the negative groups, which ones are HER2-low, that would be 1+ and 2+ — the 2+, of course, being FISH negative — those would be the HER2-low that we are more familiar with, but now the HER2-ultralow category is being added. This really does require … that the pathologist is familiar with the ultralow concept, [consisting of] this very faint, partial membrane staining, and is something that they should be able to report out. That is an important distinction, because those patients are also going to be eligible for treatment with the Enhertu [agent].
This is a chemotherapeutic drug. Enhertu uses a synthetic topoisomerase one inhibitor known as a deruxtecan. This class of drugs is known to have several side effects. One of them is myelosuppression. It can suppress the white [blood cell] count and cause neutropenia. It can also suppress the red [blood] cell and platelet count, as well as cause gastrointestinal side effects such as nausea, vomiting and diarrhea. These are the side effects that we typically see. These can, of course, be prevented with antiemetics, which are recommended, and that should be part of the order set, as well as chronic anti-nausea medications. This is because you get, not only the short-term, but some people can get delayed nausea and vomiting. You [should also manage] management for diarrhea, of course.
Other side effects include fatigue. Cardiac monitoring is important too. As with all HER2 antibody-based therapies, that is something that needs to be screened for before treatment and then during ongoing treatment.
Interstitial pneumonitis is a rare but important side effect, and that has to be monitored, really, at every visit. A lot of times, when we get our scans, we might see subclinical interstitial lung disease, which is grade 1, and that does require attention. We recommend stopping a treatment, even for grade 1, and if the patients are symptomatic, they should be placed on steroids. For grade 2 or higher, permanent discontinuation is needed. These side effects, fortunately, are rare, but they need to be looked for as well. There are other less common side effects, as well, including things like skin rash and mucositis in addition to other side effects that need to be paid attention to.
The important takeaway is that we have more options, and that's good. There may be patients who have very indolent disease and who don't have much in the way of symptoms, and we can keep them on things like endocrine therapy and targeted therapies. However, there are patients that are more symptomatic from their disease, or the kinetics of their cancer is such that they're rapidly progressing, and these patients probably do need a cytotoxic option. Therefore, antibody-drug conjugates approved in this situation, particularly within Enhertu now being approved with a HER2-targeting drug for initially, is a very important option for us to have in our armamentarium.
Transcript has been edited for clarity and conciseness.
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