DESTINY-Breast06 Redefines Treatment Paradigms, Calls Necessity of HER2 Testing for T-DXd into Question in HR+ Breast Cancer

In an interview with OncLive^® following a State of the Science Summit™ on breast cancer, Jason A. Mouabbi, MD, discussed findings from the DESTINY-Breast06 trial (NCT04494425) demonstrating the efficacy of fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) for patients with endocrine-resistant, hormone receptor (HR)–positive, HER2-low, and HER2-ultralow breast cancer; explained whether extensive HER2 status testing is necessary for the administration of T-DXd given its broad efficacy in this patient population; and noted several areas of ongoing antibody-drug conjugate (ADCs) development within breast cancer.

“[DESTINY-Breast06] is a game changer, because a lot of our patients are going to receive this drug earlier nowadays,” Mouabbi emphasized in the interview. “This is the era of the ADC.”

Mouabbi, who is an assistant professor in the Departments of Breast Medical Oncology and General Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, in Houston, also discussed novel endocrine and targeted therapies that may overcome CDK4/6 resistance along with key factors influencing CDK4/6 inhibitor selection in HR-positive disease in concurrent interviews.

OncLive: What did the DESTINY-Breast06 trial reveal about the efficacy of administering T-DXd to patients with HR-positive, HER2-low and -ultralow breast cancer and prior exposure to endocrine therapy?

Mouabbi: [One recent] study that will have the most impact on standard-of-care approaches in [the HR-positive setting is] the DESTINY-Breast06 trial. DESTINY-Breast06 [assessed] 2 things. [First], investigators [evaluated whether T-DXd could be administered] to patients as soon as they become endocrine resistant. Before, T-DXd’s approval in HR-positive breast cancer was for patients who became endocrine resistant and had received 1 prior line of chemotherapy. [Secondly, investigators] looked at a new category [of patients] called HER2-ultralow. Currently, T-DXd is approved for patients with HER2-low disease, [defined as] either 1+ or 2+ by immunohistochemistry [IHC]. HER2-ultralow is a new category [comprising IHC expression levels] between 0 and 1+. This is because IHC was never optimized to detect differences between 0 and 1+, so this is a big spectrum. [The purpose of] the HER2-ultralow category is to [specifically tease out] those patients.

[DESTINY-Breast06 was] a positive study. [The results showed that T-DXd can] be used right away when a patient becomes endocrine resistant, and that it can be used in the HER2-low and -ultralow populations.

How might findings from DESTINY-Breast06 affect the future role of T-DXd in HER2-expressing breast cancer? Should we reconsider the necessity of HER2 status testing for T-DXd administration, considering the resource implications and potential benefits for all patients?

T-DXd is now approved in HER2-positive and -low disease, and soon we will [likely] see its approval for HER2-ultralow [breast cancer]. Approximately 90% of patients with breast cancer [will fall into] 1 of those 3 categories. [Therefore], only 5% to 10% of patients will be truly HER2-zero and not qualify for T-DXd. Accordingly, I’d like to raise this question: Should we administer that drug based on the patient’s HER2 status? Do we need to try to figure out [whether] someone is the 1 patient out of 20 who is not going to benefit from this therapy, and deny them the therapy we give to everybody else?

It makes sense to invest a lot of money in finding a biomarker if the therapy only works in a small proportion of the population, because you want to spare the bulk of the population unnecessary adverse effects. However, in this case, what we’re doing is the opposite. We know that [most] patients will qualify. We’re doing so much more testing that [requires] the mobilization of enormous resources, and it can cost so much money to find a single patient who might not benefit. I’m saying might, because we have studies showing that even patient who are HER2-zero may benefit from this drug. I’m hoping that the FDA will step in, in a big way, and approve it for patients regardless of HER2 status.

What are some targets of interest for ADC development in HR-positive breast cancer?

HER2 is an attractive target in breast cancer because it tends to be expressed on the surface of a significant amount of breast cancer cells, but not expressed in a high amount in healthy cells. Another target for cancers is TROP2, which is also present on the surface of cells across multiple malignancies. It’s also expressed on healthy cells, but not highly.

Multiple TROP2-targeted ADCs have been approved. At the 2024 ASCO Annual Meeting, [there were several presentations on] other emerging ADCs that may gain approval in other cancers. There is, for example, [the ADC enfortumab vedotin-efjv (Padcev)] which targets a specific protein called NECTIN4. This agent has already been approved for patients with urothelial carcinoma, but it showed activity in breast cancer, especially in triple-negative [disease]. There is a lot of work being done with those.

One TROP2-targeted ADC that’s already FDA approved is sacituzumab govitecan-hziy [Trodelvy], but there’s a newer one coming [onto the scene]: [datopotamab deruxtecan]. It has the same payload that T-DXd does. This is exciting, because we need more options, and every pharmaceutical company is diving into ADC development at this point.

What makes ADC development such a significant step forward in breast cancer management, and what are some of the ongoing areas of innovation with these agents?

ADCs are a better way of delivering chemotherapy. Chemotherapy works well because, at the end of the day, it’s a molecule that kills cells. Historically, we’ve administered conventional chemotherapy, meaning we give the whole chemotherapy, and it doesn’t discriminate between killing cancer cells and healthy cells. The reason why we cannot give chemotherapy every day for our patients is because we’re killing the healthy cells, and we need to let the body recover enough before we give another round. The idea with ADCs is to try and deliver chemotherapy only to cancerous cells, sparing healthy ones. It’s not the perfect science, but it’s a huge step in the right direction.

There is a huge incentive to develop newer, state-of-the-art ADCs and put them on the market. Right now, we’re looking at different targets, payloads, and linkers. Some [ADCs] get cleaved and release the payload either outside the cell or inside the cell; sometimes [this happens] when it binds, sometimes before it binds. There’s a lot of innovation happening, because this is the next frontier. These therapies [are] much more powerful than what we’re currently using in multiple cancers.