Newly Approved ADCs Expand Options in HR+ Metastatic Breast Cancer

Sara Nunnery, MD, MSCI

Following the recent FDA approvals of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) investigators now have 3 antibody-drug conjugate (ADC) choices in the hormone receptor (HR)–positive breast cancer space, raising therapeutic sequencing questions and excitement for future advances, according to Sara Nunnery, MD, MSCI.

During a recent OncLive® State of the Science Summit™ (SOSS), Nunnery highlighted findings from clinical trials of multiple ADCs in HR-positive breast cancer, including the phase 3 DESTINY-Breast06 (NCT04494425) and TROPION-Breast01 (NCT05104866) studies. Data from the trials supported the January 2025 FDA approvals of T-DXd in HR-positive, HER2-low or HER2-ultralow breast cancer after progression on at least 1 endocrine therapy in the metastatic setting and Dato-DXd in unresectable or metastatic HR-positive, HER2-negative breast cancer after prior endocrine-based therapy and chemotherapy, respectively.1,2

“One of the big topics at this event, and in breast cancer in general, is this new wave of ADCs,” Nunnery said in an interview with OncLive. “It’s a whole new technology for cancer drugs, and they’ve changed the way we’re treating [patients with] metastatic breast cancer. They’re improving survival and [other] outcomes for patients. These drugs are relatively new, so there’s still a lot to learn about them, and a lot of providers are still getting used to using these drugs. The goal [of my presentation] was to educate [the audience] on these [agents] and revisit the data that’s led to their approvals.”

In the interview, Nunnery discussed the key topics from her SOSS presentation, including the significance of the recent FDA approvals of T-DXd and Dato-DXd in HR-positive breast cancer, the impact of these regulatory decisions on treatment sequencing approaches, and potential future developments regarding ADCs in the space. Nunnery is the director of breast cancer research at Tennessee Oncology in Nashville.

OncLive: You began your presentation by discussing T-DXd; what is the current standing of this agent in metastatic breast cancer?

Nunnery: T-DXd is a HER2-targeted ADC. The payload is a topoisomerase 1 inhibitor, which is a type of cytotoxic chemotherapy that we have used for years in cancer treatment as an intravenous therapy.

The exciting thing about T-DXd is that it was first developed for HER2-positive breast cancers, where we saw incredible improvement in progression-free survival [PFS] and overall survival in the metastatic setting. What we learned about these drugs is that they’re so potent that they not only kill the cancer cell which directly took up the ADC, but they [also] have a bystander effect where the chemotherapy particles can then leak out of that cell and kill neighboring cancer cells. We learned that not only does this drug work in breast cancers that are fully classified as HER2 positive, but it also works in cancers that are HER2 negative and HER2 low, which we see in HR-positive breast cancer.

It’s incredible to see the drug now work in another type of cancer that it wasn’t originally developed for; now the drug is approved for HR-positive, HER2-negative breast cancer [as well as] HR-positive breast cancers that are what we consider HER2 low or ultralow. The drug is now approved for use before any lines of chemotherapy, so once these patients with HR-positive disease have progressed on endocrine therapies, we can now go straight to using T-DXd before any chemotherapy. That was a big new approval that just happened in January of this year, and shifted how we use the drug because we can now use it in more patients and earlier than ever before, which is exciting.

What were the key data from DESTINY-Breast06 that led to the January FDA approval of T-DXd in HER2-low or -ultralow breast cancer?

[These data] were presented at the 2024 ASCO Annual Meeting and in this trial [investigators] included patients with HR-positive, HER2-low or -ultralow breast cancer. These are patients that have just a bit of membrane staining of HER2 and had progressed on endocrine therapy but had not been given any chemotherapy. Patients were randomly assigned 1:1 to treatment with regular chemotherapy or T-DXd.

We found that when we use T-DXd before chemotherapy, there was a 5.1-month improvement in PFS. T-DXd really outperformed chemotherapy, and that’s what led to this new FDA approval.

What were the key safety data from the DESTINY-Breast06 update?

There were no new safety concerns from what we had seen in previous clinical trials of T-DXd, but one of the things we worry about with this drug is nausea. Fatigue can also be challenging, but the most serious adverse effect [AE] of special interest is this risk of interstitial lung disease [ILD] or pneumonitis. T-DXd can cause inflammation in the lungs, and it can be life threatening and fatal. We have seen that in previous trials and in the real world, so that’s something that we always watch out for with this drug.

In [DESTINY-Breast06] there were 3 cases of grade 5 pneumonitis, and those are the [kind] of things that we don’t see with regular chemotherapy. [Although] we saw a huge improvement in outcomes for patients it’s also important to monitor these patients closely for the risk of ILD.

How has the FDA approval of Dato-DXd affected the space so far?

Dato-DXd is [one of the] newest ADCs on the market that was also just approved in January 2025. It has a similar structure to T-DXd and these other ADCs that we’ve seen. [The payload for this] ADC is [also] a topoisomerase 1 inhibitor, but this ADC targets TROP2 [instead of] HER2.

TROP2 is an antigen on cancer cells that’s widely expressed in breast cancer. Dato-DXd can directly deliver that cytotoxic chemotherapy payload straight into the cancer cells, so it’s more potent and hopefully has less off-target toxicities than what we see with regular chemotherapy.

What were the key safety and efficacy findings from TROPION-Breast01 that supported the January FDA approval of Dato-DXd?

TROPION-Breast01 was a large phase 3 trial of Dato-DXd in patients with HR-positive, HER2-negative breast cancer. This trial included patients who had already received endocrine therapy and 1 or 2 lines of chemotherapy. These were patients that were heavily pretreated with more advanced disease.

Patients were randomly assigned 1:1 Dato-DXd or physician’s choice of chemotherapy. In this trial, we found that Dato-DXd improved PFS for patients over chemotherapy; the median PFS for Dato-DXd was 6.9 months [95% CI, 5.7-7.4] compared with 4.9 months [95% CI, 4.2-5.5] with chemotherapy.

[In terms of safety], one of the big things that we see with Dato-DXd that we do not see with chemotherapy is stomatitis [which is] very common; 59% of patients had [any-grade] stomatitis with this drug. It’s recommended that patients use a prophylactic steroid mouthwash 4 times daily [because] that helps prevent stomatitis and typically, when using that, the stomatitis is mild.

Another thing that the drug can do is it can affect the eyes and cause dry eyes or irritation. It’s important for patients to use a lubricating eye drop 4 times daily while on study to protect their eyes and to involve an eye doctor to monitor [for these] symptoms. [One] difference from chemotherapy is that [Dato-DXd] is much less harsh on blood counts. We see much less neutropenia which means less risk of infection for patients, which is exciting.

In light of the emergence of these newer agents, where does sacituzumab govitecan currently fit into the treatment paradigm?

Sacituzumab govitecan-hziy [Trodelvy]is one of the older ADCs which has been on the market for a few years. It was first developed and approved in triple-negative breast cancer [TNBC]. It also uses a topoisomerase I inhibitor payload, and it is a TROP2-targeting antibody, so very similar to Dato-DXd in terms of payload and target.

[The agent] was first approved in TNBC following [data from] the [phase 3] TROPiCS-02 trial [NCT03901339]. This was the first phase 3 trial looking at sacituzumab govitecan in patients with HR-positive, HER2-negative breast cancer. It included patients who had progressed on endocrine therapy and who had also been treated with 2 or more lines of chemotherapy. These were patients with fairly advanced disease who were heavily pretreated.

What factors do you consider when sequencing these ADCs?

There are so many questions about what the best way is to sequence these [drugs] and we don’t have the [definitive] answers yet. We’ve been relying on retrospective data looking back at how patients have done on these drugs to help us gauge sequencing.

There are a lot of prospective trials in the works to try to help us tease this out, but I [believe] it comes down to conversations between the patient and physician [regarding] what their goals are. T-DXd is approved for patients who are HER2 low or ultralow; T-DXd is a great option if you have a patient with some HER2 staining. If there’s no HER2 staining, then you could go to Dato-DXd or sacituzumab govitecan

Ultimately, for patients who are HER2 low you can sequence all these drugs together. There are a lot of questions about whether we should sequence them back-to-back-to-back, or whether we change it up and use a regular chemotherapy in between them. Right now, there’s not any clear guidance, so it comes down to the AE profile and how the patient is doing to make that decision.

What upcoming research of ADCs in HR-positive breast cancer are you the most interested in?

Everybody is excited to see ADCs with new payloads. I mentioned that all these drugs use a topoisomerase 1 inhibitor, [but] a lot of companies are working on developing compounds with microtubule inhibitor payloads and there are also a lot of new ADCs with new targets. We [also] have HER3-targeted ADCs in trials for breast cancer.

We’re excited to see new drugs with new targets and payloads, with the hopes that we can prevent any resistance that could develop with these other ADCs that have similar targets and payloads. It’ll be exciting to see these new drugs move into bigger trials.

References

1. FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HR-positive, HER2-low or HER2-ultralow breast cancer. FDA. Updated February 6, 2025. Accessed March 27, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-hr-positive-her2-low-or-her2
2. FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic, HR-positive, HER2-negative breast cancer. FDA. January 17, 2025. Accessed March 27, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-Datopotamab-deruxtecan-dlnk-unresectable-or-metastatic-hr-positive-her2-negative-breast