Advancements in HER2-Directed Therapies Abound for HER2+ Metastatic Breast Cancer

As the role of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) expands for patients with metastatic HER2-positive breast cancer and novel antibody-drug conjugates (ADCs) enter the scene, increasing familiarity with these agents can optimize treatment outcomes and minimize toxicities, according to Aditya Bardia, MD, MPH, FASCO.

“It’s an exciting paradigm in terms of newer therapies that are coming in that are improving survival,” Bardia said in an interview with OncLive^®. “Hopefully, we can continue to build on the progress with combinations with ADCs, as well as newer ADCs, so we continuously improve survival and quality of life for patients with metastatic breast cancer.”

In the interview, Bardia discussed the evolving role of T-DXd for patients with HER2-positive advanced breast cancer, considerations for sequencing ADCs, and how the novel designation of HER2-ultralow disease emphasizes the need for more sensitive HER2 tests.

Bardia noted how T-DXd, which received regular FDA approval in 2022 for select adult patients with unresectable or metastatic HER2-positive breast cancer who had previously received HER2-directed therapy, has solidified its role as a standard second-line treatment for this patient population.1 He also commented on findings from the phase 3 DESTINY-Breast06 trial (NCT04494425), which showed that T-DXd elicited a median progression-free survival of 13.2 months (95% CI, 9.8-17.3) and a 12-month overall survival rate of 84.0% in patients with HER2-ultralow metastatic breast cancer (n = 76).²

Bardia is a professor in the Department of Medicine in the Division of Hematology/Oncology and the director of Translational Research Integration at the University of California, Los Angeles Jonsson Comprehensive Cancer Center.

OncLive: How has the clinical use of T-DXd shifted the treatment paradigm for patients with HER2-positive advanced breast cancer?

Bardia: T-DXd has been a transformative medication. It’s a HER2-directed ADC with deruxtecan as the payload and is approved for [patients with] HER2-positive metastatic breast cancer [and those with] HER2-low metastatic breast cancer, both hormone receptor (HR)–positive and HR-negative disease. [The agent] has impressive efficacy in both these groups; the major adverse effects are nausea, pneumonitis, and hair loss. [Using this agent] requires early recognition and management of pneumonitis.

The DESTINY-Breast 06 trial focused on patients with HER2-low and HER2-ultralow metastatic breast cancer. Now that there are many different classifications of HER2 expression, is there a need for improved HER2 testing to better classify these patients beyond simply HER2-positive and HER2-negative?

The HER2 immunohistochemistry [IHC] assay was designed to identify high expressers. It was never designed to identify low expression of HER2 in breast cancer. We’ve seen in different studies that T-DXd works even in low HER2-expressing tumors. DESTINY-Breast06 included patients with HER2-low and HER2-ultralow disease. It begs the question: Do we need better assays? Because the HER2 IHC assay was never designed to identify low-expressing tumors.

Since approximately 85% of patients with metastatic breast cancer could have HER2-ultralow disease, how much of an impact could T-DXd have on the overall breast cancer population?

Possibly even a larger proportion [of patients with metastatic disease could benefit from T-DXd] because there is decent variability among pathologists regarding the HER2-ultralow definition, and it’s a bit subjective. It’s possible we’ll see more reports of HER2-ultralow [disease]. T-DXd could be a medication that’s used regardless of [patients’] biomarker [status], similar to sacituzumab govitecan-hziy [Trodelvy], which is used regardless of patients’ TROP2 expression.

What patient characteristics and disease factors do you consider when choosing a treatment option for patients with HER2-positive disease in the first- or second-line metastatic setting?

At this time, the management for a patient with HER2-positive metastatic breast cancer in the first-line setting includes a taxane plus trastuzumab [Herceptin] and pertuzumab [Perjeta]. Then, after a few cycles of taxanes, usually 6 to 8 cycles, you can stop the taxanes and continue trastuzumab plus pertuzumab. In the second-line setting, [patients receive] T-DXd. That’s the uniform standard for most patients. However, we’re looking forward to additional studies, which are looking at T-DXd in the first-line setting vs taxanes plus trastuzumab and pertuzumab, which could change this workflow.

What treatment options exist in the third line and beyond for patients with HER2-positive disease who have progressed on an ADC?

The third line and beyond is pretty open at this time. Many oncologists use tucatinib [Tukysa] in combination with capecitabine [Xeloda] and trastuzumab. Some oncologists use ado-trastuzumab emtansine [T-DM1; Kadcyla]; some would consider trastuzumab plus other chemotherapy agents. It’s also a setting where newer HER2-directed therapies, such as TKIs and ADCs, are being evaluated.

What ADCs are under investigation in HER2-positive breast cancer that may change the treatment paradigm in the future?

There is a lot of interest in a drug called BB-1701, which is a HER2-directed ADC that has eribulin as the payload. Disitamab vedotin [RC48] is another HER2-directed ADC with a vedotin payload. There is interest in newer ADCs that might target HER2 but with a different payload. We know that works. T-DXd had activity even in patients who had received prior T-DM1, so there’s not complete cross-resistance based on the antibody. If you use a different payload that might show efficacy or activity.

As more ADCs become available, will ADC sequencing become an option?

Absolutely. We do that all the time with chemotherapy. We use 1 chemotherapy after the next. These ADCs allow more delivery of payloads, including chemotherapies, to cancer cells. I do see sequencing of ADCs being an option in the future.

What unmet needs remain for patients with HER2-positive breast cancer that could be addressed with future trials?

Unmet needs for patients with HER2-positive metastatic breast cancer [can be classified into] 3 broad themes. The first is brain metastases. Many patients continue to have morbidity and mortality from brain metastases. We need better agents to control brain metastases.

The second theme relates to understanding the biomarkers governing response and resistance to these agents, so we can more effectively sequence the different agents. Additionally, as the newer HER2-directed ADCs are coming in, [we need to] understand resistance and sequencing.

The third theme, which is a lofty goal but could be achieved, is: Can we combine different drugs to cure metastatic HER2-positive breast cancer? We generally don’t use the term cure for patients with metastatic disease, but I think it’s reasonable, at least to test this in a clinical trial setting, once we identify biomarkers and good combinations, to see if we can [achieve cures] at least for a subset of patients with metastatic HER2-positive breast cancer.

References

1. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. FDA. May 4, 2022. Accessed June 18, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-fam-trastuzumab-deruxtecan-nxki-breast-cancer
2. Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): primary results from DESTINY-Breast06 (DB-06). J Clin Oncol. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_suppl.LBA1000