Expert Insights into the T-DXd Approval for HER2-Low or Ultralow Breast Cancer

Aditya Bardia, MD, MPH, FASCO, professor in the Department of Medicine, Division of Hematology/Oncology, and Director of Translational Research Integration at the University of California Los Angels Health Johnsson Comprehensive Cancer Center

In January 2025, the FDA approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for patients with unresectable or metastatic hormone receptor (HR)–positive, HER2-low or HER2-ultralow breast cancer, based on findings from the phase 3 DESTINY-Breast06 trial (NCT04494425).^1,2

Aditya Bardia, MD, MPH, FASCO, professor in the Department of Medicine, Division of Hematology/Oncology, and director of Translational Research Integration at the University of California Los Angels Health Jonsson Comprehensive Cancer Center, speaks about how this approval marks a significant advancement in the treatment of this patient population, as it eliminates the requirement for prior chemotherapy and allows for the use of T-DXd in earlier lines of therapy following endocrine-based treatment. He explains the significance of the HER2-low and HER2-ultralow designations, describes the efficacy and safety profile of T-DXd, and shares his approach to integrating this novel therapy into the treatment algorithm for patients with metastatic breast cancer.

Additionally, Bardia highlights the DESTINY-Breast06 trial’s findings, which demonstrated superior progression-free survival (PFS) with T-DXd compared with standard chemotherapy. The median PFS with T-DXd was 13.2 months vs 8.1 months with chemotherapy (HR, 0.62; 95% CI, 0.51-0.74; P <.0001). He also addresses the management of adverse effects (AEs) associated with T-DXd, emphasizing the importance of proactive monitoring strategies to mitigate potential risks such as nausea, myelosuppression, and pneumonitis.

Furthermore, Bardia discusses the evolving landscape of antibody drug conjugates (ADCs) in breast cancer treatment and shares his perspective on the optimal sequencing of therapies for patients with HER2-low or HER2-ultralow metastatic breast cancer. He notes that T-DXd is now the preferred ADC for this patient population, based on the results of phase 3 DESTINY-Breast04 (NCT03734029) and DESTINY-Breast06 trials.

CancerNetwork: What does the approval of T-DXd for patients with HR–positive, HER2-low- or-ultralow breast cancer mean for this space?

Bardia: In January of 2025, the FDA approved T-DXD, based on DESTINY-Breast06, for patients with both HER2-low as well as HER2-ultralow, metastatic [HR]–positive breast cancer. This was different from [the previous approval] because there was no requirement for prior chemotherapy for the use of T-DXd, so essentially, this could be used in the first line setting after prior endocrine-based treatment.⁴ It’s a broader approval. What do HER2-low and HER2-ultralow mean? Essentially, it refers to the amount of tumor cells that have HER2 expression by immunohistochemistry. If there’s less than 10% of tumor cells, it’s called HER2-ultralow, and if it’s more than 10% of tumor cells, it's HER2-low. It was an operational definition for the trial. As for the approval, you can use T-DXd in tumors that have very low expression of HER2. In part, [the way the drug works] is probably because of the bystander effect that it has activity even in tumors with very low expression of HER2.

Looking at the results from DESTINY-Breast06, how does the efficacy of T-DXd compare with other available treatment options in the space?

In DESTINY-Breast06, T-DXd was superior to standard chemotherapy with both capecitabine as well as taxanes for patients with metastatic HR–positive breast cancer. The median PFS was about 13.5 months--so more than a year in terms of median PFS--and the previous most was about 8 months with standard chemotherapy--so a significant improvement in PFS survival is seen with T-DXd in this setting.

How are AEs managed with T-DXd, and how are you proactive with monitoring strategies?

There are 3 important AEs to remember with T-DXd. The first one is nausea, which is the most common AE seen with T-DXd. Generally, we recommend primary prophylaxis with the 3-drug antiemetic regimen. Usually, that’s quite effective. In breakthrough instances, you can use olanzapine [Zyprexa]. The second AE is myelosuppression. It can cause neutropenia as well as thrombocytopenia, so it’s important to monitor the counts. The third is a rare but known AE of T-DXd, which is pneumonitis. It’s important to monitor for pneumonitis when you’re getting restaging scans, not only looking at efficacy but also evidence of pneumonitis, so you can intervene early and prevent this from increasing.

What is your approach to sequencing therapies in this setting? How do you integrate T-DXd into the overall treatment algorithm for this patient population?

Based on the results we’ve seen from both DESTINY-Breast04 as well as DESTINY-Breast06, out of the different ADCs that are available in this setting, so that includes T-DXd, sacituzumab govitecan-hziy [Trodelvy], and now datopotamab deruxtecan-dlnk [Datroway], T-DXd is the preferred ADC for patients with HER2-low and now HER2-ultralow metastatic breast cancer. It can be used just after patients have disease progression on endocrine-based therapy in the first line setting, vs chemotherapy such as capecitabine. Some would prefer to use [T-DXd] after capecitabine in the second line setting, but generally that’s the preferred ADC based on the magnitude of benefit we’ve seen with this agent.

The DESTINY-Breast06 trial included patients with both HER2-low and HER2-ultralow expression. Is there any evidence to suggest differential efficacy in these 2 subgroups? Does HER2-ultralow expression impact your treatment decisions?

In DESTINY-Breast06, the benefit of T-DXd was similar between HER2-low as well as HER2-ultralow, so that does not influence my decision in terms of using the drug, given the magnitude of benefit we’ve seen in ultralow as well as low.

Where do you hope to see this field headed?

ADCs are replacing chemotherapy, and more and more, they are being moved to earlier lines, even in early breast cancer. In the future, these ADCs will likely replace chemotherapy. We have to be mindful of the AEs, including [clinical decision support] for AEs, so we need better management strategies of AEs. We also need biomarker development, as we have multiple ADCs that are available in this space [on top of the] additional ones that are being developed in this space.

References

1. Enhertu approved in the US as first HER2-directed therapy for patients with HER2-low or HER2-ultralow metastatic breast cancer following disease progression after one or more endocrine therapies. News release. FDA. January 27, 2024. Accessed January February 627, 20254. https://tinyurl.com/5n8ab8sk
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
3. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690
4. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer. News release. FDA. August 5, 2022. Accessed February 6, 2025. https://tinyurl.com/4ysbz27s