T-DXd Approval Appears Significant in HER2-Low/Ultralow Breast Cancer

The FDA recently approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for patients with unresectable or metastatic HER2-low or ultralow breast cancer who have previously received 1 prior line of endocrine therapy in the metastatic setting.¹

CancerNetwork® spoke with Aditya Bardia, MD, MPH, FASCO, about the approval and how the results of the phase 3 DESTINY-Breast06 trial (NCT04494425) helped lead to the FDA decision.²

Bardia, professor in the Department of Medicine, Division of Hematology/Oncology, and Director of Translational Research Integration at the University of California Los Angeles Health Jonsson Comprehensive Cancer Center, discussed the difference between this approval and the August 2022 T-DXd approval based on results from phase 3 DESTINY-Breast04 (NCT03734029).^3,4 The 2022 approval was for patients with unresectable or metastatic HER2-low breast cancer who had prior chemotherapy in the metastatic setting or developed disease recurrence within 6 months of completing adjuvant chemotherapy.

During the interview, Bardia also touched on how this is a broader approval and will help with treating more patients because there is no need to have prior chemotherapy before T-DXd use.

Transcript:

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

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 27, 2024. 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. 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
4. 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