FDA Approves Trastuzumab Deruxtecan for Pretreated HER2-Low and -Ultralow Metastatic Breast Cancer

The FDA has approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for the treatment of adult patients with unresectable or metastatic, hormone receptor–positive, HER2-low (immunohistochemistry [IHC] 1+ or 2+/in situ hybridization [ISH] negative) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on 1 or more endocrine therapies in the metastatic setting.1

This regulatory decision was supported by findings from the phase 3 DESTINY-Breast06 trial (NCT04494425), in which treatment with T-DXd generated a 36% reduction in the risk of disease progression or death compared with chemotherapy (HR, 0.64; 95% CI, 0.54-0.76; P < .0001) in the overall population of patients with chemotherapy-naive, HER2-low or -ultralow metastatic breast cancer.1,2 The median progression-free survival (PFS) was 13.2 months (95% CI, 12.0-15.2) with T-DXd vs 8.1 months (95% CI, 7.0-9.0) with chemotherapy. Additionally, the confirmed overall response rate (ORR) was 62.6% with T-DXd compared with 34.4% with chemotherapy.

“Endocrine therapy is typically used in the initial treatment of hormone receptor–positive metastatic breast cancer, and following progression, subsequent chemotherapy is associated with poor outcomes," Aditya Bardia, MD, MPH, program director of Breast Oncology and director of Translational Research Integration at the UCLA Health Jonsson Comprehensive Cancer Center, as well as the lead study author of the DESTINY-Breast06 trial, stated in a news release.1 "With a median PFS exceeding 1 year and [an ORR of 62.6%], T-DXd offers a potential new standard of care for patients with hormone receptor–positive, HER2-low or HER2-ultralow metastatic breast cancer following endocrine therapy.”

The multicenter, open-label DESTINY-Breast06 trial enrolled patients with hormone receptor–positive metastatic breast cancer with low HER2 expression (defined as IHC 1+ or 2+/ISH negative) or ultralow HER2 expression (defined as IHC 0 with membrane staining) who had previously received at least 1 line of endocrine-based therapy and had no history of chemotherapy for metastatic breast cancer.2 Patients were randomly assigned 1:1 to receive T-DXd or physician's choice of chemotherapy. PFS among patients with HER2-low disease served as the primary end point. Secondary end points included PFS among all randomly assigned patients, overall survival (OS), and safety.

Additional findings from DESTINY-Breast06, which were presented at the 2024 ASCO Annual Meeting and published in The New England Journal of Medicine, showed that among the patients with HER2-low disease (n = 713), the median PFS was 13.2 months (95% CI, 11.4-15.2) with T-DXd vs 8.1 months (95% CI, 7.0-9.0) with chemotherapy (HR, 0.62; 95% CI, 0.52-0.75; P < .001).

Furthermore, an exploratory analysis showed that patients with HER2-ultralow disease had outcomes consistent with those seen with patients with HER2-low expression. Among the patients with HER2-ultralow disease (n = 153), the median PFS was 13.2 months (95% CI, 9.8-17.3) with T-DXd vs 8.3 months (95% CI, 5.8-15.2) with chemotherapy (HR, 0.78; 95% CI, 0.50-1.21).

The OS data were immature.

Grade 3 or higher adverse effects were reported in 52.8% of patients in the T-DXd arm and 44.4% of those in the chemotherapy arm. Notably, adjudicated interstitial lung disease was seen in 11.3% of patients in the T-DXd arm; 3 of these events were grade 5.

“We are excited to see more treatment options for these patients, which enable more personalized care," Krissa Smith, vice president of Education at Susan G. Komen, added in the news release.1 "It is critical for patients to understand the HER2 status of their metastatic breast cancer to help them make informed treatment decisions. Patients with tumors that are HER2-low or HER2-ultralow now have more options to consider with their health care team.”

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. AstraZeneca. January 27, 2025. Accessed January 27, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-approved-in-us-for-breast-cancer-post-et.html
2. Bardia A, Hu X, Dent R, et al. Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. N Engl J Med. 2024;391(22):2110-2122. doi:10.1056/NEJMoa2407086