T-DXd Wins EU Approval for HR+, HER2-Low or -Ultralow Metastatic Breast Cancer After Endocrine Therapy

Image Credit: © Sebastian Kaulitzki – stock.adobe.com

The European Commission has approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for the treatment of adult patients with unresectable or metastatic hormone receptor–positive, HER2-low or HER2-ultralow breast cancer who have received at least 1 endocrine therapy in the metastatic setting and who are not considered suitable for endocrine therapy as the next line of treatment.1

The regulatory decision was supported by data from the phase 3 DESTINY-Breast06 trial (NCT04494425). Findings presented at the 2024 ASCO Annual Meeting showed that patients with HER2-low disease treated with T-DXd (n = 359) achieved a median progression-free survival (PFS) of 13.2 months compared with 8.1 months for those given physician’s choice of chemotherapy (n = 354; HR, 0.62; 95% CI, 0.51-0.74; P < .0001).2

In the intention-to-treat (ITT) population, which comprised patients with HER2-low and HER2-ultralow disease, the median PFS was 13.2 months for T-DXd (n = 436) vs 8.1 months for chemotherapy (n = 430; HR, 0.63; 95% CI, 0.53-0.75; P < .0001). In the HER2-ultralow population, the median PFS was 13.2 months for T-DXd (n = 76) vs 8.3 months for chemotherapy (n = 76; HR, 0.78; 95% CI, 0.50-1.21).

“This approval introduces a new treatment option for hormone receptor–positive metastatic breast cancers that express HER2,” Giuseppe Curigliano, MD, PhD, professor of medical oncology at the University of Milan and the head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, in Italy, and principal investigator for DESTINY-Breast06, stated in a news release.1 “In DESTINY-Breast06, [T-DXd] outperformed chemotherapy, providing PFS of more than 1 year for patients with hormone receptor–positive, HER2-low or HER2-ultralow metastatic breast cancer, demonstrating the benefit of treating these patients with [T-DXd] instead of chemotherapy.”

In January 2025, the FDA approved T-DXd 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.3 This regulatory decision was also supported by data from DESTINY-Breast06.

DESTINY-Breast06 Overview

The multicenter, open-label, randomized trial enrolled patients with hormone receptor–positive metastatic breast cancer that had low (IHC 1+ or IHC 2+/ISH–) or ultralow (IHC 0 with membrane staining) expressions of HER2.2 Patients needed to be naive to chemotherapy in the metastatic setting. They were required to have received at least 2 lines of endocrine therapy with or without targeted therapy in the metastatic setting; or 1 line of prior endocrine therapy in the metastatic setting along with disease progression within 6 months of starting first-line treatment with a CDK4/6 inhibitor and endocrine therapy or disease recurrence within 24 months of beginning adjuvant endocrine therapy.

Patients were randomly assigned 1:1 to receive T-DXd at 5.4 mg/kg once every 3 weeks or physician’s choice of chemotherapy, which comprised capecitabine, nab-paclitaxel (Abraxane), or paclitaxel.

PFS in the HER2-low population per blinded independent central review (BICR) served as the trial’s primary end point. Secondary end points consisted of PFS in the ITT population per BICR; overall survival (OS) in the HER2-low and ITT populations; investigator-assessed PFS in the HER2-low population; overall response rate; safety/tolerability; and patient-reported outcomes.

With data approximately 40% mature, OS trends favoring T-DXd were observed in the HER2-low (HR, 0.83; 95% CI, 0.66-1.05; P = .1181), ITT (HR, 0.81; 95% CI, 0.65-1.00), and HER2-ultralow (HR, 0.75; 95% CI, 0.43-1.29) populations.

Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in 98.8% of patients treated with T-DXd (n = 434) vs 95.2% of patients given chemotherapy (n = 417). Treatment-related TEAEs were reported at rates of 96.1% and 89.4%, respectively; the respective rates of grade 3 or higher treatment-related TEAEs were 40.6% and 31.4%. Serious TEAEs were reported in 20.3% of patients in the T-DXd arm vs 16.1% of patients in the control arm.

In the T-DXd group, TEAEs led to treatment discontinuation, dose interruptions, and dose reductions in 14.3%, 48.4%, and 24.7% of patients, respectively. In the chemotherapy group, these respective rates were 9.4%, 38.4%, and 38.6%. TEAEs led to death in 2.5% of patients in the experimental arm vs 1.4% of patients in the control arm. Treatment-related TEAEs leading to death were noted in 1.2% of patients given T-DXd vs no patients treated with chemotherapy.

“[T-DXd] continues to open up new approaches to the diagnosis and treatment of patients with metastatic breast cancer,” Dave Fredrickson, executive vice president of the Oncology Haematology Business Unit at AstraZeneca, stated in a news release.1 This approval underscores the importance of testing metastatic breast cancer tumors for any IHC staining to identify patients with hormone receptor–positive, HER2-low or HER2-ultralow disease who may be eligible for [T-DXd] once sustained responses are no longer achieved with endocrine-based therapy.”

References

1. Enhertu approved in the EU as first HER2-directed therapy for patients with HR-positive, HER2-low or HER2-ultralow metastatic breast cancer following at least one endocrine therapy. News release. AstraZeneca. April 4, 2025. Accessed April 4, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-approved-in-eu-in-post-et-breast-cancer.html#!
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. 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 April 4, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-approved-in-us-for-breast-cancer-post-et.html