T-DXd Receives Positive CHMP Opinion for HER2-Low or HER2-Ultralow Metastatic Breast Cancer

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending the approval of trastuzumab deruxtecan (T-DXd; Enhertu) for the treatment of adult patients with unresectable or metastatic hormone receptor—positive, HER2 low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH]–) or HER2 ultralow (IHC 0 with membrane staining) 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 recommendation was supported by data from the phase 3 DESTINY-Breast06 trial (NCT04494425), which were presented at the 2024 ASCO Annual Meeting and published in the New England Journal of Medicine. Findings showed that patients with HER2-low disease enrolled in the T-DXd arm (n = 359) achieved a median progression-free survival (PFS) of 13.2 months per blinded independent central review (BICR) assessment compared with 8.1 months for those given investigator’s choice of chemotherapy (n = 354; HR, 0.62; 95% CI, 0.51-0.74; P <.0001).2

The intention-to-treat (ITT) population included patients with HER2-low and -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 patients with HER2-ultralow disease, T-DXd (n = 76) generated a median PFS of 13.2 months compared with 8.3 months for chemotherapy (n = 76; HR, 0.78; 95% CI, 0.50-1.21).

“[T-DXd] is the first HER2-directed treatment and antibody-drug conjugate to show a PFS of more than 1 year in patients with HER2-low or HER2-ultralow metastatic breast cancer following endocrine therapy,” Ken Takeshita, MD, global head of R&D at Daiichi Sankyo, stated in a news release.1 “The CHMP recommendation is encouraging and supports our goal of further developing and advancing the way breast cancer is classified and treated.”

In January 2025, the FDA approved T-DXd for the treatment of adult patients with unresectable or metastatic, hormone receptor–positive, HER2-low or HER2-ultralow 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 findings from DESTINY-Breast06.

DESTINY-Breast06 Overview

The open-label, multicenter, randomized study enrolled patients with hormone receptor–positive, HER2-low (IHC 1+ or IHC2+/ISH–) or HER2-ultralow (IHC 0 with membrane staining) metastatic breast cancer who were naive to chemotherapy in the metastatic setting.2 Patients 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 endocrine therapy in the metastatic setting with disease progression within 6 months of starting first-line endocrine therapy plus a CDK4/6 inhibitor, or recurrence within 24 months of starting adjuvant endocrine therapy.

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

Key stratification factors included prior CDK4/6 inhibitor use (yes vs no), HER2 expression (low vs ultralow), and prior taxane exposure in the nonmetastatic setting (yes vs no).

PFS per BICR assessment in the HER2-low population served as the trial’s primary end point. Secondary end points consisted of BICR-assessed PFS in the ITT population; overall survival (OS) in the HER2-low and ITT populations; investigator-assessed PFS in the HER2-low population; overall response rate; and safety.

Additional Efficacy and Safety Data

OS data reached maturity of approximately 40% at the study’s primary analysis, and findings showed trends favoring T-DXd in the HER2-low population (HR, 0.83; 95% CI, 0.66-1.05; P = .1181), ITT population (HR, 0.81; 95% CI, 0.65-1.00), and HER2-ultralow population (HR, 0.75; 95% CI, 0.43-1.29).

The confirmed ORR for T-DXd was 56.5% in the HER2-low population, 57.3% in the ITT population, and 61.8% in the HER2-ultralow population. These respective rates were 32.2%, 31.2%, and 26.3% for chemotherapy.

Safety for all treated patients showed that any-grade treatment-emergent AEs (TEAEs) occurred in 98.8% of patients given T-DXd (n = 434) vs 95.2% of patients given chemotherapy (n = 417). Treatment-related TEAEs (TR-TEAEs) were reported in 96.1% of patients administered T-DXd and 89.4% of those given chemotherapy. The respective rates of grade 3 or higher TR-TEAEs were 40.6% and 31.4%. Serious TEAEs occurred at rates of 20.3% and 16.1%, respectively.

References

1. Enhertu recommended for approval in the EU by CHMP for patients with HER2 low or HER2 ultralow metastatic breast cancer following at least one endocrine therapy. News release. Daiichi Sankyo. February 28, 2025. Accessed February 28, 2025. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202502/20250228_E.pdf
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 February 28, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-approved-in-us-for-breast-cancer-post-et.html