Trastuzumab Deruxtecan Approved in Japan for HER2-Low or -Ultralow Metastatic Breast Cancer

Japan’s Ministry of Health, Labour, and Welfare has approved fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) for use in adult patients with hormone receptor–positive, HER2-low or -ultralow metastatic breast cancer after at least 1 endocrine therapy.1

The decision is supported by findings from the phase 3 DESTINY-Breast06 trial (NCT04494425), which were shared during the 2024 ASCO Annual Meeting.2 In with HER2-low subgroup, the antibody-drug conjugate (n = 359; ADC) led to a 38% reduction in the risk of disease progression or death vs physician’s choice of chemotherapy (n = 354; TPC). The median progression-free survival with T-DXd was 13.2 months (95% CI, 11.4-15.2) vs 8.1 months (95% CI, 7.0-9.0) with TPC (HR, 0.62; 95% CI, 0.51-0.74; P < .0001). Moreover, in the HER2-ultralow subgroup, the median PFS with T-DXd (n = 76) was 13.2 months (95% CI, 9.8-17.3) vs 8.3 months (95% CI, 5.8-15.2) with TPC (n = 76), translating to a 22% reduction in the risk of disease progression or death (HR, 0.78; 95% CI, 0.50-1.21).

“Enhertu continues to transform the way breast cancer is treated, becoming the first HER2-directed medicine approved in Japan for patients with [hormone receptor–]positive, HER2-low or HER2-ultralow metastatic breast cancer,” Yuki Abe, PhD, head of R&D Division in Japan and Head of Research at Daiichi Sankyo, stated in a news release.1 “This approval, which is the fifth indication for Enhertu in Japan in 5 years, brings this important medicine to an earlier treatment setting and a broader patient population with lower levels of HER2 expression.”

Diving Into DESTINY-Breast06: Design, Treatment, Objectives

The randomized, multicenter, open-label study enrolled patients with hormone receptor–positive metastatic breast cancer, including those who were HER2-low, defined as immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization (ISH)–) or HER2-ultralow, defined has IHC 0 with membrane staining.2 Patients were required to receive at least 2 prior lines of endocrine therapy with or without targeted therapy for metastatic disease or 1 prior line for metastatic disease and have experienced progression within 6 months of initiation of frontline endocrine therapy plus CDK4/6 inhibition or experienced recurrence within 24 months or beginning adjuvant endocrine therapy.

They were randomly assigned 1:1 to receive 5.4 mg/kg of T-DXd every 3 weeks or TPC, which could have included capecitabine, nab-paclitaxel (Abraxane), or paclitaxel. They were stratified based on previous CDK4/6 inhibitor use (yes vs no), HER2 expression (IHC 1+ vs IHC 2+/ISH– vs IHC 0 with membrane staining), or previous taxane in the nonmetastatic setting (yes vs no).

The primary end point of the study was to examine PFS by blinded independent central review (BICR) in the HER2-low population, and key secondary end points included PFS by BICR in the intention-to-treat (ITT) population, which included both HER2-low and -ultralow subgroups; overall survival (OS) in the HER2-low subgroup; and OS in the ITT population. Investigators also examined PFS by investigator assessment in the HER2-low subgroup, objective response rate (ORR) and duration of response (DOR) by BICR and investigator assessment in both the HER2-low and ITT populations, safety and tolerability, and patient-reported outcomes.

Additional Efficacy Outcomes

OS data at the time of the presentation were at approximately 40% maturity. In the HER2-low population (n = 713), the OS rates at 12 months in the T-DXd and TPC arms were 87.6% and 81.7%, respectively (HR, 0.83; 95% CI, 0.66-1.05; P = .1181). In this population, 20.1% of those in the standard chemotherapy arm received the ADC after treatment discontinuation. In the ITT population (n = 866), the 12-month OS rates in the respective arms were 87.0% and 81.1% (HR, 0.81; 95% CI, 0.65-1.00). In this group, 17.9% of those in the TPC arm received T-DXd after treatment discontinuation. Additionally, in the HER2-ultralow group (n = 152), the 12-month OS rate with T-DXd was 84.0% vs 78.7% with TPC (HR, 0.75; 95% CI, 0.43-1.29).

In the HER2-low population, the ORR with T-DXd was 56.5% vs 32.2% with TPC. The median DORs in the respective arms were 14.1 months vs 8.6 months. In the ITT population, the ORR for the ADC was 57.3% vs 31.2% with TPC; the median DORs were 14.3 months and 8.6 months, respectively. Lastly, in the HER2-ultralow population, the ORRs for T-DXd and TPC were 61.8% and 26.3%, respectively; the median DORs were 14.3 months and 14.1 months, respectively.

Safety Spotlight

Any treatment-emergent adverse effects (TEAEs) were reported in 98.8% of patients in the T-DXd arm (n = 434) and 95.2% of those in the TPC arm (n = 417). Treatment-related TEAEs were reported in 96.1% of those given the ADC and 89.4% of those who received TPC; they were grade 3 or higher for 40.6% and 31.4% of patients, respectively. Serious TEAEs occurred in 20.3% and 16.1% of patients in the respective arms. In the T-DXd arm, TEAEs led to dose reductions or interruptions for 24.7% and 48.4% of patients, and discontinuation for 14.3% of patients; they proved fatal for 2.5% of patients. In the TPC arm, TEAEs resulted in dose reductions or interruptions for 38.6% and 38.4% of patients, and discontinuation for 9.4% of patients; they led to death in 1.4% of patients.

The most common drug-related TEAEs in the ADC arm were nausea (any grade, 65.9%; grade ≥3, 1.6%), fatigue (46.8%; 3.7%), alopecia (45.4%; 0%), neutropenia (37.6%; 20.7%), increased transaminases (29.3%; 2.3%), anemia (28.1%; 5.8%), vomiting (27.2%; 1.4%), diarrhea (23.7%; 1.8%), decreased appetite (23.5%; 1.4%), leukopenia (23.3%; 6.9%), and Palmar-plantar erythrodysesthesia.

T-DXd is greenlit in Japan with a warning for interstitial lung disease.1 According to the news release issued by Daiichi Sankyo, “As cases of ILD, including fatal cases, have occurred in Enhertu-treated patients, Enhertu is to be used in close collaboration with a respiratory disease expert. Patients should be closely observed during therapy by monitoring for early signs or symptoms of ILD (such as dyspnea, cough, fever) and performing regular peripheral artery oxygen saturation (SpO2) tests, chest X-ray scans and chest CT scans. If abnormalities are observed, discontinue administration of Enhertu and take appropriate measures, such as corticosteroid administration.”

Significance of T-DXd in the HER-low and -ultralow Paradigm

In January 2025, the FDA approved T-DXd for the treatment of adult patients with unresectable or metastatic, hormone receptor–positive, HER2-low or -ultralow breast cancer, as determined by an FDA-approved test, that has progressed on at least 1 endocrine therapy in the metastatic setting.3

“This is a drug that can be used in hormone receptor–positive metastatic breast cancer, and it can be used in earlier lines compared with [its previous indications],” Aditya Bardia, MD, MPH, FASCO, said in a recent interview with OncLive.4 Bardia is a professor in the Department of Medicine in the Division of Hematology/Oncology, the director of Translational Research Integration, and a member of Signal Transduction and Therapeutics at the UCLA Health Jonsson Comprehensive Cancer Center in Los Angeles, California.

References

1. Enhertu approved in Japan as first HER2 directed medicine for patients with HER2 low or HER2 ultralow metastatic breast cancer following at least one endocrine therapy. News release. Daiichi Sankyo. August 25, 2025. Accessed August 26, 2025. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202508/20250825_E2.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 August 26, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-approved-in-us-for-breast-cancer-post-et.html
4. Wahner A. T-DXd’s role expands into HER2-low/-ultralow metastatic breast cancer, reinforcing need for enhanced HER2 testing. March 5, 2025. Accessed August 26, 2025. https://www.onclive.com/view/t-dxd-s-role-expands-into-her2-low--ultralow-metastatic-breast-cancer-reinforcing-need-for-enhanced-her2-testing