Japan’s Ministry of Health, Labour and Welfare (MHLW) has approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in combination with pertuzumab (Perjeta) as well as datopotamab deruxtecan (dato-DXd; Datroway) as first-line treatment options for patients with 2 aggressive subtypes of metastatic breast cancer, according to a news release from Daiichi Sankyo.1
T-DXd plus pertuzumab is now approved for adult patients with HER2-positive unresectable or recurrent breast cancer based on results from the phase 3 DESTINY-Breast09 trial (NCT04784715). Dato-DXd received approval for adults with hormone receptor–negative, HER2-negative unresectable or recurrent breast cancer, a subtype commonly referred to as triple-negative breast cancer (TNBC), based on findings from the phase 3 TROPION-Breast02 trial (NCT05374512). Both agents are DXd antibody-drug conjugates (ADCs) discovered by Daiichi Sankyo, which develops and commercializes them in Japan.
The Japanese approvals follow regulatory decisions in the US. The FDA approved T-DXd plus pertuzumab in December 2025 as a frontline treatment for patients with unresectable or metastatic HER2-positive breast cancer, and approved dato-DXd in May 2026 for adults with unresectable or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy.2,3
According to Yuki Abe, PhD, senior executive officer, head of the Research and Development Division in Japan, and head of research at Daiichi Sankyo, T-DXd plus pertuzumab represents “the first new treatment regimen in more than a decade” for patients with metastatic HER2-positive disease. Abe added that dato-DXd is the only TROP2-directed agent to have demonstrated an overall survival (OS) benefit in the first-line metastatic TNBC setting, and that the approvals make 2 of the company’s agents available in Japan as first-line options across the most aggressive subtypes of metastatic breast cancer.1
DESTINY-Breast09 Efficacy and Safety
In DESTINY-Breast09, T-DXd plus pertuzumab reduced the risk of disease progression or death by 44% vs a taxane, trastuzumab (Herceptin), and pertuzumab (THP; HR, 0.56; 95% CI, 0.44-0.71; P <.00001). Per blinded independent central review (BICR), the median progression-free survival (PFS) was 40.7 months (95% CI, 36.5-not estimable [NE]) with the combination compared with 26.9 months (95% CI, 21.8-NE) with THP. These data were presented at the 2025 American Society of Clinical Oncology Annual Meeting and subsequently published in The New England Journal of Medicine.
The safety profile of T-DXd was consistent with previous clinical trials, with no new safety concerns identified. Adverse reactions occurred in 373 patients (97.9%) who received T-DXd at 5.4 mg/kg plus pertuzumab, including 39 Japanese patients. The most common adverse reactions were nausea (71.1%), diarrhea (55.9%), alopecia (46.2%), vomiting (42.0%), and anemia (34.9%). Among Japanese patients who received the combination, interstitial lung disease (ILD) occurred in 33.3%, as determined by an independent ILD adjudication committee.
The global, multicenter, randomized, open-label DESTINY-Breast09 trial enrolled 1157 patients with HER2-positive metastatic breast cancer at sites in Africa, Asia, Europe, North America, and South America. Eligible patients had not received prior chemotherapy or HER2-targeted therapy or had received neoadjuvant or adjuvant HER2-targeted therapy more than 6 months before their diagnosis of advanced or metastatic disease. Patients were randomly assigned 1:1:1 to T-DXd monotherapy with a pertuzumab-matching placebo, T-DXd plus pertuzumab, or THP. Randomization was stratified by prior treatment (de novo metastatic disease vs progression from early-stage disease), hormone receptor status, and PIK3CA mutation status.
The primary end point was BICR-assessed PFS in the T-DXd monotherapy and T-DXd combination arms. Secondary end points included investigator-assessed PFS, OS, overall response rate (ORR), duration of response (DOR), pharmacokinetics, and safety. The investigational arm comparing T-DXd monotherapy with THP remains blinded to patients and investigators and will continue to the final PFS analysis.
TROPION-Breast02 Efficacy and Safety
In TROPION-Breast02, dato-DXd yielded a statistically significant and clinically meaningful 5.0-month improvement in median OS vs investigator’s choice of chemotherapy, at 23.7 months vs 18.7 months, respectively (HR, 0.79; 95% CI, 0.64-0.98; P = .029). Dato-DXd also reduced the risk of disease progression or death by 43% vs chemotherapy per BICR (HR, 0.57; 95% CI, 0.47-0.69; P <.0001), with median PFS of 10.8 months and 5.6 months in each respective arm. These findings were presented at the 2025 European Society for Medical Oncology Congress and subsequently published in Annals of Oncology.
The safety profile of dato-DXd was also consistent with previous clinical trials, with no new safety concerns identified. Adverse reactions occurred in 296 patients (92.8%) who received dato-DXd at 6 mg/kg, including 17 Japanese patients. The most common adverse reactions included stomatitis (57.1%), nausea (44.5%), alopecia (40.8%), dry eye (23.8%), and constipation (22.6%). ILD was not observed among the 17 Japanese patients treated with dato-DXd.
The global, multicenter, randomized, open-label TROPION-Breast02 trial enrolled 644 patients with previously untreated locally recurrent inoperable or metastatic TNBC for whom immunotherapy was not an option. This population included patients whose tumors did not express PD-L1, as well as those with PD-L1–expressing tumors who could not receive immunotherapy because of prior exposure in early-stage disease, comorbidities, or lack of access in their geography. Patients with de novo or recurrent disease were eligible regardless of disease-free interval, as were those with poor prognostic factors such as stable brain metastases. Patients received dato-DXd or investigator’s choice of paclitaxel, nab-paclitaxel, capecitabine, carboplatin, or eribulin.
The dual primary end points were OS and BICR-assessed PFS. Secondary end points included investigator-assessed PFS, ORR, DOR, disease control rate, pharmacokinetics, and safety.
ILD Warning and Monitoring
Both T-DXd and dato-DXd are approved in Japan with a warning for ILD in their prescribing information. Across multiple clinical trials, ILD occurred in 11.7% of patients treated with T-DXd and 3.1% of those treated with dato-DXd. Because ILD cases, including fatal events, have been reported with both agents, each is to be used in close collaboration with a respiratory disease expert.
Before initiating either agent, clinicians should perform a chest CT scan and take a medical history to confirm the absence of comorbid or prior ILD and should carefully consider each patient’s eligibility for treatment. During therapy, patients should be closely observed for early signs or symptoms of ILD such as dyspnea, cough, or fever, with periodic percutaneous oxygen saturation (SpO2) tests, chest X-rays, and chest CT scans. If abnormalities are observed, treatment should be discontinued and appropriate measures, such as corticosteroid administration, should be taken.
Addressing Unmet Needs in First-Line Treatment
Although HER2-targeted therapies have improved outcomes for patients with HER2-positive metastatic breast cancer, prognosis remains poor, with most patients experiencing disease progression within 2 years of first-line THP, which has been the standard of care for more than a decade. In metastatic TNBC, adding immunotherapy to chemotherapy has improved first-line outcomes for patients with PD-L1–expressing tumors; however, chemotherapy has been the standard first-line treatment for the approximately 70% of patients with metastatic TNBC who are not candidates for immunotherapy.
References
1. Enhertu and Datroway approved in Japan for two new first-line indications for patients with metastatic breast cancer. News release. Daiichi Sankyo. September 16, 2026. Accessed September 17, 2026. https://tinyurl.com/4vdv4fz9
2. FDA approves fam-trastuzumab deruxtecan-nxki with pertuzumab for unresectable or metastatic HER2-positive breast cancer. News release. FDA. December 15, 2025. Accessed September 17, 2026. https://tinyurl.com/59n2f8bs
3. FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic triple-negative breast cancer. News release. FDA. May 22, 2026. Accessed September 17, 2026. https://tinyurl.com/2s45pcrr
