Japan Approves Enhertu Plus Pertuzumab and Datroway as First-Line Metastatic Breast Cancer Regimens
核心洞察
Japan's MHLW approved trastuzumab deruxtecan plus pertuzumab for HER2 (搜索)-positive unresectable or recurrent breast cancer and datopotamab deruxtecan for triple-negative disease on September 16, 2026.
DESTINY-Breast09 showed the T-DXd combination cut the risk of progression or death by 44% versus THP, with median PFS of 40.7 versus 26.9 months.
TROPION-Breast02 demonstrated a 5.0-month median overall survival gain with datopotamab deruxtecan over chemotherapy in patients who were not candidates for PD-1/PD-L1 (搜索) inhibitors.
Japan's Ministry of Health, Labour and Welfare approved two DXd antibody-drug conjugates (ADCs) from Daiichi Sankyo as first-line treatment options for patients with aggressive subtypes of metastatic breast cancer (搜索) on September 16, 2026. Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) was cleared in combination with pertuzumab (Perjeta) for adults with HER2 (搜索)-positive unresectable or recurrent breast cancer, while datopotamab deruxtecan (dato-DXd; Datroway) was approved for adults with hormone receptor-negative, HER2-negative unresectable or recurrent disease, the subtype commonly referred to as triple-negative breast cancer (搜索) (TNBC).
The decisions rest on two phase 3 trials that addressed distinct first-line populations. DESTINY-Breast09 (NCT04784715) supported the HER2 (搜索)-positive indication, and TROPION-Breast02 (NCT05374512) supported the TNBC indication. Both agents are DXd ADCs discovered by Daiichi Sankyo, which develops and commercializes them in Japan.
DESTINY-Breast09: A New Benchmark Against THP
For more than a decade, taxane plus trastuzumab (Herceptin) and pertuzumab (THP) has been the standard first-line regimen for HER2 (搜索)-positive metastatic breast cancer (搜索). DESTINY-Breast09 tested whether T-DXd plus pertuzumab could improve on that backbone.
The combination reduced the risk of disease progression or death by 44% versus THP (HR, 0.56; 95% CI, 0.44-0.71; P <.00001). By blinded independent central review (BICR), median progression-free survival (PFS) was 40.7 months (95% CI, 36.5-not estimable) with T-DXd plus pertuzumab compared with 26.9 months (95% CI, 21.8-not estimable) with THP, a difference of nearly 14 months. The data were presented at the 2025 American Society of Clinical Oncology Annual Meeting and subsequently published in The New England Journal of Medicine.
The global, multicenter, randomized, open-label trial enrolled 1157 patients with HER2 (搜索)-positive metastatic breast cancer (搜索) 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, with randomization stratified by prior treatment (de novo metastatic disease versus 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, overall survival (OS), overall response rate, duration of response, pharmacokinetics, and safety. The monotherapy arm remains blinded to patients and investigators and will continue to the final PFS analysis, leaving open how much incremental benefit pertuzumab contributes when added to T-DXd.
Yuki Abe, PhD, senior executive officer, head of the Research and Development Division in Japan, and head of research at Daiichi Sankyo, said the combination represents "the first new treatment regimen in more than a decade" for patients with metastatic HER2 (搜索)-positive disease.
TROPION-Breast02: An OS Gain Without an Immunotherapy Option
The TNBC approval addresses a different gap. Adding immunotherapy to chemotherapy has improved first-line outcomes for patients with PD-L1 (搜索)-expressing tumors, but chemotherapy has remained the standard first-line treatment for the approximately 70% of patients with metastatic TNBC who are not candidates for immunotherapy.
TROPION-Breast02 enrolled 644 patients with previously untreated locally recurrent inoperable or metastatic TNBC for whom immunotherapy was not an option. The population included patients whose tumors did not express PD-L1 (搜索), 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. Participants received dato-DXd or investigator's choice of paclitaxel, nab-paclitaxel, capecitabine, carboplatin, or eribulin.
Dato-DXd produced a statistically significant and clinically meaningful 5.0-month improvement in median OS versus chemotherapy, at 23.7 months versus 18.7 months (HR, 0.79; 95% CI, 0.64-0.98; P = .029). The agent also reduced the risk of disease progression or death by 43% per BICR (HR, 0.57; 95% CI, 0.47-0.69; P <.0001), with median PFS of 10.8 months versus 5.6 months. The findings were presented at the 2025 European Society for Medical Oncology Congress and subsequently published in Annals of Oncology. The dual primary end points were OS and BICR-assessed PFS; secondary end points included investigator-assessed PFS, overall response rate, duration of response, disease control rate, pharmacokinetics, and safety.
Abe noted that dato-DXd is the only TROP2 (搜索)-directed agent to have demonstrated an OS benefit in the first-line metastatic TNBC setting.
Safety Profiles and ILD Monitoring
Both agents are approved in Japan with a warning for interstitial lung disease (搜索) (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.
In DESTINY-Breast09, 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 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, ILD occurred in 33.3%, as determined by an independent ILD adjudication committee, a figure derived from a small national subgroup.
In TROPION-Breast02, adverse reactions occurred in 296 patients (92.8%) who received dato-DXd at 6 mg/kg, including 17 Japanese patients. The most common reactions were stomatitis (57.1%), nausea (44.5%), alopecia (40.8%), dry eye (23.8%), and constipation (22.6%). No ILD was observed among the 17 Japanese patients treated with dato-DXd. The safety profiles of both agents were consistent with previous clinical trials, with no new safety concerns identified.
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 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.
Regulatory Reach and Sequencing Questions
The Japanese approvals follow US decisions. The FDA approved T-DXd plus pertuzumab in December 2025 as a frontline treatment for patients with unresectable or metastatic HER2-positive breast cancer (搜索), and approved dato-DXd in May 2026 for adults with unresectable or metastatic TNBC who are not candidates for PD-1/PD-L1 (搜索) inhibitor therapy. T-DXd plus pertuzumab is now approved in more than 40 countries and regions for first-line unresectable or metastatic HER2 (搜索)-positive disease, while Datroway is approved in more than 30 countries and regions for unresectable or metastatic TNBC when patients are not candidates for PD-1/PD-L1 inhibitor treatment.
The shift of ADCs into first line raises questions about what follows progression. Clinicians increasingly need to determine whether sequential ADC therapy remains effective, particularly when agents share topoisomerase I payloads. Whether cross-resistance is driven primarily by antigen expression, internalization, linker biology, payload resistance, drug-efflux mechanisms, or tumor evolution remains incompletely understood, making rational sequencing after resistance a priority for metastatic breast cancer (搜索) research.