Japan Approves T-DXd, Dato-DXd in Select First-Line Metastatic Breast Cancers Indications

Japan's Ministry of Health, Labour and Welfare (MHLW) has approved trastuzumab deruxtecan (T-DXd; Enhertu) in combination with pertuzumab (Perjeta) for the first-line treatment of adult patients with HER2-positive unresectable or recurrent breast cancer; and datopotamab deruxtecan (Dato-DXd; Datroway) for the first-line treatment of adult patients with unresectable or recurrent triple-negative breast cancer (TNBC) who are not candidates for PD-1/PD-L1 inhibitor therapy.¹

The HER2-positive approval is based on data from the phase 3 DESTINY-Breast09 trial (NCT04784715), in which 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).^1,2 The median progression-free survival (PFS) was 40.7 months for the T-DXd–based regimen vs 26.9 months for THO.

The TNBC approval is supported by findings from the phase 3 TROPION-Breast02 trial (NCT05374512), where Dato-DXd extended median overall survival (OS) to 23.7 months vs 18.7 months with investigator's choice of chemotherapy (HR, 0.79; 95% CI, 0.64-0.98; P = .029).¹,³

"[T-DXd] in combination with pertuzumab is the first new treatment regimen in more than a decade for patients with metastatic HER2-positive disease, and [Dato-DXd] is the only TROP2-directed medicine to demonstrate an OS benefit for patients with metastatic TNBC in the first-line setting," Yuki Abe, PhD, senior executive officer and head of the Research and Development Division in Japan at Daiichi Sankyo, stated in the news release.

In December 2025, the FDA approved fam-trastuzumab deruxtecan-nxki in combination with pertuzumab for the frontline treatment in adult patients with unresectable or metastatic HER2-positive (immunohistochemistry 3+ or in situ hybridization–positive) breast cancer, as determined by an FDA-approved test.4 In May 2026, datopotamab deruxtecan-dlnk was approved by the FDA for the treatment of adult patients with unresectable or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy.5 These decisions were also backed by data from DESTINY-Breast09 and TROPION-Breast02, respectively.^4,5

How was DESTINY-Breast09 conducted, and what additional data were reported?

DESTINY-Breast09 was a global, randomized, open-label phase 3 trial that enrolled patients with HER2-positive advanced or metastatic breast cancer who had received no prior chemotherapy or HER2-directed therapy for metastatic disease.²

Patients were randomly assigned 1:1:1 to received T-DXd plus pertuzumab, T-DXd plus placebo, or THP. PFS by blinded independent central review (BICR) served as the primary end point.

At the prespecified interim analysis, data were reported for the T-DXd–plus–pertuzumab arm (n = 383) and the THP arm (n = 387), while the T-DXd monotherapy arm remained blinded.

Beyond the PFS benefit, T-DXd plus pertuzumab generated a confirmed objective response rate of 85.1% vs 78.6% with THP, including complete response rates of 15.1% and 8.5%, respectively. The median duration of response was 39.2 months with the T-DXd–based regimen vs 26.4 months with THP.

What was the design of TROPION-Breast02? What other supporting data were reported?

TROPION-Breast02 was a randomized, open-label, international phase 3 trial in patients with previously untreated, locally recurrent inoperable or metastatic TNBS for whom immunotherapy was not an option.³

Patients were randomly assigned 1:1 to Dato-DXd at 6 mg/kg intravenously every 3 weeks (n = 323) or investigator's choice of chemotherapy (n = 321), with randomization stratified by geographic region, disease-free interval, and PD-L1 status.

The trial's dual primary end points were PFS by BICR and OS.

Dato-DXd produced a median PFS of 10.8 months (95% CI, 8.6-13.0) vs 5.6 months (95% CI, 5.0-7.0) with chemotherapy, reflecting a 43% reduction in the risk of progression or death (HR, 0.57; 99% CI, 0.44-0.73; P < .0001).

What safety data were reported across the 2 trials?

In DESTINY-Breast09, grade 3 or higher adverse effects (AEs) occurred in 63.5% of patients treated with T-DXd plus pertuzumab vs 62.3% with THP; the most common with the T-DXd regimen were neutropenia, hypokalemia, and anemia.² Adjudicated drug-related interstitial lung disease or pneumonitis was reported in 12.1% of patients receiving T-DXd plus pertuzumab, including 2 grade 5 events, vs 1.0% of those receiving THP. Investigators reported that safety was consistent with the known profiles of the individual agents.

In TROPION-Breast02, grade 3 or higher treatment-related AEs were reported in 33% of patients treated with Dato-DXd vs 29% with chemotherapy, and treatment-related AEs led to discontinuation in 4% and 7% of patients, respectively.³ There were no treatment-related deaths in either arm, and the safety profile was consistent with prior reports for Dato-DXd.

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 16, 2026. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202609/20260916_E.pdf
2. Tolaney SM, Jiang Z, Zhang Q, et al. Trastuzumab deruxtecan plus pertuzumab for HER2-positive metastatic breast cancer. N Engl J Med. 2025;394(6):551-562. doi:10.1056/NEJMoa2508668
3. Dent R, Shao Z, Schmid P, et al. Datopotamab deruxtecan in patients with untreated, advanced triple-negative breast cancer (TROPION-Breast02): a randomised, open-label, international, phase III trial. Ann Oncol. 2026;37(8):1066-1080. doi:10.1016/j.annonc.2026.03.008
4. FDA approves fam-trastuzumab deruxtecan-nxki with pertuzumab for unresectable or metastatic HER2-positive breast cancer. FDA. December 15, 2025. Accessed September 16, 2026. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-fam-trastuzumab-deruxtecan-nxki-pertuzumab-unresectable-or-metastatic-her2-positive
5. Datroway approved in the U.S. as first TROP2 directed antibody drug conjugate for first-line treatment of patients with metastatic triple negative breast cancer who are not PD-1/PD-L1 inhibitor candidates. News release. Daiichi Sankyo. May 22, 2026. Accessed September 16, 2026. https://daiichisankyo.us/web/dsi/press-releases/-/article/datroway-approved-in-the-us-as-first-trop2-directed-antibody-drug-conjugate-for-first-line-treatment-of-patients-with-metastatic-triple-negative-breast-cancer-who-are-not-pd-1pd-l1-inhibitor-candidates