EMA Validates T-DXd for First-Line HER2+ Metastatic Breast Cancer

The European Medicines Agency (EMA) has validated a Type II Variation application for fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in combination with pertuzumab (Perjeta) for the first-line treatment of adult patients with HER2-positive metastatic breast cancer.¹ The validation signals the start of the scientific review process by the Committee for Medicinal Products for Human Use (CHMP) and could herald a significant shift in the standard of care for treatment-naive patients in this setting.¹

The application is primarily supported by data from the global, open-label, randomized phase 3 DESTINY-Breast09 trial (NCT04784715).² The study evaluated the efficacy and safety of T-DXd with or without pertuzumab vs the current standard of care—a combination of pertuzumab and trastuzumab (Herceptin) plus a taxane (docetaxel or paclitaxel; THP).

“This validation in the [European Union (EU)] is an important step in moving us closer to offering [T-DXd] in combination with pertuzumab as a potential new first-line treatment option for patients with HER2-positive metastatic breast cancer,” said Ken Takeshita, MD, global head, Research and Development, Daiichi Sankyo, in a news release.¹ “Following the recent approval in the US for this indication, we look forward to working closely with the EMA to bring [T-DXd] to eligible patients in the EU who may benefit from improved outcomes in a setting where the standard of care has not changed in more than a decade.”

In December 2025, the FDA approved this combination for the same indication, also supported by DESTINY-Breast09.³

DESTINY-Breast09 Clinical Outcomes

In the DESTINY-Breast09 trial, T-DXd plus pertuzumab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with the taxane-based regimen. Results from the trial presented at the 2025 European Society of Medical Oncology (ESMO) Congress indicated that the antibody-drug conjugate (ADC) combination significantly reduced the risk of disease progression or death in all patient subgroups.⁴ The PFS for patients with de novo disease and treated with T-DXd plus pertuzumab was not calculable (NC; 95% CI, 36.5–NC) compared with 31.2 months (95% CI, 23.5–NC) for patients treated with THP (HR, 0.49; 95% CI, 0.35–0.70). The PFS for those with recurrent disease in the T-DXd plus pertuzumab arm was 38.0 months (95% CI, 26.9–NC) and 22.5 months (95% CI, 18.1–NC) for those in the THP arm (HR, 0.63; 95% CI, 0.46–0.87).

Patient-reported outcomes were presented at the 2025 San Antonio Breast Cancer Symposium (SABCS).⁵ Compared with THP, T-DXd plus pertuzumab presented a distinct quality-of-life profile. Patients receiving T-DXd plus pertuzumab experienced fewer gastrointestinal symptoms, including nausea, vomiting, constipation, and appetite loss. This patient group also experienced fewer issues with skin and mucosal symptoms, nosebleeds, and extremity swelling.

The safety profile of the ADC combination remained consistent with previous clinical investigations, with no new safety signals identified. The most common adverse events included nausea, fatigue, and neutropenia. Notably, interstitial lung disease or pneumonitis remains a known risk of T-DXd therapy, requiring vigilant monitoring and management according to established clinical guidelines.¹

Regulatory and Clinical Outlook

The EMA validation follows a similar regulatory trajectory in other regions, as the oncology community increasingly moves toward chemotherapy-free or chemotherapy-sparing regimens in the first-line setting. If approved, T-DXd plus pertuzumab would provide oncologists with a potent alternative to traditional triplet therapy, potentially altering the sequential treatment algorithm for HER2-positive metastatic disease.

Further data regarding the monotherapy arm of DESTINY-Breast09 and long-term survival results will be critical for determining the definitive role of the ADC in treatment-naive patients. For now, the validation marks a major milestone in the expansion of ADC utility within the European Union.

REFERENCES

1. ENHERTU® plus pertuzumab Type II Variation application validated in the EU as first-line treatment of patients with HER2 positive metastatic breast cancer. News release. Daiichi Sankyo. January 19, 2026. Accessed January 19, 2026. https://tinyurl.com/yc3nv9pe

2. Trastuzumab deruxtecan (T-DXd) with or without pertuzumab versus taxane, trastuzumab and pertuzumab in HER2-positive metastatic breast cancer (DESTINY-Breast09). ClinicalTrials.gov. Updated November 12, 2025. Accessed January 19, 2026. https://clinicaltrials.gov/study/NCT04784715

3. FDA approves fam-trastuzumab deruxtecan-nxki with pertuzumab for unresectable or metastatic HER2-positive breast cancer. US FDA. December 15, 2025. Accessed January 19, 2026. https://tinyurl.com/bd7m9atz

4. Loibl S, Jiang Z, Barroso-Sousa R, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab vs taxane + trastuzumab + pertuzumab (THP) for patients with HER2+ advanced/metastatic breast cancer: additional analyses of DESTINY-Breast09 in key subgroups of interest. Presented at the European Society for Medical Oncology Congress 2025, October 17-21, 2025; Berlin, Germany. LBA18.

5. Rimawi M, Loibl S, Jiang Z, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab vs taxane + trastuzumab + pertuzumab (THP) for first-line treatment of patients with HER2+ advanced/metastatic breast cancer: patient-reported outcomes from the DESTINY-Breast09 study. Presentation RF6-07. San Antonio Breast Cancer Symposium. December 10, 2025.