EU Approves T-DXd/Pertuzumab for Frontline HER2+ Metastatic Breast Cancer

The European Commission has approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in combination with pertuzumab (Perjeta) for the first-line treatment of adult patients with unresectable or metastatic HER2-positive breast cancer, according to a news release from AstraZeneca and Daiichi Sankyo.¹ The decision marks the first new regimen in more than a decade to be approved in the European Union (EU) for the frontline setting of this disease.

The approval follows a positive opinion from the Committee for Medicinal Products for Human Use of the European Medicines Agency and is supported by findings from the phase 3 DESTINY-Breast09 trial (NCT04784715), which were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meetingand later published in The New England Journal of Medicine.²

DESTINY-Breast09 was a global, multicenter, randomized, open-label trial that enrolled 1157 adults with HER2-positive advanced or metastatic breast cancer who had not received prior chemotherapy or HER2-targeted therapy, or who had received neoadjuvant or adjuvant HER2-targeted therapy more than 6 months before their advanced or metastatic diagnosis.^1,2 Patients were randomly assigned 1:1:1 to receive T-DXd plus pertuzumab, T-DXd plus placebo, T-DXd plus pertuzumab, or a taxane plus trastuzumab (Herceptin) and pertuzumab (THP) regimen. Randomization was stratified by prior treatment setting, hormone receptor status, and PIK3CA mutation status.

The primary end point was progression-free survival (PFS) by blinded independent central review (BICR) in the monotherapy and combination arms. Secondary end points included investigator-assessed PFS, overall survival (OS), objective response rate, duration of response, and safety.

T-DXd plus pertuzumab reduced the risk of disease progression or death by 44% compared with THP (HR, 0.56; 95% CI, 0.44-0.71; P <.00001).¹ Median PFS by BICR was 40.7 months with T-DXd plus pertuzumab vs 26.9 months with THP. The confirmed objective response rate was 85.1% (95% CI, 81.2%-88.5%) with the combination vs 78.6% (95% CI, 74.1%-82.5%) with THP, with complete responses in 15.1% and 8.5% of patients, respectively, and a median duration of response of 39.2 months (95% CI, 35.1-not calculable [NC]) vs 26.4 months (95% CI, 22.3-NC). OS data remained immature at that analysis.

The safety profile of the combination was consistent with the known profiles of each individual agent, with no new safety signals identified.¹ Grade 3 or higher adverse events occurred in 63.5% of patients on the combination vs 62.3% on THP, with neutropenia, hypokalemia, and anemia as the most common higher-grade events with the combination. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 12.1% of patients on T-DXd plus pertuzumab, including 2 grade 5 events, compared with 1.0% of patients on THP. Left ventricular dysfunction was reported in 11.0% vs 7.1% of patients, respectively. The prescribing information carries warnings for neutropenia and left ventricular dysfunction.

The recommended regimen is T-DXd at 5.4 mg/kg on cycle 1, day 1, followed by pertuzumab at 840 mg; for subsequent cycles, T-DXd is given at 5.4 mg/kg followed by pertuzumab at 420 mg, all by intravenous infusion every 3 weeks.³

Cristina Saura, MD, PhD, of Vall d’Hebron University Hospital and the Vall d’Hebron Institute of Oncology in Barcelona, Spain, and a steering committee member and investigator on DESTINY-Breast09, said maintaining disease control for as long as possible is a critical goal in the frontline setting for these patients.¹ “The combination of [T-DXd] and pertuzumab represents a significant therapeutic advance, with [PFS] exceeding 3 years compared [with] approximately 2 years with the current standard of care, and has the potential to become the new first-line standard of care,” Saura said in the release.¹

The FDA approved the same combination in the US in December 2025 for adults with unresectable or metastatic HER2-positive breast cancer selected by an FDA-approved test.³ T-DXd is also under review in the EU for patients with HER2-positive breast cancer who have residual invasive disease following neoadjuvant HER2-targeted treatment based on the DESTINY-Breast05 trial (NCT04622319).¹

References

1. Enhertu plus pertuzumab approved in the EU as first new regimen in more than a decade for the 1st-line treatment of patients with HER2-positive metastatic breast cancer. News release. AstraZeneca. September 1, 2026. Accessed September 2, 2026. https://tinyurl.com/ddwc52xk
2. Tolaney SM, Jiang Z, Zhang Q, et al. Trastuzumab deruxtecan plus pertuzumab for HER2-positive metastatic breast cancer. N Engl J Med. 2026;394(6):551-562. Doi:10.1056/NEJMoa2508668
3. FDA approves fam-trastuzumab deruxtecan-nxki with pertuzumab for unresectable or metastatic HER2-positive breast cancer. News release. FDA. December 15, 2025. Accessed September 2, 2026. https://tinyurl.com/59n2f8bs