FDA Approves T-DXd With Pertuzumab for First-Line Treatment of Advanced HER2+Breast Cancer

The FDA approved fam-trastuzumab deruxtecan-nxki (T-DXd, Enhertu; Daiichi Sankyo, Inc.) in combination with pertuzumab (Perjeta; Genentech) for the first-line treatment of adults with unresectable or metastatic HER2-positive (HER2+; IHC 3+ or ISH+) breast cancer as determined by an FDA-approved test.

Simultaneously, the FDA also approved the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and HER2 Dual ISH DNA Probe Cocktail as companion diagnostic devices for selecting HER2-positive (HER2 IHC3+ or ISH+) breast cancer patients for treatment with T-DXd in combination with pertuzumab.¹

The Phase 3 DESTINY-Breast09 Clinical Trial

The approval is supported by positive findings from the randomized, 3-arm, multicenter, global phase 3 clinical trial, DESTINY-Breast09 (NCT04784715), which compared T-DXd with or without pertuzumab to taxane, trastuzumab (Herceptin; Genentech), and pertuzumab (THP).

The trial consisted of 1157 adults with HER2+ advanced or metastatic breast cancer who had not received prior chemotherapy or HER2-targeted therapy or had received neoadjuvant or adjuvant HER2-targeted therapy more than 6 months prior to the diagnosis of advanced or metastatic disease.²

Patients were randomly assigned to receive either T-DXd plus pertuzumab (n = 383), or THP (n = 387), or an investigational therapy (n = 387) via intravenous (IV) infusion every 3 weeks until unacceptable toxicity or disease progression. The major efficacy outcome measure was progression-free survival (PFS), and additional efficacy outcome measures were overall survival (OS) and confirmed objective response rate (ORR).^1,2

The findings demonstrated median PFS was about 40.7 months (95% CI: 36.5, not estimable [NE]) in the T-DXd plus pertuzumab arm and 26.9 months (95% CI: 21.8, NE) in the THP arm (HR: 0.56 [95% CI: 0.44, 0.71); P < .0001). Confirmed ORR was 87% (95% CI: 83, 90) and 81% (95% CI: 77, 85), respectively. Additionally, at the time of the PFS analysis, OS data was not mature, with approximately 16% (n = 126) of patients who died across both study arms in the overall population.¹

Other findings presented at the 2025 San Antonio Breast Cancer Symposium demonstrated the median time to deterioration in pain was not reached in either group, and the risk of pain worsening was comparable between arms (HR: 0.95; 95% CI, 0.74–1.21; maturity 35%).

On the QLQ-C30/-BR45 scales, patients who were treated with T-DXd and pertuzumab more often reported deterioration in nausea and vomiting, constipation, and appetite loss. In PRO-CTCAE assessments, nosebleeds and extremity swelling were less common with T-DXd plus pertuzumab than with THP. Further, most patients either maintained or improved physical function.³

The recommended T-DXd dose is 5.4 mg/kg for day 1 of cycle 1, followed by 840 mg of pertuzumab. For following cycles, the recommended T-DXd dose is 5.4 mg/kg, followed by 420 mg of intravenous pertuzumab every 3 weeks. The prescribing information includes warnings and precautions for neutropenia and left ventricular dysfunction.¹

REFERENCES

1. US Food & Drug Administration. FDA approves fam-trastuzumab deruxtecan-nxki with pertuzumab for unresectable or metastatic HER2-positive breast cancer. News release. December 15, 2025. Accessed December 15, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-fam-trastuzumab-deruxtecan-nxki-pertuzumab-unresectable-or-metastatic-her2-positive

2. Trastuzumab Deruxtecan (T-DXd) With or Without Pertuzumab Versus Taxane, Trastuzumab and Pertuzumab in HER2-positive Metastatic Breast Cancer (DESTINY-Breast09). ClinicalTrials.gov identifier: NCT04784715. Updated November 12, 2025. Accessed December 15, 2025. https://clinicaltrials.gov/study/NCT04784715

3. Gerlach A. Emerging Data from the DESTINY-Breast Trials Signal Shift in Standards of Care for HER2-Positive Breast Cancer. Pharmacy Times. December 11, 2025. Accessed December 15, 2025. https://www.pharmacytimes.com/view/emerging-data-from-the-destiny-breast-trials-signal-shift-in-standards-of-care-for-her2-positive-breast-cancer