On December 15, 2025, the Food and Drug Administration approved fam-trastuzumab deruxtecan-nxki in combination with pertuzumab for the first-line treatment of adults with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer as determined by an FDA-approved test.

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 fam-trastuzumab deruxtecan-nxki in combination with pertuzumab. 

Full prescribing information for fam-trastuzumab deruxtecan-nxki will be posted on Drugs@FDA. 

Efficacy and Safety

Efficacy was evaluated in DESTINY-Breast09 (NCT04784715), a randomised, three-arm, multicenter, global trial that enrolled 1157 adults with HER2-positive 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 six months before the diagnosis of advanced or metastatic disease. A single line of prior endocrine therapy was permitted for advanced or metastatic breast cancer. Patients were randomised (1:1:1) to receive either, fam-trastuzumab deruxtecan-nxki 5.4 mg/kg plus pertuzumab (N=383), or THP (taxane [docetaxel or paclitaxel], trastuzumab, and pertuzumab) (N=387), or an investigational therapy (N=387) by intravenous infusion every three weeks until unacceptable toxicity or disease progression.

The major efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR) based on RECIST v1.1. Additional efficacy outcome measures were overall survival (OS) and confirmed objective response rate (ORR) assessed by BICR. Median PFS was 40.7 months (95% CI: 36.5, not estimable [NE]) in the fam-trastuzumab deruxtecan-nxki plus pertuzumab arm and 26.9 months (95% CI: 21.8, NE) in the THP arm (Hazard ratio 0.56 [95% CI: 0.44, 0.71); p-value <0.0001). Confirmed ORR was 87% (95% CI: 83, 90) and 81% (95% CI: 77, 85) in the respective arms. At the time of the PFS analysis, OS data was not mature with 126 (16%) of patients who died across both study arms in the overall population.
The prescribing information includes warnings and precautions for neutropenia and left ventricular dysfunction.

The recommended fam-trastuzumab deruxtecan-nxki dose for Cycle 1, Day 1 is 5.4 mg/kg, followed by pertuzumab 840 mg. For subsequent cycles, the recommended fam-trastuzumab deruxtecan-nxki dose is 5.4 mg/kg, followed by pertuzumab 420 mg by intravenous infusion every three weeks.

Expedited Programs

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with Switzerland’s Swissmedic (SMC). The application reviews are ongoing at the other regulatory agencies.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review. Fam-trastuzumab deruxtecan-nxki in combination with pertuzumab was granted breakthrough designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.

Source: FDA