FDA Approves T-DXd Plus Pertuzumab as a First-Line Standard in HER2+ Breast Cancer

The FDA has approved T-DXd (Enhertu) plus pertuzumab as first-line therapy for unresectable or metastatic HER2-positive breast cancer, the first new option in over a decade. In the Phase III DESTINY-Breast09 trial, the regimen reduced progression or death by 44%, extending median progression-free survival to 40.7 months versus 26.9 months with standard THP.

The US Food and Drug Administration has approved fam-trastuzumab deruxtecan-nxki (Enhertu), in combination with pertuzumab (Perjeta) for the first-line treatment of adults with unresectable or metastatic HER2-positive breast cancer, as determined by an FDA-approved test. The decision marks the first new first-line option in more than a decade for this patient population and reflects a meaningful advance in disease control for HER2-driven metastatic disease.

The approval is based on results from the global Phase III DESTINY-Breast09 trial, which demonstrated a substantial progression-free survival advantage for Enhertu plus pertuzumab compared with the long-standing standard regimen of taxane, trastuzumab, and pertuzumab, THP. In the study, the combination reduced the risk of disease progression or death by 44% versus THP, corresponding to a hazard ratio of 0.56 with a 95% confidence interval of 0.44 to 0.71 and a p value below 0.0001. Median progression-free survival reached 40.7 months with Enhertu plus pertuzumab compared with 26.9 months for THP, translating into more than three years without disease progression for many patients.

DESTINY-Breast09 enrolled 1,157 adults with HER2-positive advanced or metastatic breast cancer who had not received prior chemotherapy or HER2-targeted therapy for metastatic disease, or who had completed neoadjuvant or adjuvant HER2-directed therapy more than six months before recurrence. Patients were randomized 1:1:1 to receive Enhertu plus pertuzumab, THP, or an investigational arm that remains blinded. Progression-free survival was assessed by blinded independent central review according to RECIST v1.1 criteria, with overall survival and objective response rate as key secondary endpoints.

“Trastuzumab deruxtecan plus pertuzumab is the only 1st-line treatment approved in more than a decade to demonstrate a statistically significant improvement in progression-free survival over the current standard regimen for patients with HER2-positive metastatic breast cancer. With a median progression-free survival exceeding three years, versus approximately two years with THP, trastuzumab deruxtecan combined with pertuzumab should become a new 1st-line standard of care in this setting,” said Dr. Sara Tolaney, MD, Chief of the Division of Breast Oncology, Dana-Farber Cancer Institute and principal investigator for the trial.  

Beyond progression-free survival, the combination also delivered a high confirmed objective response rate. In DESTINY-Breast09, confirmed ORR reached 87% with Enhertu plus pertuzumab compared with 81% for THP. Overall survival data remain immature, with 16% of patients having died across both arms at the time of the progression-free survival analysis. Importantly for clinicians, the progression-free survival benefit was consistent across predefined subgroups, including hormone receptor status and PIK3CA mutation status.

The safety profile of Enhertu plus pertuzumab was consistent with the known toxicities of each agent, with no new safety signals identified in the combination arm. The prescribing information includes warnings and precautions for neutropenia and left ventricular dysfunction, reflecting established risks associated with HER2-directed therapies and cytotoxic payloads.

Dave Fredrickson, Executive Vice President, Oncology Haematology Business Unit, AstraZeneca, said: “With this approval, we are bringing Enhertu to the earliest setting for HER2-positive metastatic breast cancer, where optimising efficacy has an important impact on long‑term outcomes. The treatment approach with Enhertu plus pertuzumab in DESTINY-Breast09 sets a new benchmark of more than three years without disease progression or death for patients in this setting.”

Enhertu is a HER2-directed DXd antibody drug conjugate discovered by Daiichi Sankyo and jointly developed and commercialized with AstraZeneca. The FDA review was conducted under the Real-Time Oncology Review program and Project Orbis, facilitating rapid assessment and parallel review by international regulatory partners. 

Companion diagnostic approval accompanied the therapeutic decision, with the PATHWAY anti-HER-2/neu Rabbit Monoclonal Primary Antibody and HER2 Dual ISH DNA Probe Cocktail cleared to identify eligible HER2-positive patients.

Dosing recommendations specify fam-trastuzumab deruxtecan-nxki at 5.4 mg/kg by intravenous infusion every three weeks, combined with pertuzumab, with an initial loading dose of 840 mg followed by 420 mg in subsequent cycles.