FDA Approves Fam-Trastuzumab Deruxtecan-Nxki for Metastatic HER2-Positive Breast Cancer

The FDA approved fam-trastuzumab derextecan-nki (Enhertu; Daiichi Sankyo, Inc), a HER2-directed antibody-drug conjugate (ADC), in combination with pertuzumab as a first-line treatment for patients with unresectable or metastatic HER2-positive breast cancer.1

The approval was based on findings from the DESTINY-Breast09 phase 3 trial that showed fam-trastuzumab derextecan-nki (T-DXd) plus pertuzumab reduced the risk of disease progression or death by 44% when compared with other targeted therapies (trastuzumab, pertuzumab, and a taxane [THP]) in patients with HER2-positive metastatic breast cancer who had not received prior chemotherapy or HER2-targeted therapy or had received neoadjuvant HER2-targeted therapy more than six months before diagnosis. Patients treated with T-DXd plus pertuzumab experienced a median progression-free survival (PFS) of 40.7 months (95% CI, 36.5-not estimable [NE]) when compared with 26.9 months (95% CI, 21.8-NE) for patients treated with THP.

The FDA approved the HER2-directed DXd antibody-drug conjugate, fam-trastuzumab deruxtecan-nxki, for patients with unresectable or metastatic HER2-positive breast cancer. | Image Credit: aznan - stock.adobe.com .jpeg

The confirmed objective response rate (ORR) in the T-DXd plus pertuzumab was 87% (95% CI, 83-90) when compared with 81% ORR (95% CI, 77-85) with THP.

“With a median progression-free survival exceeding three years versus approximately two years with THP, trastuzumab deruxtecan combined with pertuzumab should become a new first-line standard of care in this setting,” said Sara Tolaney, MD, MPH, chief of the Division of Breast Oncology at the Dana-Farber Cancer Institute and principal investigator for the DESTINY-Breast09 trial, in a press release.

At the time of the PFS analysis, OS data were not mature, with 16% of patients who died across both study arms in the overall population.

The DESTINY-Breast09 Trial Safety & Efficacy

The DESTINY-Breast09 trial was a randomized 3-arm, multicenter, global trial with a population of 1157 adults with HER2-positive advanced or metastatic breast cancer. Patients were randomized 1:1:1 to receive either T-DXd plus pertuzumab, THP, or an investigational therapy.

The primary end points were PFS in the T-DXd monotherapy and combination arms assessed by the blinded independent central review. The secondary end points included investigator-assessed PFS, overall survival, ORR, duration of response, pharmacokinetics, and safety.

Safety of the combination therapy was evaluated in 381 patients. The most common adverse events occurred in more than 20% of patients and included laboratory abnormalities, decreased white blood cell count, decreased hemoglobin, and decreased lymphocyte count, amongst others. Serious adverse events occurred in 27% of patients receiving T-DXd plus pertuzumab and included diarrhea, pneumonia, febrile neutropenia, hypokalemia, vomiting, ILD, pulmonary embolism, and sepsis. Fatalities due to adverse events occurred in 3.5% of patients.

The recommended dose for the combination therapy is 5.4 mg/kg of T-DXd for cycle 1, day 1, followed by 840 mg of pertuzumab. For subsequent cycles, the recommended dosage is 5.4 mg/kg of T-DXd followed by 420 mg of pertuzumab by intravenous infusion every 3 weeks.

“Since its initial approval six years ago, ENHERTU has transformed the treatment of HER2-positive metastatic breast cancer,” said Ken Keller, global head of Oncology Business, and president, CEO, of Daiichi Sankyo, in a press release. “With this approval in the first-line metastatic setting, ENHERTU once again offers significant improvements in progression-free survival and has practice-changing potential when used in combination with pertuzumab.”

References

1. ENHERTU® plus pertuzumab approved in the US as first new treatment in more than a decade for first-line treatment of patients with HER2-positive metastatic breast cancer. News release. Daiichi Sankyo, Inc. December 15, 2025. Accessed December 15, 2025. https://daiichisankyo.us/press-releases/-/article/enhertu-plus-pertuzumab-approved-in-the-us-as-first-new-treatment-in-more-than-a-decade-for-first-line-treatment-of-patients-with-her2-positive-metastatic-breast-cancer-2