Trastuzumab Deruxtecan Approved for Early-stage Breast Cancer

The FDA has approved fam-trastuzumab deruxtecan-nxki for neoadjuvant or adjuvant treatment of HER2-positive early-stage breast cancer.

The U.S. Food and Drug Administration (FDA) approved fam-trastuzumab deruxtecan-nxki (T-DXd, Enhertu) for two indications in adult patients with human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer:

T-DXd was approved for use before surgery (neoadjuvant treatment) and followed by neoadjuvant treatment with the THP regimen, consisting of a taxane chemotherapy drug, trastuzumab (Herceptin), and pertuzumab (Perjeta), for adults with HER2-positive, stage 2 or 3 breast cancer.
T-DXd was also approved for use after surgery (adjuvant treatment) for adults with HER2-positive breast cancer who have residual invasive disease after neoadjuvant treatment with trastuzumab (with or without pertuzumab) and taxane-based therapy. Residual invasive disease refers to cancer cells that remain in the breast or regional lymph nodes after neoadjuvant treatment. In this case, residual invasive disease indicates that neoadjuvant therapy did not eradicate the tumor.

In both indications, high expression of HER2 has to be confirmed at the protein level by immunohistochemistry or at the gene level by in situ hybridization through one of the two companion diagnostic devices included in the approval.

T-DXd is an antibody-drug conjugate (ADC) comprised of a monoclonal antibody targeting HER2 (trastuzumab) and the cytotoxic drug deruxtecan (DXd). The HER2-targeted antibody enables the ADC to latch onto HER2-expressing cells, after which the complex enters the cells and then releases the payload drug (DXd) inside the targeted cells to kill them. In addition to directly killing HER2-positive cells, T-DXd elicits a “bystander effect” since the membrane-permeable payload diffuses out of the dying cells and kills adjacent cancer cells regardless of their HER2 expression levels.

Pertuzumab is another HER2-targeted therapy that works through a slightly different mechanism than trastuzumab. Dual HER2 blockade with pertuzumab and trastuzumab affords a stronger pathway inhibition.

T-DXd was initially approved for the treatment of metastatic HER2-positive breast cancer. With the new approval, T-DXd treatment may now be used for early-stage disease.

The neoadjuvant indication was based on results from DESTINY-Breast11, a randomized, three-arm, open-label, multicenter phase III study that enrolled 927 participants to evaluate the efficacy of T-DXd followed by THP in adult patients with HER2-positive, high-risk, early-stage breast cancer. Patients were randomly assigned (1:1:1) to receive neoadjuvant treatment with one of the following:

T-DXd followed by THP (T-DXd-THP arm, N=321);
chemotherapy followed by THP (ddAC-THP arm, N=320); or
an additional investigational therapy (N=286).

There was a statistically significant difference in the pathological complete response rate, defined as the absence of invasive cancer in the breast and axillary lymph nodes following surgery, between the T-DXd-THP arm (67.3%) and the ddAC-THP arm (56.3%).

The adjuvant indication was based on results from DESTINY-Breast05, a randomized, two-arm, open-label, multicenter phase III study that enrolled 1,635 participants to assess efficacy of T-DXd for adjuvant treatment in adult patients with HER2-positive breast cancer who had residual invasive disease after neoadjuvant therapy. Patients were randomly assigned (1:1) to receive either T-DXd (N=818) or the HER2-targeted ADC trastuzumab emtansine (T-DM1, N=817).

Among patients in the T-DXd arm, 92.4% had not experienced invasive disease recurrence, development of invasive cancer in the opposite breast, or death within three years of follow up, as compared with 83.7% of patients in the T-DM1 arm. This corresponded to a 53% lower risk of invasive disease recurrence or death with T-DXd treatment.

Patients treated with adjuvant T-DXd were also 53% less likely than those treated with T-DM1 to have experienced noninvasive or localized disease recurrence or death within three years.

The prescribing information for T-DXd includes a boxed warning for interstitial lung disease and pneumonitis.

The recommended dose of T-DXd for neoadjuvant treatment is 5.4 mg/kg every three weeks for four cycles, followed by the THP regimen for four cycles. The recommended dose of T-DXd for adjuvant treatment is 5.4 mg/kg every three weeks for a maximum of 14 cycles or until disease recurrence or unacceptable toxicity.

Breast cancer is the most common cancer diagnosed in women excluding skin cancers, and it is the second-leading cause of cancer-related death in women in the United States. Breast cancers are classified into subtypes based on whether they express certain cell surface markers, including hormone receptor (HR) and HER2. Thirteen percent of breast cancers are HER2-positive. The National Cancer Institute estimated that 321,910 individuals would be diagnosed with breast cancer and 42,140 patients would die of the disease in the United States in 2026. 

The FDA rendered its decision on May 15, 2026. Check this resource for updated information on all therapeutics regulated by the FDA.