FDA Approves T-DXd for Early-Stage HER2+ Breast Cancer

The FDA has approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for the neoadjuvant treatment of adult patients with HER2-positive (immunohistochemistry [IHC] 3+ or in situ hybridization [ISH]+) stage II or III breast cancer, as determined by an FDA-authorized test, followed by taxane, trastuzumab (Herceptin), and pertuzumab (Perjeta; THP); and for the treatment of adult patients with HER2-positive (IHC 3+ or ISH+) breast cancer who have residual invasive disease after neoadjuvant HER2-targeted treatment.¹

Approval for the neoadjuvant indication was supported by data from the phase 3 DESTINY-Breast11 trial (NCT05113251), in which patients treated with T-DXd followed by THP (n = 321) achieved a pathological complete response (pCR) rate of 67.3% (95% CI, 61.9%-72.4%) compared with 56.3% (95% CI, 50.6%-61.8%) in patients treated with doxorubicin and cyclophosphamide followed by THP (ddAC-THP; n = 320; P = .003).

“Over these past several years, starting in 2019, the data with T-DXd have basically been a home run in all settings,” Rena D. Callahan, MD, said in an interview with OncLive®. “It has been tested in multiple metastatic settings, [such as] for HER2-positive and HER2-low [breast cancer]. Now we have data [showing] that we can move it into earlier-line disease. Our current standard of care [SOC] in the neoadjuvant setting for early-stage HER2-positive breast cancer is generally to a taxane plus carboplatin, trastuzumab, and pertuzumab. Some institutions may use a regimen with an anthracycline such as doxorubicin, though this is much less common. In DESTINY-Breast11, the SOC arm included a doxorubicin-containing regimen, which we don’t use as much, so that is [an aspect of the study] we need to consider. But T-DXd for 4 cycles followed by THP is potentially [a regimen] we can easily incorporate into practice.”

The adjuvant indication was backed by data from the phase 3 DESTINY-Breast05 trial (NCT04622319), which showed that T-DXd (n = 818) produced a 3-year invasive disease-free survival (iDFS) rate of 92.4% (95% CI, 89.7%-94.4%) vs 83.7% (95% CI, 80.2%-86.7%) for ado-trastuzumab emtansine (Kadcyla; T-DM1; n = 817; HR, 0.47; 95% CI, 0.34-0.66; P < .0001).

What was the design of the DESTINY-Breast11 Trial?

DESTINY-Breast11 is a global, multicenter, randomized, open-label phase 3 trial evaluating neoadjuvant T-DXd alone or followed by THP vs ddAC-THP in patients with high-risk, locally advanced or inflammatory HER2-positive early breast cancer.²

Eligible patients were required to be at least 18 years of age and have an ECOG performance status of 0 or 1, adequate organ function, and a left ventricular ejection fraction of at least 50%. Patients also needed confirmed HER2-positive disease based on central laboratory testing.

A total of 927 patients were randomly assigned 1:1:1 to receive:

• 8 cycles of T-DXd monotherapy (n = 286),
• 4 cycles of T-DXd followed by 4 cycles of THP, or
• 4 cycles of ddAC followed by 4 cycles of THP

The primary end point was pCR rate. Secondary end points included event-free survival, iDFS, overall survival, and safety.

Enrollment to the T-DXd monotherapy arm was closed early based on a prior efficacy evaluation, as recommended by an independent data monitoring committee.

How was DESTINY-Breast05 conducted?

The global, multicenter, randomized, open-label trial enrolled patients with residual invasive disease in the breast and/or axillary lymph nodes after neoadjuvant chemotherapy with a HER2-directed therapy.³ High-risk disease prior to neoadjuvant therapy, defined as inoperable early breast cancer or operable early breast cancer with axillary node–positive disease after neoadjuvant therapy, was required. Other key inclusion criteria comprised centrally confirmed HER2-positive disease and an ECOG performance status of 0 or 1.

Investigators randomly assigned patients in a 1:1 fashion to receive T-DXd at 5.4 mg/kg every 3 weeks for 14 cycles or T-DM1 at 3.6 mg/kg every 3 weeks for 14 cycles.

Concomitant adjuvant endocrine therapy was allowed per local practice protocols. Additionally, radiotherapy could be initiated concurrently with study therapy or completed prior to the initiation of study therapy, if given per investigator discretion. An interstitial lung disease (ILD) monitoring progam was required for patients who received radiotherapy.

The primary end point was iDFS, and DFS was a key secondary end point. Other secondary end points included OS, distant recurrence–free interval, brain metastasis–free interval, and safety.

What safety information is important to know regarding T-DXd in early-stage HER2-positive breast cancer?

The prescribing information for T-DXd features a boxed warning for interstitial lung disease and pneumonitis.¹ It also includes warnings and precautions for neutropenia and left ventricular dysfunction.

In the neoadjuvant setting, T-DXd is recommended at 5.4 mg/kg every 3 weeks for 4 cycles, followed by THP for 4 cycles. Adjuvant T-DXd is recommended at 5.4 mg/kg every 3 weeks for a maximum of 14 cycles, unless there is disease recurrence or unacceptable toxicity.

References

1. FDA approves two separate indications for fam-trastuzumab deruxtecan-nxki in HER2-positive early-stage breast cancer. FDA. May 15, 2026. Accessed May 15, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-two-separate-indications-fam-trastuzumab-deruxtecan-nxki-her2-positive-early-stage
2. Harbeck N, Modi S, Pusztai L, et al. Neoadjuvant trastuzumab deruxtecan alone or followed by paclitaxel, trastuzumab, and pertuzumab for high-risk HER2-positive early breast cancer (DESTINY-Breast11): a randomised, open-label, multicentre, phase III trial. Ann Oncol. 2026;37(suppl 2):166-179. doi:10.1016/j.annonc.2025.10.019
3. Geyer CE, Park YH, Shao Z, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with high-risk human epidermal growth factor receptor 2–positive (HER2+) primary breast cancer (BC) with residual invasive disease after neoadjuvant therapy (tx): interim analysis of DESTINY-Breast05. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA1.