FDA Approves Enhertu for Two HER2-Positive Early Breast Cancer Indications, Moving the AstraZeneca-Daiichi ADC Into Curative-Intent Treatment

Overview

The U.S. Food and Drug Administration on May 15 approved AstraZeneca and Daiichi Sankyo’s antibody-drug conjugate Enhertu (fam-trastuzumab deruxtecan-nxki) for two new indications in HER2-positive early breast cancer, according to OncoDaily. The simultaneous neoadjuvant and adjuvant clearances move trastuzumab deruxtecan from the metastatic setting into curative-intent treatment for the first time, supported by the Phase III DESTINY-Breast11 and DESTINY-Breast05 trials.

What We Know

The two new indications

In the neoadjuvant setting, the agency cleared Enhertu “as neoadjuvant treatment of adult patients with HER2-positive (IHC 3+ or ISH+) Stage II or III breast cancer, as determined by an FDA-authorized test followed by a taxane, trastuzumab, and pertuzumab (THP),” according to AstraZeneca’s May 15 press release. The adjuvant approval covers “adult patients with HER2-positive (IHC 3+ or ISH+) breast cancer who have residual invasive disease following neoadjuvant trastuzumab (with or without pertuzumab) and taxane-based treatment,” per the same release.

Both indications use the same 5.4 mg/kg intravenous dose every three weeks: four cycles in the neoadjuvant setting and up to 14 cycles after surgery, as reported by OncoDaily.

DESTINY-Breast11: neoadjuvant

The neoadjuvant approval rests on DESTINY-Breast11, a randomized open-label Phase III trial that enrolled 927 patients with high-risk HER2-positive early breast cancer across three arms — T-DXd alone (286 patients), T-DXd followed by THP (321 patients), and dose-dense doxorubicin-cyclophosphamide followed by THP (320 patients), according to the Annals of Oncology publication. The T-DXd monotherapy arm was closed early in March 2024.

On the primary pathologic complete response endpoint, the T-DXd-THP regimen reached 67.3% (216 of 321 patients) versus 56.3% (180 of 320) for the standard ddAC-THP comparator, an absolute difference of 11.2 percentage points (95% CI 4.0% to 18.3%; P = 0.003), as reported in Annals of Oncology. The T-DXd monotherapy arm posted a pCR of 43.0%.

The improvement held across hormone-receptor subgroups: 61.4% versus 52.3% in HR-positive patients and 83.1% versus 67.1% in HR-negative patients, as reported by OncoDaily. The same source recorded a residual cancer burden of RCB 0 or I in 81.3% of T-DXd-THP patients versus 69.1% in the ddAC-THP arm.

Grade 3 or higher adverse events were lower with T-DXd-THP than with ddAC-THP — 37.5% versus 55.8% — and serious adverse events occurred in 10.2% versus 20.2% of patients, according to OncoDaily. All-grade left-ventricular dysfunction was 1.9% with T-DXd-THP compared with 9.0% on the anthracycline-containing regimen.

Prof. Nadia Harbeck, director of the Breast Center at LMU University Hospital in Munich and the trial’s principal investigator, said: “For patients with early breast cancer who are at high risk of recurrence, using the most effective treatment at the earliest opportunity is critical,” in remarks reported by MyChesCo.

DESTINY-Breast05: post-neoadjuvant

The adjuvant approval is based on DESTINY-Breast05, which randomized 1,635 patients with residual invasive HER2-positive disease after neoadjuvant therapy to receive either trastuzumab deruxtecan (818 patients) or the previous standard trastuzumab emtansine (T-DM1, 817 patients) for up to 14 cycles, according to the New England Journal of Medicine paper published February 26, 2026.

At three years, invasive disease-free survival was 92.4% with T-DXd versus 83.7% with T-DM1, a hazard ratio of 0.47 (95% CI, 0.34 to 0.66; P<0.001), as reported in NEJM. Disease events occurred in 51 patients (6.2%) on T-DXd compared with 102 patients (12.5%) on T-DM1. AstraZeneca’s press release summarized the result as a 53% reduction in the risk of invasive disease recurrence or death, per the May 15 announcement.

Safety signal: interstitial lung disease

The DESTINY-Breast05 publication flagged interstitial lung disease as the principal differentiator on safety. Adjudicated drug-related ILD occurred in 9.6% of T-DXd patients versus 1.6% on T-DM1, according to NEJM, with two ILD deaths in the T-DXd arm. Grade 3 or higher adverse events were comparable between arms at 50.6% versus 51.9%, and treatment-related death rates were 0.4% on T-DXd versus 0.6% on T-DM1, as reported by OncoDaily.

The U.S. label retains the existing boxed warning for interstitial lung disease and pneumonitis, with additional warnings for neutropenia and left ventricular dysfunction, per OncoDaily. AstraZeneca said “no new safety concerns were identified with ENHERTU in the DESTINY-Breast11 or DESTINY-Breast05 trials,” in the May 15 press release.

What We Don’t Know

The DESTINY-Breast11 publication reported an early event-free survival hazard ratio of 0.56 (95% CI 0.26 to 1.17) at 4.5% maturity, per Annals of Oncology, so the durability of the pCR benefit on long-term survival outcomes will require more follow-up. The NEJM DESTINY-Breast05 publication established a clear three-year IDFS benefit, but overall survival readouts and the longer-term ILD profile in routine clinical use have yet to mature. Pricing impact and U.S. reimbursement details for the expanded indications were not disclosed in the materials reviewed.

Dr. Susan Galbraith, executive vice president of oncology R&D at AstraZeneca, said: “The impressive pathologic response rates and favorable safety profile seen with ENHERTU followed by THP have the potential to transform treatment,” as reported by MyChesCo. Whether real-world ILD vigilance and patient selection can preserve those Phase III safety margins as the drug moves into broader curative-intent use will be a defining question for the next several years.