FDA approves AstraZeneca, Daiichi’s Enhertu for two earlier settings for HER2 breast cancer

Edited by Robert McTiernan··4 min read

AstraZeneca (LSE/STO/NYSE: AZN) and Daiichi Sankyo have received US FDA approval for Enhertu (trastuzumab deruxtecan) in two new indications. These cover HER2-positive early breast cancer — one before surgery and one after — marking the drug’s first entry into curative-intent treatment settings after establishing itself across multiple metastatic indications.

The FDA approved Enhertu for the neoadjuvant treatment of adult patients with HER2-positive Stage II or Stage III breast cancer, administered as Enhertu followed by a taxane, trastuzumab, and pertuzumab (THP). A separate approval covers the adjuvant setting, where Enhertu is indicated for patients with HER2-positive breast cancer who have residual invasive disease following trastuzumab-based and taxane-based neoadjuvant therapy. Both submissions were reviewed under Project Orbis, a framework enabling concurrent international regulatory review. Enhertu is a HER2-directed antibody-drug conjugate (ADC) that delivers a topoisomerase I inhibitor payload, DXd, to HER2-expressing tumor cells via a cleavable linker, combining targeted binding with intracellular cytotoxic activity.

Clinical evidence: DESTINY-Breast11 and DESTINY-Breast05

The neoadjuvant approval rests on data from DESTINY-Breast11, a randomized, open-label Phase III trial enrolling 927 patients with high-risk HER2-positive early-stage breast cancer. The primary endpoint was pathologic complete response (pCR), defined as no residual invasive cancer in breast tissue or lymph nodes at surgery. Enhertu followed by THP achieved a pCR rate of 67.3%, compared with 56.3% for dose-dense doxorubicin and cyclophosphamide followed by THP (ddAC-THP), a difference of 11.2 percentage points (95% CI 3.9–18.3; p=0.003). Results were published in Annals of Oncology. The US FDA explicitly noted that EFS and OS were not statistically powered/controlled in the neoadjuvant study.

The adjuvant approval is supported by DESTINY-Breast05, a randomized Phase III trial of 1,635 patients comparing Enhertu directly against trastuzumab emtansine (T-DM1) in patients with residual invasive disease following neoadjuvant therapy. Enhertu reduced the risk of invasive disease recurrence or death by 53% relative to T-DM1 (HR 0.47; 95% CI 0.34–0.66; p<0.0001). At three years, 92.4% of patients in the Enhertu arm remained alive and free of invasive disease, versus 83.7% in the T-DM1 arm. Those results appeared in the New England Journal of Medicine.

No new safety signals were identified in either trial. In DESTINY-Breast11, Enhertu followed by THP showed comparable rates of drug-related adverse events and interstitial lung disease (ILD)/pneumonitis relative to ddAC-THP, with lower rates of Grade 3 or higher adverse events and hematological toxicities. In DESTINY-Breast05, adjudicated drug-related ILD/pneumonitis occurred in 9.6% of patients in the Enhertu arm versus 1.6% in the T-DM1 arm, though the majority of events were low grade. There were seven Grade 3 events and two Grade 5 (fatal) ILD events in the Enhertu arm, a finding that will require monitoring in clinical practice given the broader patient population now eligible for treatment.

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Mechanistic rationale in early-stage HER2-positive breast cancer

Enhertu’s structure — a HER2 monoclonal antibody conjugated to multiple DXd topoisomerase I inhibitor payloads via tetrapeptide-based cleavable linkers — enables targeted delivery of cytotoxic activity to HER2-overexpressing cells while limiting systemic exposure. A high drug-to-antibody ratio relative to earlier-generation ADCs is thought to contribute to its activity, including a potential bystander effect on neighboring tumor cells with lower HER2 expression. In the early-stage context, where the treatment goal is eradication of residual or micrometastatic disease rather than disease control, this payload potency may underpin the magnitude of benefit observed in both trials.

Competitive context: displacing T-DM1 in the adjuvant setting

In the adjuvant residual-disease setting, Enhertu is now positioned directly against ado-trastuzumab emtansine, Roche’s Kadcyla (T-DM1), which received FDA approval in 2019 based on the KATHERINE trial and had been the standard of care for this population. DESTINY-Breast05 was designed as a head-to-head comparison in this identical patient population, and the results suggest Enhertu produces superior outcomes on the primary invasive disease-free survival endpoint. In the neoadjuvant setting, the relevant comparator is the established TCHP regimen — carboplatin or anthracycline-based chemotherapy combined with dual HER2 blockade using trastuzumab and pertuzumab — against which Enhertu-based therapy demonstrated an improvement in pCR rate. Based on DESTINY-Breast05 data, trastuzumab deruxtecan has already been incorporated into NCCN Clinical Practice Guidelines as a Category 1 recommended treatment for HER2-positive early breast cancer with residual disease and high recurrence risk.

Following the approvals, AstraZeneca will pay Daiichi Sankyo USD 155 million in milestone payments covering both indications. US sales of Enhertu are recognized by Daiichi Sankyo under the terms of the companies’ 2019 collaboration agreement.

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