SUMMARY: The FDA on May 15, 2026, approved fam-Trastuzumab deruxtecan-nxki (T-DXd, ENHERTU®), followed by a taxane, Trastuzumab, and Pertuzumab (THP) for the 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. FDA also approved two companion diagnostic devices, the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and the VENTANA HER2 Dual ISH DNA Probe Cocktail, both for identifying HER2-positive (IHC3+ or ISH+) patients for treatment with T-DXd, consistent with the approved drug labeling.
Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 321,910 new cases of female breast cancer will be diagnosed in 2026, and about 42,140 women will die of the disease, largely due to metastatic recurrence.
Human Epidermal growth factor Receptor 2–positive (HER2+) breast cancer accounts for approximately 15%-20% of all breast malignancies and historically has been associated with aggressive disease biology. Over the past decade, the integration of dual HER2 blockade with Trastuzumab (HERCEPTIN®) and Pertuzumab (PERJETA®) alongside cytotoxic chemotherapy has substantially improved outcomes. In patients with Stage II–III disease, neoadjuvant therapy has become the standard treatment approach, enabling early assessment of treatment response and guiding postoperative therapy.
The present FDA approval was based on DESTINY-Breast11 trial, which explored whether Antibody-Drug Conjugate (ADC)-based therapy, could improve efficacy, while reducing the toxicity burden associated with traditional Anthracycline and Carboplatin containing regimens.
Trial Design and Patient Population
DESTINY-Breast11 was a global, multicentre, open-label Phase III study conducted across 147 sites in 18 countries. The trial enrolled patients with high-risk, locally advanced, or inflammatory HER2-positive early-stage breast cancer, defined by lymph node-positive disease (N1-3) or primary tumors staged T3-4.
A total of 927 female patients were randomized across three treatment arms:
Patients assigned to the investigational combination arm received T-DXd 5.4 mg/kg intravenously every 3 weeks for four cycles followed by Paclitaxel 80 mg/m² weekly, Trastuzumab 6 mg/kg every 3 weeks and Pertuzumab 840 mg loading dose followed by 420 mg every 3 weeks for 4 cycles (T-DXd followed by THP; N=321)
The comparator arm received Dose-dense Doxorubicin 60 mg/m² every 2 weeks, Cyclophosphamide 600 mg/m² every 2 weeks for four cycles, followed by Paclitaxel 80 mg/m² weekly with concurrent Trastuzumab 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks Pertuzumab 840 mg loading dose, followed by 420 mg every 3 weeks for 4 cycles. (Dose-dense AC followed by THP (ddAC-THP; N=320)
The T-DXd monotherapy arm evaluated eight cycles of T-DXd at 5.4 mg/kg every 3 weeks; however, enrollment into this cohort was discontinued early following an Independent Data Monitoring Committee (IDMC) review (T-DXd monotherapy; N=286)
Median patient age was 50 years, 88% had an ECOG performance status of 0, and approximately 72% had Hormone Receptor (HR)-positive disease. HER2 expression was strongly positive in most patients, with 88% classified as IHC 3+.
Primary Endpoint Met with Significant pCR Improvement
The Primary endpoint was centrally assessed pathological Complete Response (pCR), defined as ypT0/is ypN0 following surgery.
Results demonstrated 67.3% pCR rate with T-DXd-THP vs 56.3% with ddAC-THP. This translated into an absolute improvement of 11% (95% CI: 4.0%-18.3%; P=0.003). Importantly, benefit was observed across hormone receptor subgroups:
- HR-positive disease: 61.4% vs 52.3%
- HR-negative disease: 83.1% vs 67.1%
The magnitude of benefit in the HR-negative cohort was particularly notable, with an absolute pCR improvement exceeding 16%. Investigators also reported improved Residual Cancer Burden (RCB) outcomes with T-DXd-THP, with RCB-0/I rates reaching 81.3% compared with 69.1% for the standard regimen.
Early EFS Signal and Safety Advantages
While Event-Free Survival (EFS) data remain immature, early findings favored the investigational approach. At 4.5% maturity, the Hazard Ratio for EFS comparing T-DXd-THP with ddAC-THP was 0.56 (95% CI: 0.26-1.17). Equally important for clinical practice, the ADC-based regimen demonstrated a more favorable toxicity profile than the anthracycline-containing comparator.
Grade ≥3 adverse events occurred in 37.5% of patients receiving T-DXd-THP vs 55.8% with ddAC-THP. Serious adverse events were also reduced and occurred in 10.6% with T-DXd-THP vs 20.2% with ddAC-THP. Cardiac toxicity rates were lower with the investigational regimen, with all-grade left ventricular dysfunction reported in only 1.3% of patients receiving T-DXd-THP compared with 6.1% in the ddAC-THP arm.
Given ongoing concerns regarding anthracycline-associated cardiotoxicity, these findings may be particularly relevant when selecting therapy for patients with baseline cardiovascular risk factors.
Interstitial lung disease (ILD)/pneumonitis, an established toxicity associated with T-DXd, was infrequent and comparable across treatment groups, occurring in approximately 4%-5% of patients. Three treatment-related deaths were reported overall.
Closure of the T-DXd Monotherapy Arm
Although the T-DXd monotherapy arm passed a predefined futility analysis, enrollment was halted early after IDMC review. Investigators cited multiple contributing factors, including lower pCR rates, reduced likelihood of superiority over standard therapy, and timing considerations surrounding surgery. Observed pCR rates were 43.0% with T-DXd alone, 67.3% with T-DXd-THP, and 56.3% with ddAC-THP. Interpretation of the monotherapy cohort was further complicated by protocol-directed transitions to local standard-of-care therapy after enrollment closure.
Clinical Implications
DESTINY-Breast11 introduces compelling evidence supporting ADC-based neoadjuvant therapy in high-risk HER2-positive early breast cancer. The combination of T-DXd followed by THP not only improved pCR rates compared with an anthracycline-based standard but also reduced severe toxicities and cardiac adverse events.
The findings are especially notable given the trial’s predominantly HR-positive and high-risk patient population, where pCR rates are historically more difficult to achieve. As clinicians continue to balance efficacy against long-term toxicity risks, DESTINY-Breast11 raises the possibility that Anthracycline- and Carboplatin-free regimens may emerge as a new treatment paradigm for selected patients with HER2-positive early-stage disease. Longer follow-up will be essential to determine whether the substantial pCR gains observed in DESTINY-Breast11 ultimately translate into durable improvements in Event-Free and Overall Survival.
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. Harbeck N, Modi S, Pusztai L, et al., for the DESTINY-Breast11 Trial Investigators. Annals of Oncology, 2025; 37:166-179.
