ENHERTU® (fam-trastuzumab deruxtecan-nxki) granted Priority Review in the US as post-neoadjuvant treatment for patients with HER2-positive early breast cancer

Based on DESTINY-Breast05 Phase III trial results which showed ENHERTU reduced the risk of invasive disease recurrence or death by 53% compared with T-DM1

If approved, AstraZeneca and Daiichi Sankyo’s ENHERTU has the potential to become a new standard of care in this early breast cancer setting

WILMINGTON, Del.--(BUSINESS WIRE)--AstraZeneca and Daiichi Sankyo’s supplemental Biologics License Application (sBLA) for ENHERTU^® (fam-trastuzumab deruxtecan-nxki) has been accepted and granted Priority Review in the US for the treatment of adult patients with HER2-positive breast cancer who have residual invasive disease after neoadjuvant HER2-targeted treatment.

The Food and Drug Administration (FDA) grants Priority Review to applications for medicines that, if approved, would offer significant improvements over available treatment options by demonstrating safety or efficacy improvements, preventing serious conditions or enhancing patient compliance. The Prescription Drug User Fee Act date, the FDA action date for its regulatory decision, is anticipated during the third quarter of 2026.

ENHERTU was recently granted Breakthrough Therapy Designation (BTD) by the FDA in this setting. BTD accelerates the development and regulatory review of potential new medicines intended to treat a serious condition and address a significant unmet medical need.

The sBLA also is being reviewed under Project Orbis, which provides a framework for concurrent submission and review of oncology medicines among participating international partners.

Around one in five breast cancers are considered HER2-positive, a subtype that is often associated with aggressive disease and poor prognosis.^1-3 Currently, approximately half of patients with HER2-positive early breast cancer have residual disease following neoadjuvant treatment (before surgery), putting them at an increased risk of disease recurrence.^4-9 Despite receiving additional treatment in the post-neoadjuvant setting with current standards of care, some patients still experience tumor progression to metastatic disease, where the five-year survival rate drops from nearly 90% to approximately 30%.^10,11

Susan Galbraith, Executive Vice President, Oncology Haematology R&D, AstraZeneca, said: “While there has been significant progress in treating HER2-positive early breast cancer, managing patients at a higher risk of recurrence remains challenging. With this Priority Review, we move closer to bringing ENHERTU to the post-neoadjuvant setting, offering more patients the opportunity for sustained long-term outcomes and a potential path to cure.”

Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: “For patients with residual invasive disease after neoadjuvant therapy, identifying additional treatments following surgery is critical to help further reduce the risk of recurrence and help prevent progression to metastatic disease. This Priority Review reinforces the potential of ENHERTU to become a new standard of care for HER2-positive early breast cancer based on the results of DESTINY-Breast05.”

The sBLA is based on data from the DESTINY-Breast05 Phase III trial presented at the European Society for Medical Oncology (ESMO) 2025 Congress and subsequently published in The New England Journal of Medicine.¹

In the trial, ENHERTU significantly reduced the risk of invasive disease recurrence or death (invasive disease-free survival [IDFS]) by 53% compared with trastuzumab emtansine (T-DM1; based on a hazard ratio [HR] of 0.47; 95% confidence interval [CI] 0.34-0.66; p<0.0001) as a post-neoadjuvant treatment for patients with HER2-positive breast cancer. ENHERTU demonstrated a three-year IDFS rate of 92.4% compared with 83.7% with T-DM1. IDFS findings were consistent across all prespecified subgroups.

ENHERTU also significantly reduced the risk of disease recurrence or death (disease-free survival [DFS]), a key secondary endpoint, by 53% versus T-DM1 (HR 0.47; 95% CI 0.34-0.66; p<0.0001). Further, ENHERTU lowered the risk of distant disease recurrence (distant recurrence-free interval) by 51% and the risk of brain metastases (brain metastasis-free interval) by 36% compared with T-DM1 (HR 0.64; 95% CI 0.35-1.17).

The safety profile of ENHERTU observed in DESTINY-Breast05 was consistent with its known profile with no new safety concerns identified.

Regulatory submissions for ENHERTU based upon DESTINY-Breast05 are also under review in the EU and Japan. In addition, an sBLA for ENHERTU followed by paclitaxel, trastuzumab and pertuzumab (THP) currently is under review in the US for the neoadjuvant treatment of patients with HER2-positive early breast cancer based on results from the DESTINY-Breast11 trial.

ENHERTU is already approved in more than 90 countries as a treatment for patients with HER2-positive metastatic breast cancer.

ENHERTU is a specifically engineered HER2-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialized by AstraZeneca and Daiichi Sankyo.

INDICATION AND IMPORTANT SAFETY INFORMATION FOR ENHERTU^® (fam-trastuzumab deruxtecan-nxki)

Indications
ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated:

• HER2-Positive Metastatic Breast Cancer
  • In combination with pertuzumab as first-line treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer, as determined by an FDA-approved test
  • As monotherapy for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or, in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy
    
    
• HER2-Low and HER2-Ultralow Metastatic Breast Cancer
  • As monotherapy for the treatment of adult patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on one or more endocrine therapies in the metastatic setting
  • As monotherapy for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy
    
    
• HER2-Mutant Unresectable or Metastatic Non-Small Cell Lung Cancer (NSCLC)
  • As monotherapy for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy
    
    This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
    
    
• HER2-Positive Locally Advanced or Metastatic Gastric Cancer
  • As monotherapy for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen
    
    
• HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors
  • As monotherapy for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options
    
    This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Important Safety Information

Contraindications
None.

Warnings and Precautions
Interstitial Lung Disease / Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU monotherapy or ENHERTU in combination with pertuzumab. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose 1 level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
ENHERTU as Monotherapy
In patients treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Median time to first onset was 5.5 months (range: 0.9 to 31.5). Fatal outcomes due to ILD and/or pneumonitis occurred in 0.9% of patients treated with ENHERTU.

ENHERTU in Combination with Pertuzumab
In patients treated with ENHERTU 5.4 mg/kg in combination with pertuzumab (N=431), ILD occurred in 12% of patients. Median time to first onset was 8.0 months (range: 0.6 to 33.8). Fatal outcomes due to ILD and/or pneumonitis occurred in 0.5% of patients treated with ENHERTU in combination with pertuzumab.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21).

Neutropenia
Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU monotherapy or ENHERTU in combination with pertuzumab. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L), interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L), interrupt ENHERTU until resolved to Grade 2 or less, then reduce dose by 1 level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by 1 level.

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
ENHERTU as Monotherapy
In patients treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients. Nineteen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 939). Febrile neutropenia was reported in 1.2% of patients.

ENHERTU in Combination with Pertuzumab
In patients treated with ENHERTU 5.4 mg/kg in combination with pertuzumab (N=431), decreased neutrophil count occurred in 79% of patients. Median time to first onset was 22 days (range: 5 to 994). Twenty-nine percent had Grade 3 or 4 decreased neutrophil count. Febrile neutropenia was reported in 2.6% of patients.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

Left Ventricular Dysfunction
Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
ENHERTU as Monotherapy
In patients treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 4.6% of patients, of which 0.6% were Grade 3 or 4.

ENHERTU in Combination with Pertuzumab
In patients treated with ENHERTU 5.4 mg/kg in combination with pertuzumab (N=431), LVEF decrease was reported in 11% of patients, of which 2.1% were Grade 3 or 4.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF.

Embryo-Fetal Toxicity
ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose of ENHERTU.

Additional Dose Modifications
Thrombocytopenia
For Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then reduce dose by 1 level.

Adverse Reactions
HER2-Positive, HER2-Low, and HER2-Ultralow Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
ENHERTU as Monotherapy
The pooled safety population reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 2233 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast02, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Breast06, DESTINY-Lung01, DESTINY-Lung02, DESTINY-CRC02, and DESTINY-PanTumor02. Among these patients, 67% were exposed for >6 months and 38% were exposed for >1 year. In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count (73%), nausea (72%), decreased hemoglobin (67%), decreased neutrophil count (65%), decreased lymphocyte count (60%), fatigue (55%), decreased platelet count (48%), increased aspartate aminotransferase (46%), increased alanine aminotransferase (44%), increased blood alkaline phosphatase (39%), vomiting (38%), alopecia (37%), constipation (32%), decreased blood potassium (32%), decreased appetite (31%), diarrhea (30%), and musculoskeletal pain (24%).

ENHERTU in Combination with Pertuzumab
The pooled safety population reflects exposure to ENHERTU 5.4 mg/kg in combination with pertuzumab intravenously every 3 weeks in 431 patients in DESTINY-Breast07 (n=50), and DESTINY-Breast09 (n=381). Among these patients, 86% were exposed for >6 months and 73% were exposed for >1 year. In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count (86%), decreased hemoglobin (80%), decreased neutrophil count (79%), nausea (74%), increased alanine aminotransferase (65%), diarrhea (64%), increased aspartate aminotransferase (63%), decreased lymphocyte count (61%), decreased platelet count (55%), increased blood alkaline phosphatase (54%), decreased blood potassium (54%), fatigue (53%), alopecia (48%), vomiting (46%), upper respiratory tract infection (32%), constipation (31%), decreased appetite (31%), decreased weight (28%), musculoskeletal pain (23%), abdominal pain (22%), and increased blood bilirubin (23%).

HER2-Positive Metastatic Breast Cancer
DESTINY-Breast09
The safety of ENHERTU 5.4 mg/kg in combination with pertuzumab was evaluated in DESTINY-Breast09, a randomized, three-arm, multicenter study including 763 patients with HER2-positive (IHC 3+ or ISH+) unresectable or metastatic breast cancer. Three hundred eighty-one patients received ENHERTU in combination with pertuzumab and 382 patients received THP (taxane [docetaxel or paclitaxel], trastuzumab, and pertuzumab). Among patients who received ENHERTU in combination with pertuzumab, the median duration of treatment was 22 months (range: 0.3 months to 44.5 months).

Serious adverse reactions occurred in 27% of patients receiving ENHERTU in combination with pertuzumab. Serious adverse reactions in >1% of patients were diarrhea, pneumonia, febrile neutropenia, hypokalemia, vomiting, ILD, pulmonary embolism, and sepsis. Fatalities due to adverse reactions occurred in 3.4% of patients including pneumonia (n=3), ILD (n=2), sepsis (n=2), pulmonary embolism, septic shock, acute kidney injury, dyspnea, febrile neutropenia, and intestinal ischemia (one patient each).

ENHERTU was discontinued for adverse reactions in 21% of patients. The most frequent adverse reaction (>2%) associated with permanent discontinuation was ILD/pneumonitis (6.6%). Dose interruptions due to adverse reactions occurred in 69% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were COVID-19, neutropenia, upper respiratory tract infection, fatigue, anemia, hypokalemia, ILD/pneumonitis, thrombocytopenia, pneumonia, diarrhea, transaminase increased, leukopenia, cough, pyrexia, decreased appetite, and blood bilirubin increased. Dose reductions occurred in 46% of patients treated with ENHERTU in combination with pertuzumab. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, neutropenia, nausea, diarrhea, ILD/pneumonitis, thrombocytopenia, vomiting, transaminases increased, decreased weight, febrile neutropenia, and hypokalemia.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count (87%), decreased hemoglobin (80%), decreased neutrophil count (78%), nausea (75%), increased alanine aminotransferase (66%), diarrhea (64%), increased aspartate aminotransferase (62%), decreased lymphocyte count (62%), decreased platelet count (56%), increased blood alkaline phosphatase (55%), decreased blood potassium (54%), fatigue (53%), alopecia (48%), vomiting (46%), upper respiratory tract infection (33%), constipation (33%), decreased appetite (32%), decreased weight (30%), COVID-19 (28%), musculoskeletal pain (24%), increased blood bilirubin (23%), and abdominal pain (23%).

DESTINY-Breast03
The safety of ENHERTU was evaluated in 257 patients with unresectable or metastatic HER2-positive breast cancer who received at least 1 dose of ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast03. The median duration of treatment was 14 months (range: 0.7 to 30) for patients who received ENHERTU.

Serious adverse reactions occurred in 19% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were vomiting, ILD, pneumonia, pyrexia, and urinary tract infection. Fatalities due to adverse reactions occurred in 0.8% of patients including COVID-19 and sudden death (1 patient each).

ENHERTU was permanently discontinued in 14% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 44% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis. Dose reductions occurred in 21% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, neutropenia, and fatigue.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (74%), decreased neutrophil count (70%), increased aspartate aminotransferase (67%), decreased hemoglobin (64%), decreased lymphocyte count (55%), increased alanine aminotransferase (53%), decreased platelet count (52%), fatigue (49%), vomiting (49%), increased blood alkaline phosphatase (49%), alopecia (37%), decreased blood potassium (35%), constipation (34%), musculoskeletal pain (31%), diarrhea (29%), decreased appetite (29%), headache (22%), respiratory infection (22%), abdominal pain (21%), increased blood bilirubin (20%), and stomatitis (20%).

HER2-Low and HER2-Ultralow Metastatic Breast Cancer
DESTINY-Breast06
The safety of ENHERTU was evaluated in 434 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast06.

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