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ENHERTU® (fam-trastuzumab deruxtecan-nxki) Logo
For US Healthcare Professionals

DESTINY-Breast11 Trial

A superiority trial evaluating neoadjuvant ENHERTU followed by THP vs ddAC-THP in HER2+ eBC1,2

A Phase 3, global, open-label, multicenter, randomized clinical trial

The DESTINY-Breast09 trial (N=1157), a head-to-head study of ENHERTU (n=383), THP: taxane for greater or equal to 6 cycles + trastuzumab + pertuzumab Q3W (n=387), and ENHERTU + placebo IQ Q3W (n=387) The DESTINY-Breast09 trial (N=1157), a head-to-head study of ENHERTU (n=383), THP: taxane for greater or equal to 6 cycles + trastuzumab + pertuzumab Q3W (n=387), and ENHERTU + placebo IQ Q3W (n=387)

Primary efficacy endpoint1

  • Pathological complete response (pCR) rate (ypT0/Tis ypN0)c

Select secondary efficacy endpoints2

  • Event-free survival (EFS)
  • Invasive disease–free survival (iDFS)
  • Overall survival (OS)

Select exclusion criteria1

  • History of ILD/pneumonitis requiring treatment with steroids
  • ILD/pneumonitis at screening
  • ECOG PS >1

Stratification factors1

  • Hormone receptor status
  • Central assessment of HER2+ status

aThe ENHERTU monotherapy arm was prematurely closed by IDMC recommendations. The reasons for closure were multifactorial, including a lower pCR rate, low likelihood that ENHERTU alone would be superior to ddAC-THP, and the timing of surgery. The IDMC recommendation was not based on new safety findings. Patients already receiving ENHERTU monotherapy could continue treatment until completion of 8 cycles or meeting any discontinuation criteria, or switch to investigator’s choice of local SoC. Following cessation of enrollment to the ENHERTU monotherapy arm, patients were randomized 1:1 to ENHERTU–THP and ddAC-THP.2

bFollowing surgery, treatment was determined by investigator and administered as part of the standard of care. Study protocol recommended radiotherapy with concomitant trastuzumab ± pertuzumab as post-neoadjuvant treatment in patients who achieved pCR and radiotherapy with concomitant T-DM1 in patients who did not achieve pCR.2

cypT0/Tis ypN0 is defined as the absence of invasive disease in the breast and the axillary lymph nodes following surgery.1

DESTINY-Breast11 included patients with a range of disease characteristics2

DESTINY-Breast11 included patients with a range of disease characteristics2

Select patient characteristics ENHERTU–THP
(n=321) 		ddAC-THP
(n=320)
Age, median 50 years (range: 41-58) 50 years (range: 42-58)
Female, % 100 100
Race, % White 43.6 42.8
Asian 49.8 49.1
Black/African American 1.6 2.2
American Indian/Alaska Native 0.6 0
Native Hawaiian/other Pacific Islander 0.3 0.3
Other race 2.8 2.8
Not reported 1.2 2.8
ECOG PS at baseline, % 0 86.6 87.5
1 13.4 12.5
Hormone receptor status, % HR+ 73.5 73.4
HR− 25.9 26.6
HER2 IHC status (by central lab), % IHC 3+ 87.2 88.4
Other 12.5 11.3
Clinical tumor stage, % cT0–2 54.8 58.8
cT3–4 45.2 41.3
Nodal status, % N0 8.1 10.9
N+ 89.4 87.8
AJCC stage, % Stage I 0.3 0.3
Stage II 49.5 51.9
Stage III 50.2 47.8
Select patient characteristics ENHERTU–THP
 ENHERTU
–THP (n=321) 		ddAC-THP
 ddAC-
THP (n=320)
Age, median 50 years (range: 41-58) 50 years (range: 42-58)
Female, % 100 100
Race, %
White 43.6 42.8
Asian 49.8 49.1
Black/African American 1.6 2.2
American Indian/Alaska Native 0.6 0
Native Hawaiian/other Pacific Islander 0.3 0.3
Other race 2.8 2.8
Not reported 1.2 2.8
ECOG PS at baseline, %
0 86.6 87.5
1 13.4 12.5
Hormone receptor status, %
HR+ 73.5 73.4
HR− 25.9 26.6
HER2 IHC status (by central lab), %
IHC 3+ 87.2 88.4
Other 12.5 11.3
Clinical tumor stage, %
cT0–2 54.8 58.8
cT3–4 45.2 41.3
Nodal status, %
N0 8.1 10.9
N+ 89.4 87.8
AJCC stage, %
Stage I 0.3 0.3
Stage II 49.5 51.9
Stage III 50.2 47.8
Patient characteristics were well balanced across treatment arms

AJCC, American Joint Committee on Cancer; BC, breast cancer; ddAC, dose-dense doxorubicin and cyclophosphamide; eBC, early breast cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; EFS, event-free survival; HER2, human epidermal growth factor receptor 2; HR–, hormone receptor-negative; HR+, hormone receptor-positive; iDFS, invasive disease–free survival; IDMC, Independent Data Monitoring Committee; IHC, immunohistochemistry; ILD, interstitial lung disease; OS, overall survival; pCR, pathological complete response; Q2W, every 2 weeks; Q3W, every 3 weeks; SoC, standard of care; T-DM1, ado-trastuzumab emtansine; THP, taxane (paclitaxel), trastuzumab, and pertuzumab.

INDICATION AND IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNINGS Expand

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY

  • Interstitial lung disease (ILD) and pneumonitis, including severe, life-threatening, and fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.
  • Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.
INDICATION

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

  • HER2-Positive Early Breast Cancer

    • 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)

    • As adjuvant treatment of 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

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. 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. In the adjuvant HER2+ breast cancer setting, if drug-induced ILD is suspected, rule out radiotherapy-related pneumonitis. If only radiotherapy-related pneumonitis is suspected, consider interruption of ENHERTU for Grade 2 and permanently discontinue ENHERTU for Grade ≥3.

HER2-Positive Breast Cancer and Other Solid Tumors (5.4 mg/kg)

ENHERTU followed by THP

In patients treated with ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11, ILD occurred in 4.4% of patients. Median time to first onset was 2.7 months (range: 1.1 to 6.0). Fatal outcomes due to ILD and/or pneumonitis occurred in 1 patient (0.3%) treated with ENHERTU followed by THP.

Neutropenia

Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. 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 Breast Cancer and Other Solid Tumors (5.4 mg/kg)

ENHERTU followed by THP

In patients treated with ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11, a decrease in neutrophil count was reported in 58% of patients. Seventeen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 42 days (range: 11 to 165). Febrile neutropenia was reported in 0.9% of patients.

Left Ventricular Dysfunction

Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular dysfunction (LVD) has been observed with anti-HER2 therapies, including ENHERTU. Assess left ventricular ejection fraction (LVEF) prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVD 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 Breast Cancer and Other Solid Tumors (5.4 mg/kg)

ENHERTU followed by THP

In patients treated with ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11, LVD was reported in 1.3% of patients, of which 0.3% were Grade 3.

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 Early Breast Cancer

DESTINY-Breast11

The safety of ENHERTU followed by THP was evaluated in 320 patients with HER2-positive (IHC 3+ or ISH+) early breast cancer who received at least 1 dose of ENHERTU 5.4 mg/kg followed by THP in DESTINY-Breast11. ENHERTU was administered by intravenous infusion once every three weeks for 4 cycles followed by THP for 4 cycles. The median duration of treatment was 5.6 months (range: 0.7 to 9.1) for patients who received ENHERTU followed by THP.

Serious adverse reactions occurred in 11% of patients receiving ENHERTU followed by THP, including COVID-19 (0.9%) and ILD/pneumonitis (0.6%). Fatal adverse reactions occurred in 0.6% of patients, including ILD/pneumonitis and death not otherwise specified (1 patient each).

In patients treated with ENHERTU followed by THP, the permanent discontinuation of ENHERTU due to adverse reactions occurred in 1.3%, of which ILD/pneumonitis accounted for 0.6%. Dose interruptions of ENHERTU due to adverse reactions occurred in 11% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count and COVID-19. Dose reductions of ENHERTU occurred in 2.5% of patients treated with ENHERTU.

The most common (≥20%) adverse reactions in patients treated with ENHERTU followed by THP, including laboratory abnormalities, were decreased hemoglobin (83%), increased alanine aminotransferase (79%), increased aspartate aminotransferase (74%), decreased white blood cell count (67%), nausea (65%), peripheral neuropathy (59%), diarrhea (59%), decreased neutrophil count (58%), alopecia (48%), fatigue (41%), decreased lymphocyte count (40%), rash (31%), musculoskeletal pain (30%), decreased blood potassium (29%), constipation (29%), vomiting (29%), stomatitis (23%), and decreased appetite (20%).

DESTINY-Breast05

The safety of ENHERTU was evaluated in 806 patients with HER2-positive breast cancer with residual invasive disease following neoadjuvant HER2-targeted therapy who then received at least one dose of ENHERTU 5.4 mg/kg. ENHERTU was administered by intravenous infusion once every three weeks for 14 cycles. The median duration of treatment was 10 months (range: 0.7 to 16) for patients who received ENHERTU.

Serious adverse reactions occurred in 17% of patients receiving ENHERTU. Serious adverse reactions in ≥1% of patients who received ENHERTU were ILD/pneumonitis, radiation pneumonitis, pneumonia, and platelet count decreased. Fatal adverse reactions occurred in 0.4% of patients including ILD/pneumonitis (2 patients) and respiratory tract infection (1 patient).

Permanent discontinuation of ENHERTU due to an adverse reaction occurred in 18% of patients. The adverse reaction which resulted in permanent discontinuation of ENHERTU >2% included ILD/pneumonitis. Dose interruptions of ENHERTU due to an adverse reaction occurred in 50% of patients. Adverse reactions which required dosage interruptions in >2% included radiation pneumonitis, neutrophil count decreased, COVID-19, white blood cell count decreased, ILD/pneumonitis, platelet count decreased, upper respiratory tract infection, fatigue, cough, and pyrexia. Dose reductions of ENHERTU due to an adverse reaction occurred in 26% of patients. Adverse reactions which required dose reductions in >2% of patients included nausea, fatigue, platelet count decreased, ILD/pneumonitis, and neutrophil count decreased.

The most common (≥20%) adverse reactions, including laboratory abnormalities, in patients receiving ENHERTU were decreased white blood cell count (80%), decreased lymphocyte count (72%), decreased neutrophil count (72%), nausea (71%), decreased hemoglobin (61%), increased aspartate aminotransferase (60%), fatigue (54%), increased alanine aminotransferase (53%), decreased platelet count (46%), increased blood alkaline phosphatase (39%), constipation (32%), vomiting (31%), decreased blood potassium (27%), diarrhea (23%), musculoskeletal pain (23%), and decreased appetite (20%).

ILD was reported in 17% of patients receiving ENHERTU, which included COVID-19 pneumonia, interstitial lung disease, lung opacity, organizing pneumonia, pneumocystis jirovecii pneumonia, pneumonia, and pneumonitis which was adjudicated as ILD (irrespective of causality). Adjudicated drug-related ILD for ENHERTU was 10% for all Grades and 0.9% for Grades 3 or 4.

Use in Specific Populations

  • Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months after the last dose of ENHERTU.
  • Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.
  • Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for 7 months after the last dose. Males: 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. Infertility: ENHERTU may impair male reproductive function and fertility.
  • Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.
  • Geriatric Use: ENHERTU followed by THP: Of the 320 patients with HER2-positive early breast cancer treated with ENHERTU 5.4 mg/kg followed by THP, 12% were ≥65 years and 1.6% were ≥75 years. No overall differences in efficacy were observed between patients ≥65 years compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients ≥65 years (38%) as compared to younger patients (30%).
  • Renal Impairment: A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Monitor patients with moderate renal impairment more frequently. The recommended dosage of ENHERTU has not been established for patients with severe renal impairment (CLcr <30 mL/min).
  • Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, monitor for increased adverse reactions related to the topoisomerase inhibitor, DXd. The recommended dosage of ENHERTU has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST).

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please click here for full Prescribing Information, including Boxed WARNINGS, and click here for Medication Guide.

INDICATION

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

  • HER2-Positive Early Breast Cancer

    • 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)

    • As adjuvant treatment of 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

References
  • ENHERTU. Prescribing information. Daiichi Sankyo, Inc.; 2026.
  • Harbeck N, Modi S, Pusztai L, et al; DESTINY-Breast11 Trial Investigators. 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(2):166-179.
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