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ENHERTU (fam-trastuzumab deruxtecan-nxki) Logo
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    • Additional Data

    ENHERTU continues to change what is possible with HER2-directed treatment

    In 2022, ENHERTU was approved as the first HER2-directed therapy for eligible previously treated patients with HER2-low (IHC 1+ or IHC 2+/ISH–) mBC1,2

    ENHERTU was investigated in DESTINY-Breast04, a landmark, Phase 3, international trial1,3-5

    A Phase 3, multicenter, randomized, open-label trial that included patients with1,3,a:

    • Unresectable or metastatic HER2-low (HER2 IHC 1+b or IHC 2+/ISH–) breast cancer
    • Tumors previously not classified as HER2-positive on any prior pathology testing4

    The key efficacy endpoints in DESTINY-Breast04 were tested hierarchically1:

    Primary endpoint1

    • PFS in the HR+ population, as determined by BICR

    Key secondary endpoints1

    • PFS (BICR)e in the overall study population (HR+ and HR–)
    • OS in the HR+ population
    • OS in the overall study population (HR+ and HR–)

    Select secondary endpoints3,e,f

    • Confirmed ORR and DOR in the HR+ population
    • Confirmed ORR and DOR in the overall study population (HR+ and HR–)

    Select exploratory endpoints5,6

    • PFS, OS, ORR, and DOR in the HR– population

    Stratification factors5

    • HER2 IHC status (IHC 1+ or IHC 2+/ISH–)
    • Number of prior lines of chemotherapy in the metastatic setting (1 or 2)
    • HR status/prior CDK4/6 inhibitor (HR+ with prior CDK4/6 inhibitor, HR+ without prior CDK4/6 inhibitor, or HR–)

    Patients with HER2-low mBC in DESTINY-Breast04 had 1 or 2 prior lines of chemotherapy in the metastatic setting and, if HR+, were ineligible for or had progressed on endocrine therapy1

    aPatients had received no prior HER2-directed therapy.3

    bIHC 1+ tumors were ISH– or ISH untested.3

    cTreatment was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity.1

    d In the control arm, 51.1% of patients received eribulin, 20.1% received capecitabine, 10.3% received nab-paclitaxel, 10.3% received gemcitabine, and 8.2% received paclitaxel.5

    eAccording to mRECIST v1.1.3

    fBoth BICR and investigator assessment were performed.3

    DESTINY-Breast04 evaluated patients with HER2-low mBC (IHC 1+ and IHC 2+/ISH–)1

    Select baseline patient demographics and clinical characteristics1,6,g,h

    DESTINY-Breast04
    (N=557)
    Age, median 57 years (range: 28-81)
    Hormone receptor status HR+ 89%
    HR- 11%
    HER2 IHC score 1+ 58%
    2+/ISH– 42%
    Number of prior lines of endocrine therapy in the metastatic setting in HR+/HER2-low mBC patients (n=494) 0 9%
    1 31%
    2 33%
    ≥3 27%
    Prior CDK4/6 inhibitor in HR+/HER2-low mBC patients (n=494) 70%
    Number of prior
    chemotherapy regimens in the metastatic setting     		1 58%
    2 41%
    Prior lines of systemic therapy in the metastatic setting, mediani 3 (range: 1 to 9)
    Sites of metastases Liver metastases 70%
    Lung metastases 33%
    Brain metastases j 6%
    DESTINY-Breast04
    (N=557)
    Age, median 57 years
    (range: 28-81)
    Hormone receptor status
    HR+ 89%
    HR- 11%
    HER2 IHC score
    1+ 58%
    2+/ISH– 42%
    Number of prior lines of endocrine therapy in the metastatic setting in HR+/HER2-low mBC patients (n=494)
    0 9%
    1 31%
    2 33%
    ≥3 27%
    Prior CDK4/6 inhibitor in HR+/HER2-low mBC patients (n=494) 70%
    Number of prior
    chemotherapy regimens in the metastatic setting
    1 58%
    2 41%
    Prior lines of systemic therapy in the metastatic setting, mediani 3 (range: 1 to 9)
    Sites of metastases
    Liver metastases 70%
    Lung metastases 33%
    Brain metastases j 6%
    • Gender: 99.6% were female, 0.4% were male1
    • Race/ethnicity: 48% were White, 40% were Asian, 3.8% were Hispanic/Latino, and 2% were Black or African American1
    • ECOG PS: 55% had ECOG PS 0 and 45% had ECOG PS 1 at baseline1
    • In the HR+ cohort, median prior lines of ET: 2 (range: 0-9)1
    • Early progressors (progression in the neo/adjuvant setting): 3.9%1

    gPatients with HR-negative mBC were not included in the primary efficacy analysis.5

    hIn some instances, percentages do not add up to 100% due to rounding.

    iIn the overall study population (N=557), 10% of patients had received 1 prior line of systemic therapy in the metastatic setting, 27% had received 2 prior lines, and 62% had received ≥3 prior lines.5

    jPatients with treated brain metastases who were no longer symptomatic and who required no treatment with corticosteroids or anticonvulsants could be included in the study if they had recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment.3

    Summary of DESTINY-Breast04 efficacy results by patient population1,5,6,k,l

    Overall study
    population
    (N=557)     		HR+/HER2-low
    cohort
    (n=494)     		Exploratory HR–
    /HER2-low
    cohort (n=58)
    ENHERTU
    (n=373)         		Chemo-
    therapy
    (n=184)         		ENHERTU
    (n=331)         		Chemo-
    therapy
    (n=163)         		ENHERTU
    (n=40)         		Chemo-
    therapy
    (n=18)
    mPFS (mo)
    (95% Cl)     		9.9
    (9.0, 11.3)     		5.1
    (4.2, 6.8)     		10.1
    (9.5, 11.5)     		5.4
    (4.4, 7.1)     		8.5
    (4.3, 11.7)     		2.9
    (1.4, 5.1)
    HR (95% CI; P-value) 0.50
    (0.40, 0.63;
    P<0.0001)         		0.51
    (0.40, 0.64;
    P<0.0001)         		0.46
    (0.24, 0.89)
    mOS (mo)
    (95% Cl)     		23.4
    (20.0, 24.8)     		16.8
    (14.5, 20.0)     		23.9
    (20.8, 24.8)     		17.5
    (15.2, 22.4)     		18.2
    (13.6, NE)     		8.3
    (5.6, 20.6)
    HR (95% CI; P-value) 0.64
    (0.49, 0.84;
    P=0.001)         		0.64
    (0.48, 0.86;
    P=0.0028)         		0.48
    (0.24, 0.95)
    ORR
    (n; 95% CI)     		52.3%
    (195; 47.1, 57.4)     		16.3%
    (30; 11.3, 22.5)     		52.9%
    (175; 47.3, 58.4)     		16.6%
    (27; 11.2, 23.2)     		50.0%
    (20; 33.8, 66.2)     		16.7%
    (3; 3.6, 41.4)
    CR 3.5%
    (n=13)     		1.1%
    (n=2)     		3.6%
    (n=12)     		0.6%
    (n=1)     		2.5%
    (n=1)     		5.6%
    (n=1)
    PR 49.1%
    (n=183)     		15.2%
    (n=28)     		49.5%
    (n=164)     		16.0%
    (n=26)     		47.5%
    (n=19)     		11.1%
    (n=2)
    mDOR (mo)
    (95% Cl)     		10.7
    (8.5, 13.2)     		6.8
    (6.0, 9.9)     		10.7
    (8.5, 13.7)     		6.8
    (6.5, 9.9)     		8.6
    (7.1, 13.9)     		4.9
    (3.7, 6.0)
    Overall study
    population
    (N=557)
    ENHERTU
    (n=373)         		Chemo-
    therapy
    (n=184)
    mPFS (mo)
    (95% Cl)     		9.9
    (9.0, 11.3)     		5.1
    (4.2, 6.8)
    HR (95% CI;
    P-value)     		0.50
    (0.40, 0.63;
    P<0.0001)
    mOS (mo)
    (95% Cl)     		23.4
    (20.0, 24.8)     		16.8
    (14.5, 20.0)
    HR (95% CI;
    P-value)     		0.64
    (0.49, 0.84;
    P=0.0001)
    ORR
    (n; 95% CI)     		52.3%
    (195; 47.1, 57.4)     		16.3%
    (30; 11.3, 22.5)
    CR 3.5%
    (n=13)     		1.1%
    (n=2)
    PR 49.1%
    (n=183)     		15.2%
    (n=28)
    mDOR (mo)
    (95% Cl)     		10.7
    (8.5, 13.2)     		6.8
    (6.0, 9.9)
    HR+/HER2-low cohort
    (n=494)
    ENHERTU
    (n=331)         		Chemo-
    therapy
    (n=163)
    mPFS (mo)
    (95% Cl)     		10.1
    (9.5, 11.5)     		5.4
    (4.4, 7.1)
    HR (95% CI;
    P-value)     		0.51
    (0.40, 0.64;
    P<0.0001)
    mOS (mo)
    (95% Cl)     		23.9
    (20.8, 24.8)     		17.5
    (15.2, 22.4)
    HR (95% CI;
    P-value)     		0.64
    (0.48, 0.86;
    P=0.0028)
    ORR
    (n; 95% CI)     		52.9%
    (175; 47.3, 58.4)     		16.6%
    (27; 11.2, 23.2)
    CR 3.6%
    (n=12)     		0.6%
    (n=1)
    PR 49.5%
    (n=164)     		16.0%
    (n=26)
    mDOR (mo)
    (95% Cl)     		10.7
    (8.5, 13.7)     		6.8
    (6.5, 9.9)
    Exploratory HR–/HER2-low
    cohort (n=58)
    ENHERTU
    (n=40)         		Chemo-
    therapy
    (n=18)
    mPFS (mo)
    (95% Cl)     		8.5
    (4.3, 11.7)     		2.9
    (1.4, 5.1)
    HR (95% CI;
    P-value)     		0.46
    (0.24, 0.89)
    mOS (mo)
    (95% Cl)     		18.2
    (13.6, NE)     		8.3
    (5.6, 20.6)
    HR (95% CI;
    P-value)     		0.48
    (0.24, 0.95)
    ORR
    (n; 95% CI)     		50.0%
    (20; 33.8, 66.2)     		16.7%
    (3; 3.6, 41.4)
    CR 2.5%
    (n=1)     		5.6%
    (n=1)
    PR 47.5%
    (n=19)     		11.1%
    (n=2)
    mDOR (mo)
    (95% Cl)     		8.6
    (7.1, 13.9)     		4.9
    (3.7, 6.0)

    kFor the primary and secondary endpoints, the hormone receptor status is based on data collected using the interactive web/voice response system at the time of randomization, which includes mis-stratified patients.5

    lFor other endpoints, hormone receptor status is based on data from the electronic data capture corrected for mis-stratification.5

    • The HR– cohort was an exploratory population. The data are descriptive and were not tested for statistical significance, nor powered to show a difference between treatment arms. Therefore, the clinical significance of these data is not known
    • ORR and mDOR were not tested for statistical significance and were not powered to show differences between treatment arms. Therefore, the clinical significance of these data is not known

    An established benefit-risk profile with ENHERTU in DESTINY-Breast04

    The majority of adverse reactions were Grade 1 or 21

    • The median duration of treatment was 8 months (range: 0.2-33) with ENHERTU and 3.5 months (range: 0.3-17.6) with chemotherapy1,5

    Common adverse reactions (≥10% all Grades or ≥2% Grades 3 or 4) in patients treated with ENHERTU in DESTINY-Breast041

    Adverse reactions ENHERTU 5.4 mg/kg
    (n=371)     		Chemotherapy
    (n=172)
    All Grades
    (%)     		Grades 3–4
    (%)     		All Grades
    (%)     		Grades 3–4
    (%)
    Gastrointestinal
    disorders     		Nausea 76 4.6 30 0
    Vomiting 40 1.6 13 0
    Constipation 34 0.8 22 0
    Diarrhea 27 1.3 22 1.7
    Abdominal painm 18 0.5 13 0
    Stomatitisn 13 0.3 12 0.6
    General disorders
    and administration
    site conditions     		Fatigueo 54 9 48 4.7
    Pyrexia 12 0.3 13 0
    Skin and
    subcutaneous tissue
    disorders     		Alopecia 40 0 33 0
    Rashp 13 0 23 4.7
    Metabolism and
    nutrition disorders     		Decreased appetite 32 2.4 19 1.2
    Musculoskeletal and
    connective tissue
    disorders     		Musculoskeletal painq 32 1.3 31 0.6
    Investigations Decreased weight 16 0.3 8 0
    Vascular disorders Hemorrhager 16 0 3.5 0
    Nervous system disorders Headaches 15 0.3 6 0
    Peripheral neuropathyt 13 0 29 5
    Dizzinessu 11 0.5 6 0
    Infections and infestations Upper respiratory tract infectionv 14 0.3 5 0
    Respiratory,
    thoracic, and
    mediastinal
    disorders     		Interstitial lung diseasew 12 1.3 0.6 0
    Dyspnea 10 1.3 9 1.2
    Adverse
    reactions     		ENHERTU
    5.4 mg/kg
    (n=371)     		Chemo-
    therapy
    (n=172)
    All
    Gra-
    des
    (%)     		Gra-
    des
    3–4
    (%)     		All
    Gra-
    des
    (%)     		Gra-
    des
    3–4
    (%)
    Gastrointestinal disorders
    Nausea 76 4.6 30 0
    Vomiting 40 1.6 13 0
    Constipation 34 0.8 22 0
    Diarrhea 27 1.3 22 1.7
    Abdominal painm 18 0.5 13 0
    Stomatitisn 13 0.3 12 0.6
    General disorders and administration site conditions
    Fatigueo 54 9 48 4.7
    Pyrexia 12 0.3 13 0
    Skin and subcutaneous tissue disorders
    Alopecia 40 0 33 0
    Rashp 13 0 23 4.7
    Metabolism and nutrition disorders
    Decreased appetite 32 2.4 19 1.2
    Musculoskeletal and connective tissue disorders
    Musculo-skeletal painq 32 1.3 31 0.6
    Investigations
    Decreased weight 16 0.3 8 0
    Vascular disorders
    Hemorrhager 16 0 3.5 0
    Nervous system disorders
    Headaches 15 0.3 6 0
    Peripheral neuropathyt 13 0 29 5
    Dizzinessu 11 0.5 6 0
    Infections and infestations
    Upper respiratory tract infectionv 14 0.3 5 0
    Respiratory, thoracic, and mediastinal disorders
    Interstitial lung diseasew 12 1.3 0.6 0
    Dyspnea 10 1.3 9 1.2

    mIncluding abdominal pain, abdominal discomfort, lower abdominal pain, and upper abdominal pain.

    nIncluding stomatitis, aphthous ulcer, mouth ulceration, and pharyngeal inflammation.

    oIncluding fatigue, asthenia, and malaise.

    pIncluding rash, pustular rash, pruritic rash, maculo-papular rash, palmar-plantar erythrodysesthesia syndrome, papular rash, macular rash, eczema, erythema multiforme, dermatitis, urticarial dermatitis, drug eruption, and dermatitis bullous.

    qIncluding back pain, myalgia, pain in extremity, musculoskeletal pain, bone pain, musculoskeletal chest pain, arthralgia, noncardiac chest pain, musculoskeletal stiffness, arthritis, spinal pain, and neck pain.

    rIncluding esophageal varices, hemorrhage, hemorrhoidal hemorrhage, epistaxis, hematuria, conjunctival hemorrhage, vaginal hemorrhage, gingival bleeding, genital hemorrhage, eye hemorrhage, hemoptysis, hemorrhagic cystitis, pharyngeal hemorrhage, rectal hemorrhage, upper gastrointestinal hemorrhage, and esophageal hemorrhage.

    sIncluding headache and migraine.

    tIncluding peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, polyneuropathy, paresthesia, hypoesthesia, dysesthesia, and neuralgia.

    uIncluding dizziness, postural dizziness, and vertigo.

    vIncluding upper respiratory tract infection, influenza, influenza-like illness, nasopharyngitis, pharyngitis, sinusitis, and rhinitis.

    wInterstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU: interstitial lung disease, pneumonitis, organizing pneumonia, pneumonia, and radiation pneumonitis.

    Adverse reactions may require dose modifications1

    Clinically
    relevant AR
    considerations     		ENHERTU
    5.4 mg/kg
    (n=371)     		Chemo- therapy
    (n=172)
    Serious adverse reactions1,5,6 28% 25%
    • For ENHERTU, serious ARs in >1% of patients were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to adverse reactions occurred in 4.0% of patients, including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each)1
    • For chemotherapy, the most frequent in ≥1% of patients were dyspnea, febrile neutropenia, fatigue, pleural effusion, neutropenia, disease progression, hepatic failure, hyponatremia, overdose, medication error, colitis, and femur fracture6
    Discontinuations due to adverse reactions1,5 16% 8%
    • For ENHERTU, the most frequent adverse reaction (>2%) associated with discontinuation was ILD/pneumonitis (8%). Per protocol, ENHERTU was discontinued in DESTINY-Breast04 in patients who were diagnosed with any symptomatic (Grade 2 or greater) ILD1
    • For chemotherapy, the most frequent was peripheral sensory neuropathy (2.3%)7
    Dose interruptions due to adverse reactions1,4,6 39% 42%
    • For ENHERTU, the most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia1
    • For chemotherapy, the most frequent (≥1%) were neutropenia, leukopenia, increased transaminases, palmar-plantar erythrodysesthesia syndrome, fatigue, anemia, nausea, diarrhea, and peripheral sensory neuropathy6
    Dose reductions due to adverse reactions1,5,6 23% 38%
    • For ENHERTU, the most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia1
    • For chemotherapy, the most frequent (≥1%) were neutropenia, palmar-plantar erythrodysesthesia syndrome, increased transaminases, fatigue, leukopenia, nausea, and peripheral sensory neuropathy6
    Clinically
    relevant AR
    considerations
    Serious adverse reactions1,5,6
    ENHERTU
    5.4 mg/kg
    (n=371)     		28%
    Chemotherapy
    (n=172)     		25%
    • For ENHERTU, serious ARs in >1% of patients were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to adverse reactions occurred in 4.0% of patients, including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each)1
    • For chemotherapy, the most frequent in ≥1% of patients were dyspnea, febrile neutropenia, fatigue, pleural effusion, neutropenia, disease progression, hepatic failure, hyponatremia, overdose, medication error, colitis, and femur fracture6
    Clinically relevant AR
    considerations
    Discontinuations due to adverse
    reactions1,5
    ENHERTU
    5.4 mg/kg
    (n=371)     		16%
    Chemotherapy
    (n=172)     		8%
    • For ENHERTU, the most frequent adverse reaction (>2%) associated with discontinuation was ILD/pneumonitis (8%). Per protocol, ENHERTU was discontinued in DESTINY-Breast04 in patients who were diagnosed with any symptomatic (Grade 2 or greater) ILD1
    • For chemotherapy, the most frequent was peripheral sensory neuropathy (2.3%)7
    Clinically relevant AR
    considerations
    Dose interruptions due to adverse
    reactions1,4,6
    ENHERTU
    5.4 mg/kg
    (n=371)     		39%
    Chemotherapy
    (n=172)     		42%
    • For ENHERTU, the most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia1
    • For chemotherapy, the most frequent (≥1%) were neutropenia, leukopenia, increased transaminases, palmar-plantar erythrodysesthesia syndrome, fatigue, anemia, nausea, diarrhea, and peripheral sensory neuropathy6
    Clinically relevant AR
    considerations
    Dose reductions due to adverse
    reactions1,5,6
    ENHERTU
    5.4 mg/kg
    (n=371)     		23%
    Chemotherapy
    (n=172)     		38%
    • For ENHERTU, the most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia1
    • For chemotherapy, the most frequent (≥1%) were neutropenia, palmar-plantar erythrodysesthesia syndrome, increased transaminases, fatigue, leukopenia, nausea, and peripheral sensory neuropathy6
    • Other clinically relevant adverse reactions reported in ≤10% of patients treated with ENHERTU were cough (10%), dysgeusia (10%), abdominal distension (5%), blurred vision (4.9%), pruritus (3.2%), gastritis (2.7%), skin hyperpigmentation (2.7%), flatulence (2.4%), dehydration (1.9%), febrile neutropenia (1.1%), and infusion-related reactions (0.5%)1

    In DESTINY-Breast04, Grade 5 ILD/pneumonitis events were observed in 0.8% of patients (n=3/371)1,5,x

    • Of the 371 patients treated with ENHERTU 5.4 mg/kg, ILD occurred in 12.1% of patients (n=45/371)5

    xGrade 5=fatal cases.

    AR, adverse reaction; BICR, blinded independent central review; CDK4/6, cyclin-dependent kinases 4 and 6; CI, confidence interval; CR, complete response; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; HR–, hormone receptor-negative; HR+, hormone receptor-positive; IHC, immunohistochemistry; ILD, interstitial lung disease; ISH, in situ hybridization; IV, intravenous; mBC, metastatic breast cancer; mDOR, median duration of response; mOS, median overall survival; mPFS, median progression-free survival; mRECIST, Modified Response Evaluation Criteria in Solid Tumors; NE, not evaluable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; PS, performance score; Q3W, every 3 weeks.

    IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNINGS Expand

    WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY

    • Interstitial lung disease (ILD) and pneumonitis, including 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 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
    • 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

    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.

    Metastatic Breast Cancer and Other Solid Tumors (5.4 mg/kg)

    In patients with metastatic breast cancer and other solid tumors 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.

    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.

    Metastatic Breast Cancer and Other Solid Tumors (5.4 mg/kg)

    In patients with metastatic breast cancer and other solid tumors 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.

    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.

    Metastatic Breast Cancer and Other Solid Tumors (5.4 mg/kg)

    In patients with metastatic breast cancer and other solid tumors 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.

    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

    Metastatic Breast Cancer and Other Solid Tumors (5.4 mg/kg)

    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, and other clinical trials. 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%).

    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. The median duration of treatment was 11 months (range: 0.4 to 39.6) for patients who received ENHERTU.

    Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, COVID-19, febrile neutropenia, and hypokalemia. Fatalities due to adverse reactions occurred in 2.8% of patients including ILD (0.7%); sepsis (0.5%); and COVID-19 pneumonia, bacterial meningoencephalitis, neutropenic sepsis, peritonitis, cerebrovascular accident, general physical health deterioration (0.2% each).

    ENHERTU was permanently discontinued in 14% of patients. The most frequent adverse reaction (>2%) associated with permanent discontinuation was ILD/pneumonitis. Dose interruptions due to adverse reactions occurred in 48% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were COVID-19, decreased neutrophil count, anemia, pyrexia, pneumonia, decreased white blood cell count, and ILD. Dose reductions occurred in 25% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, fatigue, decreased platelet count, and decreased neutrophil count.

    The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count (86%), decreased neutrophil count (75%), nausea (70%), decreased hemoglobin (69%), decreased lymphocyte count (66%), fatigue (53%), decreased platelet count (48%), alopecia (48%), increased alanine aminotransferase (44%), increased blood alkaline phosphatase (43%), increased aspartate aminotransferase (41%), decreased blood potassium (35%), diarrhea (34%), vomiting (34%), constipation (32%), decreased appetite (26%), COVID-19 (26%), and musculoskeletal pain (24%).

    DESTINY-Breast04
    The safety of ENHERTU was evaluated in 371 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast04. The median duration of treatment was 8 months (range: 0.2 to 33) for patients who received ENHERTU.

    Serious adverse reactions occurred in 28% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to adverse reactions occurred in 4% of patients including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each).

    ENHERTU was permanently discontinued in 16% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 39% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia. Dose reductions occurred in 23% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia.

    The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (70%), decreased hemoglobin (64%), decreased neutrophil count (64%), decreased lymphocyte count (55%), fatigue (54%), decreased platelet count (44%), alopecia (40%), vomiting (40%), increased aspartate aminotransferase (38%), increased alanine aminotransferase (36%), constipation (34%), increased blood alkaline phosphatase (34%), decreased appetite (32%), musculoskeletal pain (32%), diarrhea (27%), and decreased blood potassium (25%).

    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: Of the 1741 patients with breast cancer treated with ENHERTU 5.4 mg/kg, 24% were ≥65 years and 4.9% were ≥75 years. No overall differences in efficacy within clinical studies were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (61%) as compared to younger patients (52%).
    • 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, closely monitor for increased toxicities 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 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
    • 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
    References
    • ENHERTU. Prescribing information. Daiichi Sankyo, Inc.; 2025.
    • Tarantino P, Hamilton E, Tolaney SM, et al. HER2-low breast cancer: pathological and clinical landscape. J Clin Oncol. 2020;38(17):1951-1962.
    • Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Protocol for: Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20.
    • Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Supplement to: Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20.
    • Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20.
    • Data on file. Daiichi Sankyo, Inc. Basking Ridge, NJ.
    • Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan (T-DXd) vs treatment of physician's choice in patients with HER2-low unresectable and/or metastatic breast cancer: results of DESTINY-Breast04, a randomized, phase 3 study. Presented at: the American Society of Clinical Oncology; June 3-7, 2022; Chicago, IL.
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