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

ENHERTU has serious Warnings and Precautions. Click here for information related to monitoring for and management of ILD/pneumonitis. Please click here for full Prescribing Information, including Boxed WARNINGS, and click here for Medication Guide.

Safety Data

The ENHERTU benefit-risk profile in HER2-low mBC was further confirmed in DESTINY-Breast06 and was established in HER2-ultralow mBC1

The majority of adverse reactions were Grade 1 or 21

  • The median duration of treatment was 11 months (range: 0.4-39.6) with ENHERTU and 5.6 months (range: 0.1-35.9) with chemotherapy1,2
  • Prophylactic or supportive treatment of treatment-induced adverse reactions was at the discretion of the treating physician and institutional guidelines3

Common adverse reactions (≥10% All Grades or ≥2% Grades 3 or 4) in DESTINY-Breast061

Adverse reactions ENHERTU 5.4 mg/kg
(n=434) 		Chemotherapy
(n=417)
All Grades
(%) 		Grades 3-4 (%) All Grades
(%) 		Grades 3-4
(%)
Gastrointestinal
disorders		 Nausea 70 2.1 30 0.5
Diarrhea 34 2.3 27 2.6
Vomiting 34 1.4 12 0.2
Constipation 32 0.7 15 0.5
Abdominal paina 20 0.5 14 0.2
Stomatitisb 15 0 11 0.5
Dyspepsia 12 0 4.8 0
General disorders
and administration
site conditions		 Fatiguec 53 4.4 40 2.4
Pyrexia 12 0.2 7 0
Skin and
subcutaneous tissue
disorders		 Alopecia 48 0 21 0.5
Rashd 12 0.2 43 8
Metabolism and
nutrition disorders		 Decreased appetite 26 1.4 12 0.5
Infections and infestations COVID-19e 26 0.9 13 1
Upper respiratory tract infectionf 19 0 9 0
Musculoskeletal and
connective tissue
disorders 		Musculoskeletal paing 24 0.5 23 1.9
Nervous system disorders Headacheh 18 0.5 10 0
Dysgeusia 12 0.2 6 0
Respiratory,
thoracic, and
mediastinal
disorders		 Cough 16 0 9 0
Interstitial lung diseasei 11 0.7 0.2 0
Epistaxis 10 0 3.6 0.2
Adverse reactions ENHERTU
5.4 mg/kg
(n=434) 		Chemo-therapy
(n=417)
All
Gra-
des
(%) 		Gra-
des
3-4
(%) 		All
Gra-
des
(%) 		Gra-
des
3-4
(%)
Gastrointestinal disorders
Nausea 70 2.1 30 0.5
Diarrhea 34 2.3 27 2.6
Vomiting 34 1.4 12 0.2
Constipation 32 0.7 15 0.5
Abdominal paina 20 0.5 14 0.2
Stomatitisb 15 0 11 0.5
Dyspepsia 12 0 4.8 0
General disorders and administration site conditions
Fatiguec 53 4.4 40 2.4
Pyrexia 12 0.2 7 0
Skin and subcutaneous tissue disorders
Alopecia 48 0 21 0.5
Rashd 12 0.2 43 8
Metabolism and nutrition disorders
Decreased appetite 26 1.4 12 0.5
Infections and infestations
COVID-19e 26 0.9 13 1
Upper respiratory tract infectionf 19 0 9 0
Musculoskeletal and connective tissue disorders
Musculo-skeletal paing 24 0.5 23 1.9
Nervous system disorders
Headacheh 18 0.5 10 0
Dysgeusia 12 0.2 6 0
Respiratory, thoracic, and mediastinal disorders
Cough 16 0 9 0
Interstitial lung diseasei 11 0.7 0.2 0
Epistaxis 10 0 3.6 0.2

Events were graded using NCI-CTCAE v.5.0.

aIncluding abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, and gastrointestinal pain.

bIncluding stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, oral mucosal blistering, and oral mucosal eruption.

cIncluding fatigue, asthenia, malaise, and lethargy.

dIncluding dermatitis, dermatitis allergic, dermatitis contact, eczema, palmar-plantar erythrodysesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular.

eIncluding COVID-19 and COVID-19 pneumonia.

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

gIncluding back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, and limb discomfort.

hIncluding migraine, headache, and sinus headache.

iIncluding bronchiectasis, interstitial lung disease, lower respiratory tract infection, pneumonia, pneumonia bacterial, pneumonitis, and pulmonary toxicity.

No new safety signals were observed with use of ENHERTU after at least 1 line of ET in patients with HR+/HER2-low or HER2-ultralow mBC2

Incidence of select common adverse reactions4

  • The majority of these adverse reactions were Grade 1 or 2
Adverse reactions ENHERTU 5.4 mg/kg (n=434)
Grade 1 (%) Grade 2 (%) Grade 3 (%) Grade 4 (%)
Nausea 38.7 29 2.1 0
Fatiguej 13.8 11.1 2.1 0
Alopecia 32.5 15.9 0 0
Vomiting 20 12.2 1.4 0
Constipation 24 6.9 0.7 0
Decreased appetite 16.8 8.1 1.4 0
Diarrhea 21.4 10.4 2.3 0

ILD and pneumonitis, including Grade 5 cases, were reported in DESTINY-Breast06; the majority of events were Grade 1 or 2 (n=43/49)2,k

Adjudicated as
drug-induced ILD, n (%) 		Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 All Grades
ENHERTU
5.4 mg/kg (n=434)		 7 (1.6) 36 (8.3) 3 (0.7) 0 3 (0.7) 49 (11.3)
Chemotherapy (n=417) 0 1 (0.2) 0 0 0 1 (0.2)
  Adjudicated as
drug-induced ILD, n (%)
ENHERTU
5.4 mg/kg
(n=434) 		Chemother-
apy (n=417)
Grade 1 7 (1.6) 0
Grade 2 36 (8.3) 1 (0.2)
Grade 3 3 (0.7) 0
Grade 4 0 0
Grade 5 3 (0.7) 0
All Grades 49 (11.3) 1 (0.2)
  • Of the 434 patients treated with ENHERTU 5.4 mg/kg, ILD occurred in 11.3% of patients (n=49/434)2
    • Three Grade 5 adjudicated drug-induced ILD/pneumonitis events were observed with ENHERTU2,k
    • 88% of the ILD cases were Grade 1 or 2 (n=43/49)2
  • In DESTINY-Breast06, median time to onset of adjudicated drug-induced ILD in patients treated with ENHERTU was 141 days (range: 37 to 835)2

jIncluding fatigue, asthenia, malaise, and lethargy.

kGrade 5=fatal cases.5

Selected laboratory abnormalities in patients in DESTINY-Breast061

Laboratory parameter ENHERTU
5.4 mg/kg (n=434) 		Chemotherapy
(n=417)
All Grades
(%) 		Grades 3–4
(%) 		All Grades
(%) 		Grades 3–4
(%)
Hematology Decreased white blood cell count 86 13 71 11
Decreased neutrophil
count 		75 27 53 20
Decreased hemoglobin 69 9 58 5
Decreased lymphocyte
count 		66 19 46 8
Decreased platelet
count		 48 6 25 1
Chemistry Increased alanine
aminotransferase		 44 3.2 30 0.7
Increased blood alkaline
phosphatase 		43 0.2 22 0.2
Increased aspartate
aminotransferase 		41 2.6 27 1.2
Decreased blood potassium 35 8 15 2.9
Increased blood
bilirubin 		16 1.9 23 1.5
Increased blood creatinine 10 1.9 8 1
Labora-
tory para-
meter		 ENHERTU
5.4 mg/kg
(n=434) 		Chemo-
therapy
(n=417)
All
Gra-
des
 (%) 		Gra-
des
3–4
 (%) 		All
Gra-
des
 (%) 		Gra-
des
3–4
 (%)
Hematology
Decreased
white blood
cell count 		86 13 71 11
Decreased neutrophil count 75 27 53 20
Decreased hemoglobin 69 9 58 5
Decreased lymphocyte count 66 19 46 8
Decreased platelet count 48 6 25 1
Chemistry
Increased alanine aminotransferase 44 3.2 30 0.7
Increased blood alkaline phosphatase 43 0.2 22 0.2
Increased aspartate aminotransferase 41 2.6 27 1.2
Decreased blood potassium 35 8 15 2.9
Increased blood bilirubin 16 1.9 23 1.5
Increased blood creatinine 10 1.9 8 1

Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator. Frequencies were based on NCI-CTCAE v.5.0 grade-derived laboratory abnormalities.

Adverse reactions may require dose modifications1

Clinically relevant AR
considerations 		ENHERTU
5.4 mg/kg (n=434) 		Chemo- therapy
(n=417)
Serious adverse reactions2 20% 16%
  • For ENHERTU, serious ARs in >1% of patients 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)1
Discontinuations due to adverse reactions2 14% 9%
  • For ENHERTU, the most frequent AR (>2%) associated with discontinuation was ILD/pneumonitis. Per protocol, ENHERTU was discontinued in DESTINY-Breast06 in patients who were diagnosed with any symptomatic (Grade 2 or greater) ILD1
Dose interruptions due to adverse reactions6 48% 38%
  • For ENHERTU, the most frequent ARs (>2%) associated with dose interruption were COVID-19, decreased neutrophil count, anemia, pyrexia, pneumonia, decreased white blood cell count, and ILD1
Dose reductions due to adverse reactions2 25% 39%
  • For ENHERTU, the most frequent ARs (>2%) associated with dose reduction were nausea, fatigue, decreased platelet count, and decreased neutrophil count1
Clinically relevant AR
considerations
Serious adverse reactions2
ENHERTU
5.4 mg/kg
(n=434) 		20%
Chemotherapy
(n=417) 		16%
  • For ENHERTU, serious ARs in >1% of patients 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)1
Clinically relevant AR
considerations
Discontinuations due to adverse reactions2
ENHERTU
5.4 mg/kg
(n=434) 		14%
Chemotherapy
(n=417) 		9%
  • For ENHERTU, the most frequent AR (>2%) associated with discontinuation was ILD/pneumonitis. Per protocol, ENHERTU was discontinued in DESTINY-Breast06 in patients who were diagnosed with any symptomatic (Grade 2 or greater) ILD1
Clinically relevant AR
considerations
Dose interruptions due to adverse
reactions6
ENHERTU
5.4 mg/kg
(n=434) 		48%
Chemotherapy
(n=417) 		38%
  • For ENHERTU, the most frequent ARs (>2%) associated with dose interruption were COVID-19, decreased neutrophil count, anemia, pyrexia, pneumonia, decreased white blood cell count, and ILD1
Clinically relevant AR
considerations
Dose reductions due to adverse
reactions2
ENHERTU
5.4 mg/kg
(n=434) 		25%
Chemotherapy
(n=417) 		39%
  • For ENHERTU, the most frequent ARs (>2%) associated with dose reduction were nausea, fatigue, decreased platelet count, and decreased neutrophil count1
  • Other clinically relevant adverse reactions reported in <10% of patients treated with ENHERTU were dizziness (9%), peripheral edema (8%), decreased weight (7%), dry eye (7%), dyspnea (6%), blurred vision (5%), abdominal distension (4.8%), pneumonia (4.6%), pruritus (3.9%), flatulence (2.3%), dehydration (1.6%), febrile neutropenia (1.2%), infusion-related reactions (1.2%), skin hyperpigmentation (0.9%), and gastritis (0.7%)1

Drug interaction studies1

  • Effect of CYP3A and OATP inhibitors on DXd (clinical studies): There were no clinically meaningful drug-drug interactions between ENHERTU and itraconazole (CYP3A inhibitor), as well as ritonavir (OATP1B/CYP3A inhibitor)
  • Effect of DXd on CYP enzymes (in vitro studies): DXd did not inhibit common CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A) nor induce CYP1A2, CYP2B6, or CYP3A
  • Effect of DXd on transporters (in vitro studies): At clinically relevant concentrations, DXd has a low potential to inhibit the transporters OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, P-gp, BCRP, or BSEP
  • Effect of other drugs on DXd (in vitro studies): DXd is a substrate of OATP1B1, OATP1B3, MATE2-K, P-gp, MRP1, and BCRP

AR, adverse reaction; BCRP, breast cancer resistance protein; BSEP, bile salt export pump; CYP, cytochrome P450; DXd, deruxtecan; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; HR+, hormone receptor-positive; ILD, interstitial lung disease; mBC, metastatic breast cancer; MATE, multidrug and toxic compound extrusion; MRP, multidrug resistance protein; NCI-CTCAE, National Cancer Institute–Common Terminology Criteria for Adverse Events; OAT, organic anion transporter; OATP, organic anion transporting polypeptide; OCT, organic cation transporter; P-gp, P-glycoprotein.

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.
  • Bardia A, Hu X, Dent R, et al; DESTINY-Breast06 Trial Investigators. Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. N Engl J Med. 2024;391(22):2110-2122.
  • Bardia A, Hu X, Dent R, et al; DESTINY-Breast06 Trial Investigators. Protocol for: Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. N Engl J Med. 2024;391(22):2110-2122.
  • Data on file. Daiichi Sankyo, Inc. Basking Ridge, NJ.
  • National Cancer Institute, National Institutes of Health, US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. Published November 27, 2017.
  • Bardia A, Hu X, Dent R, et al; DESTINY-Breast06 Trial Investigators. Supplement to: Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. N Engl J Med. 2024;391(22):2110-2122.
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