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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

In DESTINY-Breast09, a head-to-head study in 1L HER2+ mBC

No new safety signals were identified in the ENHERTU + pertuzumab arm when compared with the known profiles of the individual treatments1

The majority of ARs were Grade 1 or 22

Common ARs (≥10% All Grades or ≥2% Grade ≥3) in DESTINY-Breast09

Adverse reactions ENHERTU 5.4 mg/kg
pertuzumab (n=381) 		THP
(n=382)
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Gastrointestinal
disorders		 Nausea 75 5 34 0.3
Diarrhea 64 8 62 6
Vomiting 46 2.4 18 0.5
Constipation 33 0.3 12 0
Abdominal paina 23 0.3 13 0
Stomatitisb 16 1.3 17 1.3
Dyspepsia 12 0 6 0
General disorders
and
administration
site conditions 		Fatiguec 53 8 42 2.1
Pyrexia 16 0 18 1.0
Skin and
subcutaneous
tissue disorders		 Alopecia 48 0 53 0.5
Rashd 17 0.3 22 0.3
Pruritus 11 0 11 0.3
Infections and
infestations 		Upper respiratory
tract infectione 		33 1.6 30 0.5
COVID-19 28 0.3 22 0.3
Metabolism and
nutrition disorders 		Decreased
appetite 		32 2.4 18 0.8
Hypoalbuminemia 11 0.3 8 0.3
Investigations Decreased weight 30 3.1 11 0.8
Musculoskeletal
and connective
tissue disorders		 Musculoskeletal painf 24 1 33 0.3
Nervous system
disorders		 Headacheg 19 0.3 14 0
Dysgeusia 13 0 9 0
Dizziness 12 0.3 10 0
Respiratory,
thoracic, and
mediastinal
disorders 		Cough 17 0.3 13 0
Interstitial lung diseaseh 12 0 1 0
Eye disorders Dry eye 11 0 6 0
Adverse reactions ENHERTU 5.4 mg/kg +
pertuzumab (n=381)
All Grades
(%) 		Grades
3-4 (%)
Gastrointestinal disorders
Nausea 75 5
Diarrhea 64 8
Vomiting 46 2.4
Constipation 33 0.3
Abdominal paina 23 0.3
Stomatitisb 16 1.3
Dyspepsia 12 0
General disorders and administration site conditions
Fatiguec 53 8
Pyrexia 16 0
Skin and subcutaneous tissue disorders
Alopecia 48 0
Rashd 17 0.3
Pruritus 11 0
Infections and infestations
Upper respiratory tract infectione 33 1.6
COVID-19 28 0.3
Metabolism and nutrition disorders
Decreased appetite 32 2.4
Hypoalbumi-
nemia 		11 0.3
Investigations
Decreased weight 30 3.1
Musculoskeletal and connective tissue disorders
Musculoskel-
etal painf		 24 1
Nervous system disorders
Headacheg 19 0.3
Dysgeusia 13 0
Dizziness 12 0.3
Respiratory, thoracic, and mediastinal disorders
Cough 17 0.3
Interstitial lung diseaseh 12 0
Eye disorders
Dry eye 11 0
Adverse
reactions 		THP
(n=382)
All Grades
(%) 		Grades
3-4 (%)
Gastrointestinal disorders
Nausea 34 0.3
Diarrhea 62 6
Vomiting 18 0.5
Constipation 12 0
Abdominal paina 13 0
Stomatitisb 17 1.3
Dyspepsia 6 0
General disorders and administration site conditions
Fatiguec 42 2.1
Pyrexia 18 1.0
Skin and subcutaneous tissue disorders
Alopecia 53 0.5
Rashd 22 0.3
Pruritus 11 0.3
Infections and infestations
Upper respiratory tract infectione 30 0.5
COVID-19 22 0.3
Metabolism and nutrition disorders
Decreased appetite 18 0.8
Hypoalbumi-
nemia 		8 0.3
Investigations
Decreased weight 11 0.8
Musculoskeletal and connective tissue disorders
Musculoskel-
etal painf		 33 0.3
Nervous system disorders
Headacheg 14 0
Dysgeusia 9 0
Dizziness 10 0
Respiratory, thoracic, and mediastinal disorders
Cough 13 0
Interstitial lung diseaseh 1 0
Eye disorders
Dry eye 6 0

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

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

cIncluding asthenia, fatigue, lethargy, and malaise.

dIncluding rash, rash macular, rash maculo-papular, rash pruritic, and rash pustular.

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

fIncluding back pain, bone pain, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, and pain in extremity.

gIncluding headache and migraine.

hInterstitial lung disease (grouped term) includes PTs of chronic obstructive pulmonary disease (n=1), interstitial lung disease (n=23), pneumonia (n=3), and pneumonitis (n=22). These events were adjudicated as ILD and related to use of ENHERTU.

The median duration of treatment was 22 months (range: 0.3-44.5) with ENHERTU + pertuzumab and 16.9 months (range: 0.7-41.7) with THP1,2

Clinically
relevant AR
considerations1,2 		ENHERTU +
pertuzu-
mab
(n=381) 		THP
(n=382)
Serious ARs 27% 25.1%
  • For ENHERTU + pertuzumab, serious ARs in >1% of patients were diarrhea, pneumonia, febrile neutropenia, hypokalemia, vomiting, ILD, pulmonary embolism, and sepsis. Fatalities due to ARs occurred in 3.4% of patients, including pneumonia (n=3); ILD (n=2); sepsis (n=2); and pulmonary embolism, septic shock, acute kidney injury, dyspnea, febrile neutropenia, and intestinal ischemia (1 patient each)
Permanent discontinuations due to ARs 21% 28.3%
  • For ENHERTU + pertuzumab, most frequent AR (>2%) associated with permanent discontinuation was ILD/pneumonitis (6.6%)
Dose interruptions due to ARs 69% 49%
  • For ENHERTU + pertuzumab, most frequent ARs (>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 due to ARs 46% 19.9%
  • For ENHERTU + pertuzumab, most frequent ARs (>2%) associated with dose reduction were fatigue, neutropenia, nausea, diarrhea, ILD/pneumonitis, thrombocytopenia, vomiting, transaminases increased, decreased weight, febrile neutropenia, and hypokalemia
Clinically relevant AR
considerations1,2
Serious ARs
ENHERTU + pertuzumab (n=381) 27%
THP (n=382) 25.1%
  • For ENHERTU + pertuzumab, serious ARs in >1% of patients were diarrhea, pneumonia, febrile neutropenia, hypokalemia, vomiting, ILD, pulmonary embolism, and sepsis. Fatalities due to ARs occurred in 3.4% of patients, including pneumonia (n=3); ILD (n=2); sepsis (n=2); and pulmonary embolism, septic shock, acute kidney injury, dyspnea, febrile neutropenia, and intestinal ischemia (1 patient each)
Clinically relevant AR
considerations1,2
Permanent discontinuations due to ARs
ENHERTU + pertuzumab (n=381) 21%
THP (n=382) 28.3%
  • For ENHERTU + pertuzumab, most frequent AR (>2%) associated with permanent discontinuation was ILD/pneumonitis (6.6%)
Clinically relevant AR
considerations1,2
Dose interruptions due to ARs
ENHERTU + pertuzumab (n=381) 69%
THP (n=382) 49%
  • For ENHERTU + pertuzumab, most frequent ARs (>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
Clinically relevant AR
considerations1,2
Dose reductions due to ARs
ENHERTU + pertuzumab (n=381) 46%
THP (n=382) 19.9%
  • For ENHERTU + pertuzumab, most frequent ARs (>2%) associated with dose reduction were fatigue, neutropenia, nausea, diarrhea, ILD/pneumonitis, thrombocytopenia, vomiting, transaminases increased, decreased weight, febrile neutropenia, and hypokalemia
  • Other clinically relevant ARs reported in <10% of patients treated with ENHERTU + pertuzumab were increased blood bilirubin (9%), epistaxis (8%), abdominal distension (6%), dyspnea (6%), skin hyperpigmentation (6%), blurred vision (4.2%), gastritis (3.9%), increased blood creatinine (3.1%), dehydration (2.9%), febrile neutropenia (2.9%), flatulence (2.4%), and infusion-related reaction (1.8%)2

The majority of ILD/pneumonitis cases with ENHERTU + pertuzumab were Grade 1 or 21,3

Adjudicated as drug-
related 		ENHERTU + pertuzumab (n=381)
Grade
1, n (%) 		Grade
2, n (%) 		Grade
3, n (%) 		Grade
4, n (%) 		Grade
5, n (%)i 		Any
Grade,
n (%)
ILD/pneumonitis 17 (4.5) 27 (7.1) 0 0 2 (0.5) 46 (12.1)
Adjudicated
as drug-
related 		ENHERTU +
pertuzumab (n=381)
Grade 1, n
(%) 		Grade 2, n
(%)
ILD/pneumonitis 17 (4.5) 27 (7.1)
Adjudicated
as drug-
related 		ENHERTU +
pertuzumab (n=381)
Grade 3, n
(%) 		Grade 4, n
(%)
ILD/pneumonitis 0 0
Adjudicated
as drug-
related 		ENHERTU +
pertuzumab (n=381)
Grade 5, n
(%)i 		Any
Grade, n
(%)
ILD/pneumonitis 2 (0.5) 46 (12.1)

Most common selected laboratory abnormalities in patients receiving ENHERTU + pertuzumab2

  • Decreased white blood cell count (87%), decreased hemoglobin (80%), decreased neutrophil count (78%), increased alanine aminotransferase (66%), increased aspartate aminotransferase (62%), decreased lymphocyte count (62%), decreased platelet count (56%), increased blood alkaline phosphatase (55%), decreased blood potassium (54%), increased blood bilirubin (23%), and increased blood creatinine (9%)

Management of ARs may require temporary interruption, dose reduction, or treatment discontinuation of ENHERTU as described in the dose reductions table. Refer to the Prescribing Information for pertuzumab for dose modification recommendations. Pertuzumab is not to be administered as a single agent.2

Dose modifications were implemented to help manage ARs and patients' experience while on therapy with ENHERTU + pertuzumab2

iGrade 5=fatal cases.1

1L, first line; AR, adverse reaction; HER2, human epidermal growth factor receptor 2; ILD, interstitial lung disease; mBC, metastatic breast cancer; PT, preferred term; THP, taxane (docetaxel or 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 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:

  • 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

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.

Metastatic Breast Cancer and Other Solid Tumors (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.

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.

Metastatic Breast Cancer and Other Solid Tumors (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.

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)

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.

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)

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, 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%).

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%).

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 as Monotherapy: Of the 2355 patients with breast cancer treated with ENHERTU 5.4 mg/kg, 23% were ≥65 years and 5% 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 (55%) as compared to younger patients (50%). ENHERTU in Combination with Pertuzumab: In patients with HER2-positive unresectable or metastatic breast cancer treated with ENHERTU 5.4 mg/kg in combination with pertuzumab (N=431), 17% were ≥65 years and 3% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.
  • 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:

  • 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
References
  • Tolaney SM, Jiang Z, Zhang Q, et al; DESTINY-Breast09 Trial Investigators. Trastuzumab deruxtecan plus pertuzumab for HER2-positive metastatic breast cancer. N Engl J Med. 2025. Published online ahead of print. doi:10.1056/NEJMoa2508668
  • ENHERTU. Prescribing information. Daiichi Sankyo, Inc.; 2025.
  • Tolaney SM, Jiang Z, Zhang Q, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab vs taxane + trastuzumab + pertuzumab (THP) for first-line treatment of patients with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer: interim results from DESTINY-Breast09. Presented at: American Society of Clinical Oncology Annual Meeting; June 2, 2025; Chicago, IL.
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