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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 benefit-risk profile of ENHERTU was established in DESTINY-Breast031

The majority of adverse reactions were Grade 1 or 21,2

  • May 2021 analysis: Median duration of treatment was 14 months (range: 0.7-30) with ENHERTU and 7 months (range: 0.7-25) with T-DM11

May 2021 analysis: Common adverse reactions (≥10% All Grades or ≥2% Grades 3 or 4) in patients treated with ENHERTU in DESTINY-Breast031,2

Adverse reactions ENHERTU 5.4 mg/kg
(n=257) 		T-DM1 3.6 mg/kg
(n=261)
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Gastrointestinal
disorders		 Nausea 76 7 30 0.4
Vomiting 49 1.6 10 0.8
Constipation 34 0 20 0
Diarrhea 29 1.2 7 0.4
Abdominal paina 21 0.8 8 0.4
Stomatitisb 20 0.8 5 0
Dyspepsia 11 0 6 0
General disorders
and administration
site conditions		 Fatiguec 49 6 35 0.8
Skin and
subcutaneous tissue
disorders		 Alopeciad 37 0.4 3.1 0
Musculoskeletal
and connective tissue
disorders		 Musculoskeletal paine 31 1.2 25 0.4
Metabolism and
nutritional disorders		 Decreased appetite 29 1.6 17 0.4
Investigations Decreased weight 17 1.2 6 0.4
Respiratory,
thoracic, and
mediastinal
disorders		 Respiratory infectionf 22 0.8 12 1.1
Epistaxis 11 0 16 0.4
Cough 11 0.4 10 0
Interstitial lung diseaseg 11 0.8 1.9 0
Nervous system
disorders		 Headacheh 22 0.4 16 0
Peripheral neuropathyi 13 0.4 14 0.4
Dizziness 13 0.4 8 0
Adverse reactions ENHERTU
5.4 mg/kg (n=257)
All Grades
(%) 		Grades
3-4 (%)
Gastrointestinal disorders
Nausea 76 7
Vomiting 49 1.6
Constipation 34 0
Diarrhea 29 1.2
Abdominal paina 21 0.8
Stomatitisb 20 0.8
Dyspepsia 11 0
General disorders and administration site conditions
Fatiguec 49 6
Skin and subcutaneous tissue disorders
Alopeciad 37 0.4
Musculoskeletal and connective tissue disorders
Musculoskeletal paine 31 1.2
Metabolism and nutrition disorders
Decreased appetite 29 1.6
Investigations
Decreased weight 17 1.2
Respiratory, thoracic, and mediastinal disorders
Respiratory infectionf 22 0.8
Epistaxis 11 0
Cough 11 0.4
Interstitial lung diseaseg 11 0.8
Nervous system disorders
Headacheh 22 0.4
Peripheral neuropathyi 13 0.4
Dizziness 13 0.4
Adverse
reactions 		T-DM1
3.6 mg/kg (n=261)
All Grades
(%) 		Grades
3-4 (%)
Gastrointestinal disorders
Nausea 30 0.4
Vomiting 10 0.8
Constipation 20 0
Diarrhea 7 0.4
Abdominal paina 8 0.4
Stomatitisb 5 0
Dyspepsia 6 0
General disorders and administration site conditions
Fatiguec 35 0.8
Skin and subcutaneous tissue disorders
Alopeciad 3.1 0
Musculoskeletal and connective tissue disorders
Musculoskeletal paine 25 0.4
Metabolism and nutrition disorders
Decreased appetite 17 0.4
Investigations
Decreased weight 6 0.4
Respiratory, thoracic, and mediastinal disorders
Respiratory infectionf 12 1.1
Epistaxis 16 0.4
Cough 10 0
Interstitial lung diseaseg 1.9 0
Nervous system disorders
Headacheh 16 0
Peripheral neuropathyi 14 0.4
Dizziness 8 0

Events were graded using NCI-CTCAE v.5.0.

aGrouped term of abdominal pain includes PTs of abdominal pain, abdominal discomfort, lower abdominal pain, and upper abdominal pain.

bGrouped term of stomatitis includes PTs of stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosal eruption.

cGrouped term of fatigue includes PTs of fatigue, asthenia, malaise, and lethargy.

dThis Grade 3 event was reported by the investigator. Per NCI-CTCAE v.5.0, the highest NCI-CTCAE grade for alopecia is Grade 2.

eGrouped term of musculoskeletal pain includes PTs of back pain, myalgia, pain in extremity, musculoskeletal pain, muscle spasms, bone pain, neck pain, musculoskeletal chest pain, and limb discomfort.

fGrouped term of respiratory infection includes PTs of respiratory tract infection, lower and upper respiratory tract infection, pneumonia, influenza, influenza-like illness, viral upper respiratory infection, bronchitis, and respiratory syncytial virus infection.

gInterstitial lung disease includes events that were adjudicated as drug-induced ILD for ENHERTU: pneumonitis, interstitial lung disease, organizing pneumonia, pneumonia, and pulmonary mass. For T-DM1: pneumonitis, interstitial lung disease, organizing pneumonia, and pulmonary embolism.

hGrouped term of headache includes PTs of headache and migraine.

iGrouped term of peripheral neuropathy includes PTs of peripheral neuropathy, peripheral sensory neuropathy, and paresthesia.

The majority of select adverse reactions in DESTINY-Breast03 were Grade 1 or 2

May 2021 analysis: select common adverse reactions by grade2,3

Adverse reactions ENHERTU
5.4 mg/kg (n=257)
Grade 1
(%) 		Grade 2
(%) 		Grade 3
(%) 		Grade 4
(%)
Nausea 41.6 27.6 6.6 0
Fatigue 29.2 14.0 5.8 0
Alopeciaj 26.5 9.3 0.4 0
Vomiting 31.1 16.3 1.2 0.4
Constipation 26.5 7.8 0 0
Decreased appetite 19.5 8.2 1.6 0
Diarrhea 19.8 8.2 1.2 0
Adverse
reactions 		ENHERTU
5.4 mg/kg
(n=257)
Grade 1
(%) 		Grade 2
(%)
Nausea 41.6 27.6
Fatigue 29.2 14.0
Alopeciaj 26.5 9.3
Vomiting 31.1 16.3
Constipation 26.5 7.8
Decreased appetite 19.5 8.2
Diarrhea 19.8 8.2
Adverse
reactions 		ENHERTU
5.4 mg/kg
(n=257)
Grade 3
(%) 		Grade 4
(%)
Nausea 6.6 0
Fatigue 5.8 0
Alopeciaj 0.4 0
Vomiting 1.2 0.4
Constipation 0 0
Decreased appetite 1.6 0
Diarrhea 1.2 0
  • Prophylactic or supportive treatment of ENHERTU or T-DM1–induced adverse reactions was at the discretion of the treating physician and institutional guidelines3
  • Rates of nausea and vomiting were found to be highest in cycle 1 and lower in subsequent cycles for ENHERTU
  • Majority of alopecia reported was Grade 1 (26.5%) vs Grade 2 (9.3%), defined as hair loss of <50% from baseline
    • Rates of alopecia were found to be highest in cycle 1 and lower in later cycles for ENHERTU in the DESTINY-Breast03 safety update

jThis Grade 3 event was reported by the investigator. Per NCI-CTCAE v.5.0, the highest NCI-CTCAE grade for alopecia is Grade 2.1

May 2021 analysis: ILD and pneumonitis were reported with ENHERTU in DESTINY-Breast03; no Grade 4 or 5 events were observed1-3,k

Adjudicated as
drug-induced ILD, n (%) 		ENHERTU 5.4 mg/kg (n=257) T-DM1 3.6 mg/kg
(n=261)
Grade 1 7 (2.7) 4 (1.5)
Grade 2 18 (7.0) 1 (0.4)
Grade 3 2 (0.8) 0
Grade 4 0 0
Grade 5 0 0
All Grades 27 (10.5) 5 (1.9)
Adjudicated as
drug-induced
ILD, n (%) 		ENHERTU
5.4 mg/kg
(n=257)
Grade 1 7 (2.7)
Grade 2 18 (7.0)
Grade 3 2 (0.8)
Grade 4 0
Grade 5 0
All Grades 27 (10.5)
Adjudicated as
drug-induced
ILD, n (%) 		T-DM1 3.6 mg/kg
(n=261)
Grade 1 4 (1.5)
Grade 2 1 (0.4)
Grade 3 0
Grade 4 0
Grade 5 0
All Grades 5 (1.9)
November 2023 analysis4:
  • Overall incidence of ILD was 16.7% in the ENHERTU arm and 3.4% in the T-DM1 arm
  • No Grade 4 or 5 adjudicated drug-induced ILD/pneumonitis events were observed

kGrade 5=fatal cases.3

May 2021 analysis: selected laboratory abnormalities in patients in DESTINY-Breast031,2

Laboratory parameter ENHERTU
5.4 mg/kg (n=257) 		T-DM1
3.6 mg/kg (n=261)
All Grades
(%) 		Grades 3-4
(%) 		All Grades
(%) 		Grades 3-4
(%)
Hematology Decreased white blood cell count 74 8 24 0.8
Decreased neutrophil count 70 18 30 2.3
Decreased hemoglobin 64 7 38 6
Decreased lymphocyte count 55 14 23 3.9
Decreased platelet count 52 7 79 24
Chemistry Increased aspartate aminotransferase 67 0.8 83 5
Increased alanine aminotransferase 53 1.6 67 6
Increased blood alkaline phosphatase 49 0.8 46 0.8
Decreased blood potassium 35 4.7 39 1.5
Increased blood bilirubin 20 0 14 0
Increased blood creatinine 16 0.8 8 0.4
Laboratory parameter ENHERTU
5.4 mg/kg (n=257)
All
Grades
(%) 		Grades
3-4 (%)
Hematology
Decreased white blood cell count 74 8
Decreased neutrophil count 70 18
Decreased hemoglobin 64 7
Decreased lymphocyte count 55 14
Decreased platelet count 52 7
Chemistry
Increased aspartate aminotransferase 67 0.8
Increased alanine aminotransferase 53 1.6
Increased blood alkaline phosphatase 49 0.8
Decreased blood potassium 35 4.7
Increased blood bilirubin 20 0
Increased blood creatinine 16 0.8
Laboratory parameter T-DM1
3.6 mg/kg (n=261)
All
Grades
(%) 		Grades
3-4 (%)
Hematology
Decreased white blood cell count 24 0.8
Decreased neutrophil count 30 2.3
Decreased hemoglobin 38 6
Decreased lymphocyte count 23 3.9
Decreased platelet count 79 24
Chemistry
Increased aspartate aminotransferase 83 5
Increased alanine aminotransferase 67 6
Increased blood alkaline phosphatase 46 0.8
Decreased blood potassium 39 1.5
Increased blood bilirubin 14 0
Increased blood creatinine 8 0.4

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.

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

May 2021 analysis: median duration of treatment was 14 months (range: 0.7-30) with ENHERTU and 7 months (range: 0.7-25) with T-DM11-3

Clinically
relevant AR
considerations 		ENHERTU
5.4 mg/kg
(n=257) 		T-DM1
3.6 mg/kg
(n=261)
Serious adverse reactions 19.1% 18.0%
  • For ENHERTU, serious ARs in >1% of patients were vomiting, ILD, pneumonia, pyrexia, and urinary tract infection. Fatalities occurred in 2 patients (1 due to COVID-19 and 1 due to sudden death)
  • For T-DM1, serious ARs in >1% of patients were pneumonia, anemia, and thrombocytopenia. Fatalities occurred in 2 patients (1 due to COVID-19 and 1 due to acute kidney injury)
Discontinuations due to adverse reactions 14% 7%
  • For ENHERTU, most frequent (>2%) was ILD/pneumonitis (8%). Permanently discontinue ENHERTU in patients who are diagnosed with any symptomatic ILD (Grade >2)
  • For T-DM1, most frequent (>2%) was thrombocytopenia
Dose interruptions due to adverse reactions 44% 23%
  • For ENHERTU, most frequent (>2%) were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis
  • For T-DM1, most frequent (>2%) were anemial and thrombocytopeniam
Dose reductions due to adverse reactions 21% 13%
  • For ENHERTU, most frequent (>2%) were nausea, neutropenia, and fatigue
  • For T-DM1, most frequent (>2%) were thrombocytopenia,m ALT increased, and AST increased
Clinically relevant AR
considerations
Serious adverse reactions
ENHERTU
5.4 mg/kg (n=257) 		19.1%
T-DM1
3.6 mg/kg (n=261) 		18.0%
  • For ENHERTU, serious ARs in >1% of patients were vomiting, ILD, pneumonia, pyrexia, and urinary tract infection. Fatalities occurred in 2 patients (1 due to COVID-19 and 1 due to sudden death)
  • For T-DM1, serious ARs in >1% of patients were pneumonia, anemia, and thrombocytopenia. Fatalities occurred in 2 patients (1 due to COVID-19 and 1 due to acute kidney injury)
Clinically relevant AR
considerations
Discontinuations due to adverse reactions
ENHERTU
5.4 mg/kg (n=257) 		14%
T-DM1
3.6 mg/kg (n=261) 		7%
  • For ENHERTU, most frequent (>2%) was ILD/pneumonitis (8%). Permanently discontinue ENHERTU in patients who are diagnosed with any symptomatic ILD (Grade >2)
  • For T-DM1, most frequent (>2%) was thrombocytopenia
Clinically relevant AR
considerations
Dose interruptions due to adverse reactions
ENHERTU
5.4 mg/kg (n=257) 		44%
T-DM1
3.6 mg/kg (n=261) 		23%
  • For ENHERTU, most frequent (>2%) were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis
  • For T-DM1, most frequent (>2%) were anemial and thrombocytopeniam
Clinically relevant AR
considerations
Dose reductions due to adverse reactions
ENHERTU
5.4 mg/kg (n=257) 		21%
T-DM1
3.6 mg/kg (n=261) 		13%
  • For ENHERTU, most frequent (>2%) were nausea, neutropenia, and fatigue
  • For T-DM1, most frequent (>2%) were thrombocytopenia,m ALT increased, and AST increased
  • Other clinically relevant adverse reactions reported in <10% of patients receiving ENHERTU were dyspnea (8%), pruritus (8%), skin hyperpigmentation (6%), dysgeusia (6%), dehydration (4.3%), blurred vision (3.5%), asymptomatic left ventricular ejection fraction decrease (2.7%), infusion-related reactions (2.3%), and febrile neutropenia (0.8%)1

November 2023 analysis: No new safety signals were observed for ENHERTU4

  • The median duration of treatment increased to 18.2 months for ENHERTU (range: 0.7-56.6) and remained 6.9 months for T-DM1 (range: 0.7-55.2)
  • Serious ARs were 27.6% for ENHERTU
  • Discontinuations, dose interruptions, and dose reductions due to ARs were 24.5%, 56.8%, and 28.4%, respectively, for ENHERTU

lGrouped term of anemia includes PTs of hemoglobin decreased, red blood cell count decreased, anemia, and hematocrit decreased.3

m Grouped term of thrombocytopenia includes PTs of platelet count decreased and thrombocytopenia.3

ALT, alanine aminotransferase; AR, adverse reaction; AST, aspartate aminotransferase; BCRP, breast cancer resistance protein; BSEP, bile salt export pump; CYP, cytochrome P450; DXd, deruxtecan; ILD, interstitial lung disease; 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; PT, preferred term; T-DM1, ado-trastuzumab emtansine.

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 HER2-positive (IHC 3+ or ISH positive) 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. 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-Positive Metastatic Breast Cancer

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: 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 HER2-positive (IHC 3+ or ISH positive) 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
  • ENHERTU. Prescribing information. Daiichi Sankyo, Inc.; 2025.
  • Cortés J, Kim SB, Chung WP, et al; DESTINY-Breast03 Trial Investigators. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386(12):1143-1154.
  • Data on file. Daiichi Sankyo, Inc. Basking Ridge, NJ.
  • Cortés J, Hurvitz SA, Im SA, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial. Nat Med. 2024;30(8):2208-2215.
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