Safety Data

ENHERTU has serious Warnings and Precautions. Please see full Prescribing Information, including Boxed WARNINGS, and click here for Medication Guide.

Safety data from DESTINY-Breast03 confirmed the benefit-risk profile of ENHERTU for HER2+ mBC (5.4 mg/kg) demonstrated in prior studies1,a

The majority of adverse reactions were Grade 1 or 2

  • Median duration of treatment was 14 months (range: 0.7 to 30) with ENHERTU and 7 months (range: 0.7 to 25) with T-DM11
  • Prophylactic or supportive treatment of ENHERTU or T-DM1–induced adverse reactions was at the discretion of the treating physician and institutional guidelines2

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

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 painb 21 0.8 8 0.4
Stomatitisc 20 0.8 5 0
Dyspepsia 11 0 6 0
General disorders and administration site conditions Fatigued 49 6 35 0.8
Blood and lymphatic system disorders Anemiae 33 7 17 6
Skin and subcutaneous tissue disorders Alopeciaf 37 0.4 3.1 0
Musculoskeletal and connective tissue disorders Musculoskeletal paing 31 1.2 25 0.4
Metabolism and nutrition disorders Decreased appetite 29 1.6 17 0.4
Investigations Decreased weight 17 1.2 6 0.4
Respiratory, thoracic, and mediastinal disorders Respiratory infectionh 22 0.8 12 1.1
Epistaxis  11 0 16 0.4
Cough 11 0.4 10 0
Interstitial lung diseasei 11 0.8 1.9 0
Nervous system disorders Headachej 22 0.4 16 0
Peripheral neuropathyk 13 0.4 14 0.4
Dizziness 13 0.4 8 0
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 painb 21 0.8 8 0.4
Stomatitisc 20 0.8 5 0
Dyspepsia 11 0 6 0
General disorders and administration site conditions
Fatigued 49 6 35 0.8
Blood and lymphatic system disorders
Anemiae 33 7 17 6
Skin and subcutaneous tissue disorders
Alopeciaf 37 0.4 3.1 0
Musculoskeletal and connective tissue disorders
Musculoskeletal paing 31 1.2 25 0.4
Metabolism and nutrition disorders
Decreased appetite 29 1.6 17 0.4
Investigations
Decreased weight 17 1.2 6 0.4
Respiratory, thoracic, and mediastinal disorders
Respiratory infectionh 22 0.8 12 1.1
Epistaxis 11 0 16 0.4
Cough 11 0.4 10 0
Interstitial lung diseasei 11 0.8 1.9 0
Nervous system disorders
Headachej 22 0.4 16 0
Peripheral neuropathyk 13 0.4 14 0.4
Dizziness 13 0.4 8 0

Events were graded using NCI-CTCAE v.5.0.

aPrior ENHERTU HER2+ mBC studies: Phase 2 DESTINY-Breast01 and Phase 1 DS8201-A-J101.

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

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

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

eGrouped term of anemia includes PTs of anemia, decreased hemoglobin, and decreased red blood cell count.

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

gGrouped 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.

hGrouped 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.

iInterstitial lung disease includes events that were adjudicated as 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.

jGrouped term of headache includes PTs of headache and migraine.

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

Selected laboratory abnormalities in patients in DESTINY-Breast031

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
Hypokalemia 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)		 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
Hypokalemia 35 4.7 39 1.5
Increased blood bilirubin 20 0 14 0
Increased blood creatinine 16 0.8 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.

Updated safety analysis from DESTINY-Breast03 further confirmed the benefit-risk profile of ENHERTU for HER2+ mBC (5.4 mg/kg) demonstrated in prior studies1-4

  • Initial analysis (May 2021 data cutoff): Median duration of treatment was 14 months (range: 0.7 to 30) with ENHERTU and 7 months (range: 0.7 to 25) with T-DM1

 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 anemiaI 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
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 anemiaI 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
  • 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%)
Updated analysis (July 2022)
  • The median duration of treatment increased to 18 months for ENHERTU (IQR: 9.0 to 29.4) and remained 7 months for T-DM1 (IQR: 2.8 to 12.3)
  • Discontinuations, dose interruptions, and dose reductions due to ARs were 20%, 42%, and 25%, respectively, for ENHERTU
  • No new safety signals were observed for ENHERTU

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

mGrouped term of thrombocytopenia includes PTs of platelet count decreased and thrombocytopenia.

Incidence of select common adverse reactions in DESTINY-Breast03

The majority of these adverse reactions were Grade 1 or 22,3

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
Alopecian 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

nThis 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

  • Prophylactic or supportive treatment of ENHERTU or T-DM1–induced adverse reactions was at the discretion of the treating physician and institutional guidelines2

Premedication: ENHERTU is moderately emetogenic, which includes delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting1

Drug interaction studies1

  • Clinical studies: There were no clinically meaningful drug-to-drug interactions between ENHERTU and itraconazole (CYP3A inhibitor), as well as ritonavir (OATP1B/CYP3A inhibitor)
  • In vitro studies: DXd did not inhibit common CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A) nor induce CYP1A2, CYP2B6, or CYP3A
  • 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
  • In vitro studies: DXd is a substrate of OATP1B1, OATP1B3, MATE2-K, P-gp, MRP1, and BCRP
Learn more about DESTINY-Breast01
5-HT3, 5-hydroxytryptamine 3; AE, adverse event; ALT, alanine aminotransferase; AR, adverse reaction; AST, aspartate aminotransferase; BCRP, breast cancer resistance protein; BSEP, bile salt export pump; CYP, cytochrome P450; H2, histamine type 2; HER2, human epidermal growth factor receptor 2; ILD, interstitial lung disease; IQR, interquartile range; IV, intravenous; mBC, metastatic breast cancer; MATE, multidrug and toxic compound extrusion; MedDRA, Medical Dictionary for Regulatory Activities; MRP, multidrug resistance protein 1; NCCN, National Comprehensive Cancer Network; NCI-CTCAE, National Cancer Institute–Common Terminology Criteria for Adverse Events; NK1, neurokinin-1; OAT, organic anion transporter; OATP, organic anion transporting polypeptide; OCT, organic cation transporter; P-gp, P-glycoprotein; PO, by mouth; PT, preferred term; RA, receptor antagonist; SAE, serious adverse event; SMQ, Standardised MedDRA Query; T-DM1, ado-trastuzumab emtansine; TEAE, treatment-emergent adverse event.