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) |
- 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% |
|
Discontinuations due to adverse reactions | 14% | 7% |
|
Dose interruptions due to adverse reactions | 44% | 23% |
|
Dose reductions due to adverse reactions | 21% | 13% |
|
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% |
|
|
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% |
|
|
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% |
|
|
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% |
|
- 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.