Safety Data
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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 | 0.4 |
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.
ENHERTU 5.4 mg/kg (n=257) |
T-DM1 3.6 mg/kg (n=261) |
||
---|---|---|---|
Serious adverse reactionsl | 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% |
|
ENHERTU 5.4 mg/kg (n=257) |
T-DM1 3.6 mg/kg (n=261) |
---|---|
Serious adverse reactionsl | |
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% |
|
- Other clinically relevant adverse reactions reported in <10% of patients receiving ENHERTU were dyspnea (8%), pruritus (8%), skin hyperpigmentation (6%),p dysgeusia (6%), dehydration (4.3%), blurred vision (3.5%), asymptomatic left ventricular ejection fraction decrease (2.7%), infusion-related reactions (2.3%),q and febrile neutropenia (0.8%)
lAn adverse reaction was defined as either an AE that was absent before the first dose of study drug, an AE that worsened between the first dose and 47 days after the last dose, or an SAE that occurred ≥48 days after the last dose and was considered related to treatment.
mILD includes events that were adjudicated as ILD and related to use of ENHERTU. Cases of potential ILD/pneumonitis were based on the current MedDRA v23.0 for the narrow ILD SMQ, selected terms from the broad ILD SMQ, and PTs of respiratory failure and acute respiratory failure.
nGrouped term of anemia includes PTs of hemoglobin decreased, red blood cell count decreased, anemia, and hematocrit decreased.
oGrouped term of thrombocytopenia includes PTs of platelet count decreased and thrombocytopenia.
pGrouped term includes PTs of skin hyperpigmentation, skin discoloration, and pigmentation disorder.
qGrouped term includes PTs of hypersensitivity and infusion-related reactions.
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 |
Alopeciar | 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 |
rThis 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
- NCCN Guidelines® for Antiemesis lists fam-trastuzumab deruxtecan-nxki (ENHERTU) as moderate emetic risk and recommends several prophylactic antiemetic regimens to help decrease potential vomiting4
- 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
- NCCN Guidelines® for Antiemesis lists fam-trastuzumab deruxtecan-nxki (ENHERTU) as moderate emetic risk and recommends several prophylactic antiemetic regimens to help decrease potential vomiting4
NCCN prophylactic and management strategies for acute and delayed emesis prevention: Moderate emetic risk parenteral anticancer agents4,s-u
Select treatment option D, E, or F | Days 2 and 3 | |||
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All treatment options are Category 1 and should be started before anticancer therapyv | ||||
Day 1 before infusion of fam-trastuzumab deruxtecan-nxki (ENHERTU) |
Treatment option D, use the following combination:
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Treatment option D:
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Treatment option E, use the following combinationy:
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Treatment option E:
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Treatment option F, use the following combinationy:
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Treatment option F:
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Select treatment option D, E, or F | Days 2 and 3 | |||
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All treatment options are Category 1 and should be started before anticancer therapyv | ||||
Day 1 before infusion of fam-trastuzumab deruxtecan-nxki (ENHERTU) |
Treatment option D, use the following combination:
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Treatment option D:
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Treatment option E, use the following combinationy:
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Treatment option E:
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Treatment option F, use the following combinationy:
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Treatment option F:
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Adapted with permission from the NCCN Guidelines® for Antiemesis V1.2022.
sFor details regarding recommendations and specific dosing information, please refer to the NCCN Guidelines® for Antiemesis.
tAntiemetic regimens should be chosen based on the drug with the highest emetic risk as well as patient-specific risk factors.
uWith or without lorazepam 0.5–2 mg PO or IV or sublingual every 6 hours as needed days 1-4. With or without H2 blocker or proton pump inhibitor.
vCategory 1 recommendations indicate uniform NCCN consensus that the intervention is appropriate based on high-level evidence.
wEmerging data and clinical practice suggest dexamethasone doses may be individualized. Higher doses may be considered, especially when an NK1 RA is not given concomitantly. Lower doses, given for shorter durations, or even elimination of dexamethasone on subsequent days (for delayed nausea and emesis prevention) may be acceptable for non-cisplatin regimens based on patient characteristics. If dexamethasone eliminated on subsequent days for delayed nausea and emesis prevention, consider other alternative antiemetics (eg, olanzapine).
xUse of corticosteroid premedications should be avoided with cellular therapies.
yA 3-drug prophylactic regimen (E or F) is recommended for select patients with additional patient-related risk factors or previous treatment failure with a corticosteroid + 5-HT3 RA alone.
zData suggest that a 5-mg dose of olanzapine is efficacious. Consider this dose especially for elderly or over sedated patients.
aaIf netupitant/palonosetron or fosnetupitant/palonosetron fixed combination product used, no further 5-HT3 RA is required.
bbWhen used in combination with an NK1 RA, there is no preferred 5-HT3 RA.
ccNo further 5-HT3 therapy required if palonosetron or granisetron extended-release injection administered, or if granisetron transdermal patch applied, on day 1.
- Clinical studies: There were no clinically meaningful drug-drug interactions between ENHERTU and itraconazole (CYP3A inhibitor), as well as ritonavir (OATP 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
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