Safety Data

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

The ENHERTU safety profile in HER2-low mBC was further established in DESTINY-Breast041

The majority of adverse reactions were Grade 1 or 21
  • The median duration of treatment was 8 months (range: 0.2 to 33) with ENHERTU and 3.5 months (range: 0.3 to 18) with chemotherapy1,2
  • Prophylactic or supportive treatment of treatment-induced adverse reactions was at the discretion of the treating physician3

Common adverse reactions (≥10% all Grades or ≥2% Grades 3 or 4) in patients treated with ENHERTU in DESTINY-Breast041

Adverse reactions ENHERTU
5.4 mg/kg (n=371)
Chemotherapy
(n=172)
All Grades
(%)
Grades 3 or 4
(%)
All Grades
(%)
Grades 3 or 4
(%)
Gastrointestinal disorders Nausea 76 4.6 30 0
Vomiting 40 1.6 13 0
Constipation 34 0.8 22 0
Diarrhea 27 1.3 22 1.7
Abdominal paina 18 0.5 13 0
Stomatitisb 13 0.3 12 0.6
General disorders and administration site conditions Fatiguec 54 9 48 4.7
Pyrexia 12 0.3 13 0
Skin and subcutaneous tissue disorders Alopecia 40 0 33 0
Rashd 13 0 23 4.7
Blood and lymphatic system disorders Anemiae 39 10 27 5
Metabolism and nutrition disorders Decreased appetite 32 2.4 19 1.2
Musculoskeletal and connective tissue disorders Musculoskeletal painf 32 1.3 31 0.6
Investigations Decreased weight 16 0.3 8 0
Vascular Disorders Hemorrhageg 16 0 3.5 0
Nervous system disorders Headacheh 15 0.3 6 0
Peripheral neuropathyi 13 0 29 5
Dizzinessj 11 0.5 6 0
Infections and infestations Upper respiratory tract infectionk 14 0.3 5 0
Respiratory, thoracic, and mediastinal disorders Interstitial lung diseasel 12 1.3 0.6 0
Dyspnea 10 1.3 9 1.2
Adverse reactions ENHERTU
5.4 mg/kg (n=371)
Chemotherapy
(n=172)
All Grades
(%)
Grades 3 or 4
(%)
All Grades
(%)
Grades 3 or 4
(%)
Gastrointestinal disorders
Nausea 76 4.6 30 0
Vomiting 40 1.6 13 0
Constipation 34 0.8 22 0
Diarrhea 27 1.3 22 1.7
Abdominal paina 18 0.5 13 0
Stomatitisb 13 0.3 12 0.6
General disorders and administration site conditions
Fatiguec 54 9 48 4.7
Pyrexia 12 0.3 13 0
Skin and subcutaneous tissue disorders
Alopecia 40 0 33 0
Rashd 13 0 23 4.7
Blood and lymphatic system disorders
Anemiae 39 10 27 5
Metabolism and nutrition disorders
Decreased appetite 32 2.4 19 1.2
Musculoskeletal and connective tissue disorders
Musculoskeletal painf 32 1.3 31 0.6
Investigations
Decreased weight 16 0.3 8 0
Vascular Disorders
Hemorrhageg 16 0 3.5 0
Nervous system disorders
Headacheh 15 0.3 6 0
Peripheral neuropathyi 13 0 29 5
Dizzinessj 11 0.5 6 0
Infections and infestations
Upper respiratory tract infectionk 14 0.3 5 0
Respiratory, thoracic, and mediastinal disorders
Interstitial lung diseasel 12 1.3 0.6 0
Dyspnea 10 1.3 9 1.2

Events were graded using NCI-CTCAE version 5.0.

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

bIncluding stomatitis, aphthous ulcer, mouth ulceration, and pharyngeal inflammation.

cIncluding fatigue, asthenia, and malaise.

dIncluding rash, pustular rash, pruritic rash, maculo-papular rash, palmar-plantar erythrodysesthesia syndrome, papular rash, macular rash, eczema, erythema multiforme, dermatitis, urticarial dermatitis, drug eruption, and dermatitis bullous.

eIncluding anemia, decreased hemoglobin, and decreased red blood cell count.

fIncluding back pain, myalgia, pain in extremity, musculoskeletal pain, bone pain, musculoskeletal chest pain, arthralgia, noncardiac chest pain, musculoskeletal stiffness, arthritis, spinal pain, and neck pain.

gIncluding esophageal varices, hemorrhage, hemorrhoidal hemorrhage, epistaxis, hematuria, conjunctival hemorrhage, vaginal hemorrhage, gingival bleeding, genital hemorrhage, eye hemorrhage, hemoptysis, hemorrhagic cystitis, pharyngeal hemorrhage, rectal hemorrhage, upper gastrointestinal hemorrhage, and esophageal hemorrhage.

hIncluding headache and migraine.

iIncluding peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, polyneuropathy, paresthesia, hypoesthesia, dysesthesia, and neuralgia.

jIncluding dizziness, postural dizziness, and vertigo.

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

lInterstitial lung disease includes events that were adjudicated as ILD for ENHERTU: interstitial lung disease, pneumonitis, organizing pneumonia, pneumonia, and radiation pneumonitis.

Selected laboratory abnormalities in patients in DESTINY-Breast04 1

Laboratory parameter ENHERTU
5.4 mg/kg (n=371)
Chemotherapy
(n=172)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Hematology Decreased white blood cell count 70 9 78 25
Decreased hemoglobin 64 8 53 6
Decreased neutrophil count 64 14 73 38
Decreased lymphocyte count 55 18 40 11
Decreased platelet count 44 6 21 0.6
Chemistry Increased aspartate aminotransferase 38 2.2 38 4.1
Increased alanine aminotransferase 36 0.8 38 4.1
Increased blood alkaline phosphatase 34 0.3 24 0
Hypokalemia 25 3.3 17 1.2
Increased blood bilirubin 16 2.7 15 0.6
Increased blood creatinine 15 1.1 9 0.6
Laboratory parameter ENHERTU
5.4 mg/kg (n=371)
Chemotherapy
(n=172)
All Grades
(%)
Grades 3-4
(%)
All Grades
(%)
Grades 3-4
(%)
Hematology
Decreased white blood cell count 70 9 78 25
Decreased hemoglobin 64 8 53 6
Decreased neutrophil count 64 14 73 38
Decreased lymphocyte count 55 18 40 11
Decreased platelet count 44 6 21 0.6
Chemistry
Increased aspartate amino-transferase 38 2.2 38 4.1
Increased alanine amino-transferase 36 0.8 38 4.1
Increased blood alkaline phosphatase 34 0.3 24 0
Hypokalemia 25 3.3 17 1.2
Increased blood bilirubin 16 2.7 15 0.6
Increased blood creatinine 15 1.1 9 0.6

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.

Adverse reactions that may require dose modifications 1

ENHERTU
5.4 mg/kg (n=371)
Chemotherapy
(n=172)
Serious adverse reactions1-3 28% 25%
  • For ENHERTU, serious ARs in >1% of patients were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to adverse reactions occurred in 4.0% of patients, including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each)1
  • For chemotherapy, the most frequent in >1% of patients were dyspnea, febrile neutropenia, fatigue, pleural effusion, neutropenia, disease progression, hepatic failure, hyponatremia, overdose, medication error, colitis, and femur fracture3
Discontinuations due to
adverse reactions1,2,4
16% 8%
  • For ENHERTU, the most frequent adverse reaction associated with discontinuation was ILD/pneumonitis (8%). Per protocol, ENHERTU was discontinued in DESTINY-Breast04 in patients who were diagnosed with symptomatic (Grade 2 or greater) ILD1
  • For chemotherapy, the most frequent was peripheral sensory neuropathy (2.3%)4
Dose interruptions due
to adverse reactions1,3,5
39% 42%
  • For ENHERTU, the most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia1
  • For chemotherapy, the most frequent (>2%) were neutropenia, leukopenia, increased transaminases, palmar-plantar erythrodysesthesia syndrome, fatigue, anemia, nausea, diarrhea, and peripheral sensory neuropathy3
Dose reductions due to
adverse reactions1,3,5
23% 38%
  • For ENHERTU, the most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia1
  • For chemotherapy, the most frequent (>2%) were neutropenia, palmar-plantar erythrodysesthesia syndrome, increased transaminases, fatigue, leukopenia, nausea, and peripheral sensory neuropathy3
ENHERTU
5.4 mg/kg (n=371)
Chemotherapy
(n=172)
Serious adverse reactions1,3
28% 25%
  • For ENHERTU, serious ARs in >1% of patients were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to adverse reactions occurred in 4.0% of patients, including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each)1
  • For chemotherapy, the most frequent in >1% of patients were dyspnea, febrile neutropenia, fatigue, pleural effusion, neutropenia, disease progression, hepatic failure, hyponatremia, overdose, medication error, colitis, and femur fracture3
Discontinuations due to
adverse reactions1,2,4
16% 8%
  • For ENHERTU, the most frequent adverse reaction associated with discontinuation was ILD/pneumonitis (8%). Per protocol, ENHERTU was discontinued in DESTINY-Breast04 in patients who were diagnosed with symptomatic (Grade 2 or greater) ILD1
  • For chemotherapy, the most frequent was peripheral sensory neuropathy (2.3%)4
Dose interruptions due to adverse reactions1,3,5
39% 42%
  • For ENHERTU, the most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia1
  • For chemotherapy, the most frequent (>2%) were neutropenia, leukopenia, increased transaminases, palmar-plantar erythrodysesthesia syndrome, fatigue, anemia, nausea, diarrhea, and peripheral sensory neuropathy3
Dose reductions due to adverse reactions1,3,5
23% 38%
  • For ENHERTU, the most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia1
  • For chemotherapy, the most frequent (>2%) were neutropenia, palmar-plantar erythrodysesthesia syndrome, increased transaminases, fatigue, leukopenia, nausea, and peripheral sensory neuropathy3
  • Other clinically relevant adverse reactions reported in ≤10% of patients treated with ENHERTU were cough (10%), dysgeusia (10%), abdominal distension (5%), blurred vision (4.9%), pruritus (3.2%), gastritis (2.7%), skin hyperpigmentation (2.7%), flatulence (2.4%), dehydration (1.9%), febrile neutropenia (1.1%), and infusion-related reactions (0.5%)1

The majority of these adverse reactions were Grade 1 or 23

Adverse reactions ENHERTU 5.4 mg/kg (n=371)
Grade 1 (%) Grade 2 (%) Grade 3 (%) Grade 4 (%)
Nausea 43.9 27.5 4.6 0
Fatiguem 29.4 18.6 9.4 0
Alopecia 28.6 11.1 0 0
Vomiting 25.9 12.9 1.6 0
Constipation 28.3 4.9 0.5 0.3
Decreased appetite 18.9 10.5 2.4 0
Diarrhea 19.7 5.9 1.3 0

mIncluding fatigue, asthenia, and malaise.

  • Prophylactic or supportive treatment of treatment-induced adverse events was at the discretion of the treating physician and institutional guidelines3
  • 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 nausea/vomiting6

Most common (≥20%) ARs, including laboratory abnormalities, in the pooled safety population of patients with mBC and other solid tumors treated with ENHERTU 5.4 mg/kg (N=984)1

  • Nausea (76%), decreased white blood cell count (71%), decreased hemoglobin (66%), decreased neutrophil count (65%), decreased lymphocyte count (55%), fatigue (54%), decreased platelet count (47%), increased aspartate aminotransferase (48%), vomiting (44%), increased alanine aminotransferase (42%), alopecia (39%), increased blood alkaline phosphatase (39%), constipation (34%), musculoskeletal pain (32%), decreased appetite (32%), hypokalemia (28%), diarrhea (28%), and respiratory infection (24%)
  • 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 nausea/vomiting6

NCCN Guidelines recommends the following prophylactic and management strategies for acute and delayed emesis prevention when using moderate emetic risk parenteral anticancer agents6,n-p

  Treatment Option Day 1 Days 2 and 3
Before infusion of fam-trastuzumab deruxtecan-nxki (ENHERTU)
  • Select treatment option D, E, or F
  • All treatment options are Category 1 and should be started before anticancer therapyq
D Use the following combination:
  • 5-HT3 RA
  • Dexamethasoner,s
Use one of the following:
  • Dexamethasonen,o OR
  • 5-HT3 RA monotherapyx:
    • Granisetron
    • Ondansetron
    • Dolasetron
E Use the following combinationp:
  • Olanzapineu
  • Palonosetron
  • Dexamethasoner,s
Use the following:
  • Olanzapineq
F Use the following combinationp:
  • NK1 RA
  • 5-HT3 RAv,w
  • Dexamethasoner,s
Use the following:
  • Aprepitant +/- dexamethasonen,o
Table depicting management of select common adverse reactions

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2022. © 2022 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data become available. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

nFor details regarding recommendations and specific dosing information, please refer to the NCCN Guidelines® for Antiemesis.

oAntiemetic regimens should be chosen based on the drug with the highest emetic risk as well as patient-specific risk factors.

pLorazepam 0.5–1 mg PO or IV or sublingual every 6 hours as needed on days 1-4. Start with 0.5 mg for patients who are naive to lorazepam. May be administered with or without H2 blocker or proton pump inhibitor (PPI) if patient exhibits reflux symptoms.

qCategory 1 recommendations indicate uniform NCCN consensus that the intervention is appropriate based on high-level evidence.

rEmerging 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 based on patient characteristics. If dexamethasone eliminated on subsequent days for delayed nausea and emesis prevention, consider other alternative antiemetics (eg, olanzapine).

sUse of corticosteroid premedications should be avoided with cellular therapies.

tA 3-drug prophylactic regimen is recommended for select patients with additional patient-related risk factors or previous treatment failure with a corticosteroid + 5-HT3 RA alone.

uData suggest that a 5-mg dose of olanzapine is efficacious. Consider this dose especially for elderly or oversedated patients.

vIf netupitant/palonosetron or fosnetupitant/palonosetron fixed combination product used, no further 5-HT3 RA is required.

wWhen used in combination with an NK1 RA, there is no preferred 5-HT3 RA.

xNo 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 (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
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5-HT3, 5-hydroxytryptamine 3; AR, adverse reaction; BCRP, breast cancer resistance protein; BSEP, bile salt export pump; CYP, cytochrome P450; HER2, human epidermal growth factor receptor 2; ILD, interstitial lung disease; IV, intravenous; mBC, metastatic breast cancer; MATE, multidrug and toxic compound extrusion; MRP, multidrug resistance protein; 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; RA, receptor antagonist.