Safety Data

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

Safety data from Phase 2 DESTINY-Breast01 and Phase 1 DS8201-A-J101 established the initial benefit-risk profile for ENHERTU (5.4 mg/kg, N=234)1

The majority of adverse reactions were Grade 1 or 21

The safety of ENHERTU was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2+ breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in Phase 2 DESTINY-Breast01 and Phase 1 Study DS8201-A-J1011

  • Median duration of treatment was 7 months (range: 0.7 to 31)1
  • 94% of patients had visceral disease1
  • 31% of patients had bone metastases1
  • 13% of patients had brain metastases1
  • In the clinical trials, prophylactic or supportive treatment of ENHERTU-induced adverse events was not mandated and was per investigator's discretion and institutional guidelines2

Common adverse reactions (10% all Grades or 2% Grades 3 or 4)1

Adverse Reactions ENHERTU 5.4 mg/kg (N=234)
All Grades
(%)
Grade 3 or 4
(%)
Gastrointestinal Disorders Nausea 79 7
Vomiting 47 3.8
Constipation 35 0.9
Diarrhea 29 1.7
Abdominal paina 19 1.3
Stomatitisb 14 0.9
Dyspepsia 12 0
General Disorders and Administration Site Conditions Fatiguec 59 6
Skin and Subcutaneous Tissue Disorders Alopecia 46 0.4d
Rashe 10 0
Metabolism and Nutrition Disorders Decreased appetite 32 1.3
Blood and Lymphatic System Disorders Anemiaf 31 7
Respiratory, Thoracic, and Mediastinal Disorders Cough 20 0
Dyspnea 13 1.3
Epistaxis 13 0
Interstitial lung diseaseg 9 2.6h
Nervous System Disorders Headachei 19 0
Dizziness 10 0
Infections and Infestation Upper respiratory tract infectionj 15 0
Eye Disorders Dry eye 11 0.4k
Adverse
Reactions
ENHERTU
5.4 mg/kg
(N=234)
All
Grades
(%)
Grade
3 or 4
(%)
Gastrointestinal Disorders Nausea 79 7
Vomiting 47 3.8
Constipation 35 0.9
Diarrhea 29 1.7
Abdominal
paina
19 1.3
Stomatitisb 14 0.9
Dyspepsia 12 0
General Disorders and
Administration Site Conditions
Fatiguec 59 6
Skin and Subcutaneous
Tissue Disorders
Alopecia 46 0.4d
Rashe 10 0
Metabolism and
Nutrition Disorders
Decreased appetite 32 1.3
Blood and Lymphatic
System Disorders
Anemiaf 31 7
Respiratory, Thoracic, and
Mediastinal Disorders
Cough 20 0
Dyspnea 13 1.3
Epistaxis 13 0
Interstitial lung diseaseg 9 2.6h
Nervous System
Disorders
Headachei 19 0
Dizziness 10 0
Infections and Infestation Upper respiratory tract infectionj 15 0
Eye
Disorders
Dry eye 11 0.4k

Events were graded using NCI-CTCAE version 4.03. N=number of patients exposed; PT=preferred term. Percentages were calculated using the number of patients in the Safety Analysis Set as the denominator.

aGrouped term of abdominal pain includes PTs of abdominal discomfort, gastrointestinal pain, abdominal pain, abdominal pain lower, and abdominal pain upper. bGrouped term of stomatitis includes PTs of stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosa blistering. One Grade 1 event of aphthous ulcer was not included in the summary of grouped term stomatitis (from DESTINY-Breast01). cGrouped term of fatigue includes PTs of fatigue and asthenia. dThis Grade 3 event was reported by the investigator. Per NCI-CTCAE v.4.03, the highest NCI-CTCAE grade for alopecia is Grade 2. eGrouped term of rash includes PTs of rash, rash pustular, and rash maculo-papular. fGrouped term of anemia includes PTs of anemia, hemoglobin decreased, hematocrit decreased, and red blood cell count decreased. gInterstitial lung disease includes events that were adjudicated as ILD: pneumonitis, interstitial lung disease, respiratory failure, organizing pneumonia, acute respiratory failure, lung infiltration, lymphangitis, and alveolitis. hAll events had fatal outcomes (n=6). iGrouped term of headache includes PTs of headache, sinus headache, and migraine. jGrouped term of upper respiratory tract infection includes PTs of influenza, influenza-like illness, and upper respiratory tract infection. kThis Grade 4 event was reported by the investigator. Per NCI-CTCAE v.4.03, the highest NCI-CTCAE grade for dry eye is Grade 3.1

Incidence of select common adverse reactions in DESTINY-Breast012

Adverse Reactions
ENHERTU 5.4 mg/kg (N=184)
Grade 1 (%) Grade 2 (%) Grade 3 (%) Grade 4 (%)
Nausea 41.3 28.3 7.6 0
Alopecial 36.4 10.9 0.5 0
Vomiting 27.2 14.1 3.8 0
Constipation 26.6 7.1 0.5 0
Fatigue 22.3 20.1 5.4 0
Diarrhea 16.8 8.2 1.6 0
IThis Grade 3 event was reported by the investigator. Per NCI-CTCAE v.4.03, the highest NCI-CTCAE grade for alopecia is Grade 2.2
  • NCCN Guidelines® for Antiemesis lists fam-trastuzumab deruxtecan-nxki (ENHERTU) as moderate emetic risk and recommends
    several prophylactic antiemetic regimens to decrease potential vomiting3
  • NCCN antiemesis prophylactic and management strategies3:
    • Day 1: 5-HT3 receptor antagonist with dexamethasone before fam-trastuzumab deruxtecan-nxki (ENHERTU) infusion
    • Days 2 and 3: Dexamethasone or 5-HT3 receptor antagonist
    • Day 22: Repeat cycle

Incidence of select adverse reactions (all Grades) decreased by cycle in patients who received ENHERTU in DESTINY-Breast01 (5.4 mg/kg; N=184)2,m

incidence-chart-desk incidence-chart-mob
m As reported by the investigator. nAvailable data did not allow for differentiation between prophylaxis use and treatment of these adverse reactions.
  • The majority of these select adverse reactions occurred during the first 2 cycles
  • Rates decreased in subsequent cycles for each of these select adverse reactions
  • No conclusions may be drawn on whether the decreased rates are due to increased tolerance, patient discontinuations, use of prophylactic therapies, or dose modifications

ENHERTU established the initial benefit-risk profile with further observations of other adverse reactions in pooled analysis (5.4 mg/kg, N=234)1

Other clinically relevant adverse reactions reported in <10% of patients were:
  • Injury, Poisoning, and Procedural Complications: infusion-related reactions (2.6%)
  • Blood and Lymphatic System Disorders: febrile neutropenia (1.7%)

Serious adverse reactions occurred in 20% of patients receiving ENHERTU.

Serious adverse reactions in >1% of patients included:
  • Interstitial lung disease (ILD)
  • Pneumonia
  • Vomiting
  • Nausea
  • Cellulitis
  • Hypokalemia
  • Intestinal obstruction
Fatalities due to adverse reactions occurred in 4.3% of patients:
  • Interstitial lung disease (2.6%)
  • Acute hepatic failure/acute kidney injury (0.4%)
  • General physical health deterioration (0.4%)
  • Pneumonia (0.4%)
  • Hemorrhagic shock (0.4%)

Adverse reactions may require dose discontinuation, interruption, or reduction1

In patients treated with ENHERTU 5.4 mg/kg

9%Discontinuation
Due to Adverse Reactions
  • The most frequent adverse reaction associated with permanent discontinuation was ILD (6%)
  • Permanently discontinue ENHERTU in patients who are diagnosed with any symptomatic (Grade 2 or greater) ILD
33%
Dose Interruptions
Due to Adverse Reactions
  • The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD
18%
Dose Reductions
Due to Adverse Reactions
  • The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia
Most common adverse reactions (≥20%), including laboratory abnormalities1
  • Nausea (79%)
  • White blood cell count
    decreased (70%)
  • Hemoglobin decreased (70%)
  • Neutrophil count decreased (62%)
  • Fatigue (59%)
  • Vomiting (47%)
  • Alopecia (46%)
  • Aspartate aminotransferase
    increased (41%)
  • Alanine aminotransferase
    increased (38%)
  • Platelet count decreased (37%)
  • Constipation (35%)
  • Decreased appetite (32%)
  • Anemia (31%)
  • Diarrhea (29%)
  • Hypokalemia (26%)
  • Cough (20%)

Selected laboratory abnormalities worsened from baseline reported in patients with HER2+ unresectable or mBC1

Laboratory Parameter
ENHERTU 5.4 mg/kg (N=234)
All Grades (%) Grades 3 or 4
(%)
Hematology
White blood cell count decreased
Hemoglobin decreased
Neutrophil count decreased
Platelet count decreased
70 7
70 7
62 16
37 3.4
Chemistry
Aspartate aminotransferase increased
Alanine aminotransferase increased
Hypokalemia
41 0.9
38 0.4
26 3
Laboratory
Parameter
ENHERTU
5.4 mg/kg
(N=234)
All
Grades
(%)
Grades
3 or 4
(%)
Hematology White blood cell count decreased 70 7
Hemoglobin decreased 70 7
Neutrophil count decreased 62 16
Platelet count decreased 37 3.4
Chemistry Aspartate aminotransferase
increased
41 0.9
Alanine aminotransferase increased 38 0.4
Hypokalemia 26 3
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.4.03 grade-derived laboratory abnormalities.1

Drug interaction studies1

  • 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 transporters
DESTINY-Breast01
follow-up data

(June 2020 data cutoff)
Originally presented at SABCS 2020 with an encore at Miami Breast 2021

View Additional Data bold-arrow

ILD and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor patients and initiate management at first sign of ILD1,2,o

oILD includes events that were adjudicated as ILD: pneumonitis, interstitial lung disease, respiratory failure, organizing pneumonia, acute respiratory failure, lung infiltration, lymphangitis, alveolitis.1

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5-HT3, 5-hydroxytryptamine 3; BCRP, breast cancer resistance protein; BSEP, bile salt export pump; CYP, cytochrome P450; HER2, human epidermal growth factor receptor 2; MATE, multidrug and toxic compound extrusion; mBC, metastatic breast cancer; NCCN, National Comprehensive Cancer Network; 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.