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Safety Data

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.

The benefit-risk profile of ENHERTU was established in DESTINY-Gastric01

The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma in DESTINY-Gastric01.1

  • Patients received intravenously at least 1 dose of either ENHERTU (n=125) 6.4 mg/kg once every 3 weeks or physician’s choice of chemotherapy: either irinotecan (n=55) 150 mg/m2 biweekly or paclitaxel (n=7) 80 mg/m2 weekly for 3 weeks1
  • The median duration of treatment was 4.6 months (range: 0.7-22.3) in ENHERTU-treated patients and 2.8 months (range: 0.5-13.1) in irinotecan- or paclitaxel-treated patients1
  • Prophylactic or supportive treatment of ENHERTU-induced adverse reactions was at the discretion of the treating physician and institutional guidelines2

Adverse reactions in 10% all Grades or 2% Grades 3 or 4 of patients receiving ENHERTU in DESTINY-Gastric011

Adverse reactions ENHERTU
(n=125)
Irinotecan or Paclitaxel
(n=62)
All Grades (%) Grade 3
or 4
(%)
All Grades (%) Grade 3
or 4
(%)
Gastrointestinal
disorders
Nausea 63 4.8 47 1.6
Diarrhea 32 2.4 32 1.6
Vomiting 26 0 8 0
Constipation 24 0 23 0
Abdominal paina 14 0.8 15 3.2
Stomatitisb 11 1.6 4.8 0
Metabolism and nutritional disorders Decreased appetite 60 17 45 13
Dehydration 6 2.4 3.2 1.6
Blood and lymphatic system disorders Anemiac 58 38 31 23
Febrile neutropenia 4.8 4.8 3.2 3.2
General disorders and administration site conditions Fatigued 55 9 44 4.8
Pyrexia 24 0 16 0
Peripheral edema 10 0 0 0
Skin and subcutaneous tissue disorders Alopecia 22 0 15 0
Respiratory, thoracic, and mediastinal disorders Interstitial lung diseasee 10 2.4 0 0
Hepatobiliary disorders Abnormal hepatic function 8 3.2 1.6 1.6
Adverse
reactions
All Grades (%)
ENHERTU
(n=125)
Irinotecan
or
Paclitaxel
(n=62)
Gastrointestinal disorders
Nausea 63 47
Diarrhea 32 32
Vomiting 26 8
Constipation 24 23
Abdominal paina 14 15
Stomatitisb 11 4.8
Metabolism and nutritional disorders
Decreased appetite 60 45
Dehydration 6 3.2
Blood and lymphatic system disorders
Anemiac 58 31
Febrile neutropenia 4.8 3.2
General disorders and administration site conditions
Fatigued 55 44
Pyrexia 24 16
Peripheral edema 10 0
Skin and subcutaneous tissue disorders
Alopecia 22 15
Respiratory, thoracic, and mediastinal disorders
Interstitial lung diseasee 10 0
Hepatobiliary disorders
Abnormal hepatic function 8 1.6
Adverse
reactions
Grade 3 or 4 (%)
ENHERTU
(n=125)
Irinotecan
or
Paclitaxel
(n=62)
Gastrointestinal disorders
Nausea 4.8 1.6
Diarrhea 2.4 1.6
Vomiting 0 0
Constipation 0 0
Abdominal paina 0.8 3.2
Stomatitisb 1.6 0
Metabolism and nutritional disorders
Decreased appetite 17 13
Dehydration 2.4 1.6
Blood and lymphatic system disorders
Anemiac 38 23
Febrile neutropenia 4.8 3.2
General disorders and administration site conditions
Fatigued 9 4.8
Pyrexia 0 0
Peripheral edema 0 0
Skin and subcutaneous tissue disorders
Alopecia 0 0
Respiratory, thoracic, and mediastinal disorders
Interstitial lung diseasee 2.4 0
Hepatobiliary disorders
Abnormal hepatic function 3.2 1.6
  • Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg1
  • Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage1

Other clinically relevant adverse reactions reported in less than 10% of patients were1:

  • Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (8%)
  • Infections and Infestations: pneumonia (6%)
  • Injury, Poisoning, and Procedural Complications: infusion-related reactions (1.6%)

Events were graded using NCI-CTCAE version 4.03.1

a Including abdominal discomfort, gastrointestinal pain, abdominal pain, lower abdominal pain, and upper abdominal pain.1

b Including stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosal blistering.1

c Including anemia, decreased hemoglobin, decreased red blood cell count, and decreased hematocrit.1

d Including fatigue, asthenia, and malaise.1

e Interstitial lung disease includes events that were adjudicated as drug-induced ILD: pneumonitis, interstitial lung disease, respiratory failure, organizing pneumonia, acute respiratory failure, lung infiltration, lymphangitis, and alveolitis.1

 

Selected laboratory abnormalities occurring in patients receiving ENHERTU in DESTINY-Gastric011

Laboratory parameter ENHERTU
(n=125)
Irinotecan or Paclitaxel
(n=62)
All Grades (%) Grade 3
or 4
(%)
All Grades (%) Grade 3
or 4
(%)
Hematology Decreased hemoglobin 75 38 55 23
Decreased white blood cell count 74 29 53 13
Decreased neutrophil count 72 51 45 23
Decreased lymphocyte count 70 28 53 12
Decreased platelet count 68 12 12 5
Chemistry Increased aspartate aminotransferase 58 9 32 8
Increased blood alkaline phosphatase 54 8 34 10
Increased alanine aminotransferase 47 9 17 1.7
Decreased blood potassium 30 4.8 18 8
Increased blood bilirubin 24 7 5 3.4
Laboratory
parameter
All Grades (%)
ENHERTU
(n=125)
Irinotecan
or
Paclitaxel
(n=62)
Hematology
Decreased hemoglobin 75 55
Decreased white blood cell count 74 53
Decreased neutrophil count 72 45
Decreased lymphocyte count 70 53
Decreased platelet count 68 12
Chemistry
Increased aspartate aminotransferase 58 32
Increased blood alkaline phosphatase 54 34
Increased alanine aminotransferase 47 17
Decreased blood potassium 30 18
Increased blood bilirubin 24 5
Laboratory
parameter
Grade 3 or 4 (%)
ENHERTU (n=125) Irinotecan
or
Paclitaxel
(n=62)
Hematology
Decreased hemoglobin 38 23
Decreased white blood cell count 29 13
Decreased neutrophil count 51 23
Decreased lymphocyte count 28 12
Decreased platelet count 12 5
Chemistry
Increased aspartate aminotransferase 9 8
Increased blood alkaline phosphatase 8 10
Increased alanine aminotransferase 9 1.7
Decreased blood potassium 4.8 8
Increased blood bilirubin 7 3.4

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.4.03 grade-derived laboratory abnormalities.1

  • Median time to first onset of decreased neutrophil count was 16 days (range: 4-187)1
 

Adverse reactions may require dose discontinuation, interruption, or reduction1

In patients treated with ENHERTU1

  • Discontinuation occurred in 15% of patients, of which ILD accounted for 6%
  • Dose interruptions occurred in 62% of patients due to adverse reactions
    • The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and hypokalemia
  • Dose reductions occurred in 32% of patients
    • The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia

Fatalities due to adverse reactions occurred in 2.4% of patients1

  • Disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in 1 patient each (0.8%)
  • ILD and pneumonitis, including Grade 5 cases, have been reported with ENHERTU. Monitor patients and initiate management at first sign of ILD1,f,g

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

g Grade 5=fatal cases.

HER2, human epidermal growth factor receptor 2; ILD, interstitial lung disease; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY

  • Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.
  • Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.
INDICATION

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.

Contraindications

None.

Warnings and Precautions

Interstitial Lung Disease / Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21).

Neutropenia

Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L), interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L), interrupt ENHERTU until resolved to Grade 2 or less, then reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by one level.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

Left Ventricular Dysfunction

Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF.

Embryo-Fetal Toxicity

ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose of ENHERTU.

Additional Dose Modifications

Thrombocytopenia

For Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then reduce dose by one level.

Adverse Reactions

The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg every 3 weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) for patients who received ENHERTU.

Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%).

ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and decreased blood potassium. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin (75%), decreased white blood cell count (74%), decreased neutrophil count (72%), decreased lymphocyte count (70%), decreased platelet count (68%), nausea (63%), decreased appetite (60%), increased aspartate aminotransferase (58%), fatigue (55%), increased blood alkaline phosphatase (54%), increased alanine aminotransferase (47%), diarrhea (32%), decreased blood potassium (30%), vomiting (26%), constipation (24%), increased blood bilirubin (24%), pyrexia (24%), and alopecia (22%).

Use in Specific Populations

  • Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months after the last dose of ENHERTU.
  • Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.
  • Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for 7 months after the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose. Infertility: ENHERTU may impair male reproductive function and fertility.
  • Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.
  • Geriatric Use: Of the 125 patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were ≥65 years and 14% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.
  • Renal Impairment: A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Monitor patients with moderate renal impairment more frequently. The recommended dosage of ENHERTU has not been established for patients with severe renal impairment (CLcr <30 mL/min).
  • Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor, DXd. The recommended dosage of ENHERTU has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST).

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please click here for full Prescribing Information, including Boxed WARNINGS, and click here for Medication Guide.

INDICATION

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.

References
  • ENHERTU. Prescribing information. Daiichi Sankyo, Inc.; 2024.
  • Data on file. Daiichi Sankyo, Inc. Basking Ridge, NJ.
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