Enhertu (Page 3 of 8)

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Metastatic Breast Cancer

The pooled safety population for patients with metastatic breast cancer described in the WARNINGS AND PRECAUTIONS reflects exposure to ENHERTU at 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) in 491 patients in DESTINY-Breast03, DESTINY-Breast01, and Study DS8201-A-J101. Among 491 patients who received ENHERTU, the median duration of treatment was 13 months (range: 0.7 to 37). In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (78%), decreased white blood cell count (74%), decreased hemoglobin (68%), decreased neutrophil count (68%), increased aspartate aminotransferase (58%), fatigue (57%), decreased lymphocyte count (56%), vomiting (50%), decreased platelet count (49%), increased alanine aminotransferase (48%), increased blood alkaline phosphatase (45%), alopecia (41%), constipation (35%), hypokalemia (33%), decreased appetite (32%), diarrhea (31%), musculoskeletal pain (28%), increased transaminases (27%), respiratory infection (24%), headache (21%), and abdominal pain (21%).

DESTINY-Breast03

The safety of ENHERTU was evaluated in 257 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast03 [see Clinical Studies (14.1)]. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 14 months (range: 0.7 to 30) for patients who received ENHERTU and 7 months (range: 0.7 to 25) for patients who received ado-trastuzumab emtansine.

Serious adverse reactions occurred in 19% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. Fatalities due to adverse reactions occurred in 0.8% of patients including COVID-19 and sudden death (one patient each).

ENHERTU was permanently discontinued in 14% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 44% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis. Dose reductions occurred in 21% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, neutropenia, and fatigue.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased neutrophil count, increased aspartate aminotransferase, decreased hemoglobin, decreased lymphocyte count, increased alanine aminotransferase, decreased platelet count, fatigue, vomiting, increased blood alkaline phosphatase, alopecia, hypokalemia, constipation, musculoskeletal pain, diarrhea, decreased appetite, headache, respiratory infection, abdominal pain, increased blood bilirubin, and stomatitis.

Tables 3 and 4 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast03.

Table 3: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3-4) in Patients Treated with ENHERTU in DESTINY-Breast03
Adverse Reactions ENHERTU5.4 mg/kgN=257 Ado-trastuzumab emtansine3.6 mg/kgN=261
All Grades% Grades 3-4% All Grades% Grades 3-4%
Events were graded using NCI CTCAE version 5.0. N = number of patients exposed; PT = preferred term.
*
Grouped term of abdominal pain includes PTs of abdominal pain, abdominal discomfort, lower abdominal pain, and upper abdominal pain.
Grouped term of stomatitis includes PTs of stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosal eruption.
Grouped term of fatigue includes PTs of fatigue, asthenia, malaise, and lethargy.
§
Grouped term of anemia includes PTs of anemia, decreased hemoglobin, and decreased red blood cell count.
This Grade 3 event was reported by the investigator. Per NCI CTCAE v.5.0, the highest NCI CTCAE grade for alopecia is Grade 2.
#
Grouped 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.
Þ
Grouped 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.
ß
Interstitial lung disease includes events that were adjudicated as ILD for ENHERTU: pneumonitis, interstitial lung disease, organizing pneumonia, pneumonia, and pulmonary mass. For ado-trastuzumab emtansine: pneumonitis, interstitial lung disease, organizing pneumonia, and pulmonary embolism.
à
Grouped term of headache includes PTs of headache and migraine.
è
Grouped term of peripheral neuropathy includes PTs of peripheral neuropathy, peripheral sensory neuropathy, and paresthesia.
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 pain * 21 0.8 8 0.4
Stomatitis 20 0.8 5 0
Dyspepsia 11 0 6 0
General Disorders and Administration Site Conditions
Fatigue 49 6 35 0.8
Blood and Lymphatic System Disorders
Anemia § 33 7 17 6
Skin and Subcutaneous Tissue Disorders
Alopecia 37 0.4 3.1 0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain # 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 infection Þ 22 0.8 12 1.1
Epistaxis 11 0 16 0.4
Cough 11 0.4 10 0
Interstitial lung disease ß 11 0.8 1.9 0
Nervous System Disorders
Headache à 22 0.4 16 0
Peripheral neuropathy è 13 0.4 14 0.4
Dizziness 13 0.4 8 0

Other clinically relevant adverse reactions reported in less than 10% of patients in the ENHERTU-treated group were:

  • Respiratory, Thoracic and Mediastinal Disorders: dyspnea (8%)
  • Skin and Subcutaneous Tissue Disorders: pruritus (8%) and skin hyperpigmentation (6%) [grouped term includes PTs of skin hyperpigmentation, skin discoloration, and pigmentation disorder]
  • Nervous System Disorders: dysgeusia (6%)
  • Metabolism and Nutrition Disorders: dehydration (4.3%)
  • Eye Disorders: blurred vision (3.5%)
  • Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (2.7%) [see Warnings and Precautions (5.3)]
  • Injury, Poisoning and Procedural Complications: infusion-related reactions (2.3%) [grouped term includes PTs of hypersensitivity and infusion-related reactions]
  • Blood and Lymphatic System Disorders: febrile neutropenia (0.8%)
Table 4: Selected Laboratory Abnormalities in Patients in DESTINY-Breast03
Laboratory Parameter ENHERTU5.4 mg/kgN=257 Ado-trastuzumab emtansine3.6 mg/kgN=261
All Grades% Grades 3-4% All Grades% Grades 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.5.0 grade-derived laboratory abnormalities.
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

DESTINY-Breast01 and Study DS8201-A-J101

The safety of ENHERTU was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101 (NCT02564900) [see Clinical Studies (14.1)]. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 7 months (range: 0.7 to 31).

In the pooled 234 patients, the median age was 56 years (range: 28-96), 74% of patients were <65 years, 99.6% of patients were female, and the majority were White (51%) or Asian (42%). Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (58%) or 1 (42%) at baseline. Ninety-four percent had visceral disease, 31% had bone metastases, and 13% had brain metastases.

Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.

ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, fatigue, vomiting, alopecia, increased aspartate aminotransferase, increased alanine aminotransferase, decreased platelet count, constipation, decreased appetite, diarrhea, hypokalemia, and cough.

Tables 5 and 6 summarize common adverse reactions and laboratory abnormalities observed in ENHERTU-treated patients.

Table 5: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) in Patients in DESTINY-Breast01 and Study DS8201-A-J101
Adverse Reactions ENHERTU 5.4 mg/kgN=234
All Grades% Grades 3 or 4%
Events were graded using NCI CTCAE version 4.03. N = number of patients exposed; PT = preferred term.
*
Grouped term of abdominal pain includes PTs of abdominal discomfort, gastrointestinal pain, abdominal pain, lower abdominal pain, and upper abdominal pain.
Grouped 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).
Grouped term of fatigue includes PTs of fatigue and asthenia.
§
This Grade 3 event was reported by the investigator. Per NCI CTCAE v.4.03, the highest NCI CTCAE grade for alopecia is Grade 2.
Grouped term of rash includes PTs of rash, pustular rash, and maculo-papular rash.
#
Grouped term of anemia includes PTs of anemia, decreased hemoglobin, decreased hematocrit, and decreased red blood cell count.
Þ
Interstitial 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.
ß
All events had fatal outcomes (n=6).
à
Grouped term of headache includes PTs of headache, sinus headache, and migraine.
è
Grouped term of upper respiratory tract infection includes PTs of influenza, influenza-like illness, and upper respiratory tract infection.
ð
This 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.
Gastrointestinal Disorders
Nausea 79 7
Vomiting 47 3.8
Constipation 35 0.9
Diarrhea 29 1.7
Abdominal pain * 19 1.3
Stomatitis 14 0.9
Dyspepsia 12 0
General Disorders and Administration Site Conditions
Fatigue 59 6
Skin and Subcutaneous Tissue Disorders
Alopecia 46 0.4§
Rash 10 0
Metabolism and Nutrition Disorders
Decreased appetite 32 1.3
Blood and Lymphatic System Disorders
Anemia # 31 7
Respiratory, Thoracic and Mediastinal Disorders
Cough 20 0
Dyspnea 13 1.3
Epistaxis 13 0
Interstitial lung disease Þ 9 2.6ß
Nervous System Disorders
Headache à 19 0
Dizziness 10 0
Infections and Infestations
Upper respiratory tract infection è 15 0
Eye Disorders
Dry eye 11 0.4ð

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

  • Injury, Poisoning and Procedural Complications: infusion-related reactions (2.6%)
  • Blood and Lymphatic System Disorders: febrile neutropenia (1.7%)
Table 6: Selected Laboratory Abnormalities in Patients with Unresectable or Metastatic HER2-positive Breast Cancer Treated with ENHERTU in DESTINY-Breast01 and Study DS8201-A-J101
Laboratory Parameter ENHERTU 5.4 mg/kgN=234
All Grades% Grades 3 or 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.
Hematology
Decreased white blood cell count 70 7
Decreased hemoglobin 70 7
Decreased neutrophil count 62 16
Decreased platelet count 37 3.4
Chemistry
Increased aspartate aminotransferase 41 0.9
Increased alanine aminotransferase 38 0.4
Hypokalemia 26 3

Locally Advanced or Metastatic Gastric Cancer

The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01 [see Clinical Studies (14.2)]. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg once every three 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) in the ENHERTU group and 2.8 months (range: 0.5 to 13.1) in the irinotecan/paclitaxel group.

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 hypokalemia. 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, decreased white blood cell count, decreased neutrophil count, decreased lymphocyte count, decreased platelet count, nausea, decreased appetite, increased aspartate aminotransferase, fatigue, increased blood alkaline phosphatase, increased alanine aminotransferase, diarrhea, hypokalemia, vomiting, constipation, increased blood bilirubin, pyrexia, and alopecia.

Tables 7 and 8 summarize adverse reactions and laboratory abnormalities observed in patients receiving ENHERTU 6.4 mg/kg in DESTINY-Gastric01.

Table 7: Adverse Reactions in ≥10% All Grades or ≥2% Grades 3 or 4 of Patients Receiving ENHERTU in DESTINY-Gastric01
ENHERTU 6.4 mg/kgN=125 Irinotecan or PaclitaxelN=62
Adverse Reactions All Grades% Grades 3 or 4% All Grades% Grades 3 or 4%
Events were graded using NCI CTCAE version 4.03. N = number of patients exposed; PT = preferred term.
*
Grouped term of abdominal pain includes PTs of abdominal discomfort, gastrointestinal pain, abdominal pain, lower abdominal pain, and upper abdominal pain.
Grouped term of stomatitis includes PTs of stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosal blistering.
Grouped term of anemia includes PTs of anemia, decreased hemoglobin, decreased red blood cell count, and decreased hematocrit.
§
Grouped term of fatigue includes PTs of fatigue, asthenia, and malaise.
Interstitial 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.
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 pain * 14 0.8 15 3.2
Stomatitis 11 1.6 4.8 0
Metabolism and Nutrition Disorders
Decreased appetite 60 17 45 13
Dehydration 6 2.4 3.2 1.6
Blood and Lymphatic System Disorders
Anemia 58 38 31 23
Febrile neutropenia 4.8 4.8 3.2 3.2
General Disorders and Administration Site Conditions
Fatigue § 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 disease 10 2.4 0 0
Hepatobiliary Disorders
Abnormal hepatic function 8 3.2 1.6 1.6

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

  • Cardiac Disorders: asymptomatic left ventricular ejection fraction decrease (8%) [see Warnings and Precautions (5.3)]
  • Infections and Infestations: pneumonia (6%)
  • Injury, Poisoning and Procedural Complications: infusion-related reactions (1.6%)
Table 8: Selected Laboratory Abnormalities Occurring in Patients Receiving ENHERTU in DESTINY-Gastric01
Laboratory Parameter ENHERTU 6.4 mg/kgN=125 Irinotecan or PaclitaxelN=62
All Grades% Grades 3 or 4% All Grades% Grades 3 or 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.
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
Hypokalemia 30 4.8 18 8
Increased blood bilirubin 24 7 5 3.4

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