ENHERTU SIDE EFFECTS

SIDE EFFECTS

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

• Interstitial Lung Disease/Pneumonitis
• Neutropenia
• Left Ventricular Dysfunction

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. 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 adotrastuzumab 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 1 and 2 summarize common adverse reactions and laboratory abnormalities observed in DESTINY-Breast03.

Table 1: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3-4) in Patients Treated with ENHERTU in DESTINY-Breast03

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%)
• 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 2: Selected Laboratory Abnormalities in Patients in DESTINY-Breast03

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). 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 3: Common Adverse Reactions (≥10% All Grades or ≥2% Grades 3 or 4) in Patients in DESTINY-Breast01 and Study DS8201-A-J101

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 3: Selected Laboratory Abnormalities in Patients with Unresectable or Metastatic HER2-positive Breast Cancer Treated with ENHERTU in DESTINY-Breast01 and Study DS8201-A-J101

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. 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 4 and 5 summarize adverse reactions and laboratory abnormalities observed in patients receiving ENHERTU 6.4 mg/kg in DESTINY-Gastric01.

Table 4: Adverse Reactions in ≥10% All Grades or ≥2% Grades 3 or 4 of Patients Receiving ENHERTU in DESTINY-Gastric01

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

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

Table 5: Selected Laboratory Abnormalities Occurring in Patients Receiving ENHERTU in DESTINY-Gastric01

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparisons of the incidence of antibodies to ENHERTU in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Treatment-emergent anti-fam-trastuzumab deruxtecan-nxki antibodies (ADA) developed in 2.1% (27/1311) patients who received ENHERTU across all doses. The incidence of neutralizing antibodies against fam-trastuzumab deruxtecan-nxki was 0.1% (1/1311). Due to the limited number of patients who tested positive for ADA, no conclusions can be drawn concerning a potential effect of immunogenicity on efficacy or safety.

SRC: NLM .