ENHERTU is a HER2-directed antibody and topoisomerase I inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.
This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Mechanism of action
- Provides targeted
delivery of cytotoxic agent
Potent cytotoxic agent
- Novel topoisomerase I inhibitor payload, DXd. In a cell-free DNA relaxation assay assessing topoisomerase I inhibitory activity, IC50=0.31µmol/L
- Upon release, membrane-permeable DXd causes DNA damage and apoptotic cell death, resulting in destruction of HER2+ tumor cells and surrounding cells of variable HER2 expression
- Attaches DXd to the antibody
- Cleaved specifically by lysosomal enzymes
ENHERTU has a stable and homogeneous drug-to-antibody ratio of ~8 molecules of cytotoxic agent per antibody
mAb, monoclonal antibody.
Dosage, administration, and preparation
Recommended weight-based dosage and schedule1
Until disease progression or unacceptable toxicity1
- Do not substitute ENHERTU for or with trastuzumab or ado-trastuzumab emtansine
- Slow or interrupt the infusion rate if the patient develops infusion-related symptoms
- Permanently discontinue ENHERTU in case of severe infusion reactions
- Please see below for Preparation for Administration instructions
Recommended dose reductions for ENHERTU for adverse reactions1
- Management of adverse reactions may require temporary interruption, dose reduction, or treatment discontinuation of ENHERTU per dose modifications provided in the table below
- Do not re-escalate the ENHERTU dose after a dose reduction is made
- If a planned dose is delayed or missed, administer as soon as possible; do not wait until the next planned cycle. Adjust the schedule of administration to maintain a 3-week interval between doses. Administer the infusion at the dose and rate the patient tolerated in the most recent infusion
|Dose reduction schedule
(starting dose is 5.4 mg/kg)
|Dose to be
|First dose reduction||4.4 mg/kg|
|Second dose reduction||3.2 mg/kg|
|Requirement for further dose reduction||Discontinue treatment|
Dose modifications for adverse events1
|Adverse Reaction||Severity||Treatment Modification|
|Interstitial Lung Disease (ILD/pneumonitis)||
|Left Ventricular Ejaction Fraction(LVEF) Decreased||
Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v.4.03).
ENHERTU preparation for administration1
In order to prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is ENHERTU and not trastuzumab or ado-trastuzumab emtansine.
Reconstitute and further dilute ENHERTU prior to intravenous infusion. Use appropriate aseptic technique.
ENHERTU is a cytotoxic drug. Follow applicable special handling and disposal procedures.
- Reconstitute immediately before dilution
- More than one vial may be needed for a full dose. Calculate the dose (mg), the total volume of reconstituted ENHERTU solution required, and the number of vial(s) of ENHERTU needed
- Reconstitute each 100 mg vial by using a sterile syringe to slowly inject 5 mL of Sterile Water for Injection, USP into each vial to obtain a final concentration of 20 mg/mL
- Swirl the vial gently until completely dissolved. Do not shake
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be clear and colorless to light yellow. Do not use if visible particles are observed or if the solution is cloudy or discolored
- If not used immediately, store the reconstituted ENHERTU vials in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours from the time of reconstitution, protected from light. Do not freeze
- The product does not contain a preservative. Discard unused ENHERTU after 24 hours refrigerated
- Dilute the calculated volume of reconstituted ENHERTU in an intravenous infusion bag containing 100 mL of 5% Dextrose Injection, USP. Do not use Sodium Chloride Injection, USP. ENHERTU is compatible with an infusion bag made of polyvinylchloride or polyolefin (copolymer of ethylene and polypropylene)
- Gently invert the infusion bag to thoroughly mix the solution. Do not shake
- Cover the infusion bag to protect from light
- If not used immediately, store at room temperature for up to 4 hours including preparation and infusion, or in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF) for up to 24 hours, protected from light. Do not freeze
- Discard any unused portion left in the vial
- If the prepared infusion solution was stored refrigerated (2ºC to 8ºC [36ºF to 46ºF]), allow the solution to equilibrate to room temperature prior to administration
- Administer ENHERTU as an intravenous infusion only with an infusion set made of polyolefin or polybutadiene and a 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter. Do not administer as an intravenous push or bolus
- Do not mix ENHERTU with other drugs or administer other drugs through the same intravenous line
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. In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with ENHERTU. Median time to first onset was 4.1 months (range: 1.2 to 8.3).
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 prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg prednisolone or equivalent). Upon improvement, follow by gradual taper (e.g., 4 weeks).
Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Of the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, a decrease in neutrophil count was reported in 30% of patients and 16% had Grade 3 or 4 events. Median time to first onset was 1.4 months (range: 0.3 to 18.2). Febrile neutropenia was reported in 1.7% of patients.
Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. Based on the severity of neutropenia, ENHERTU may require dose interruption or reduction. 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. Reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3ºC or a sustained temperature of ≥38ºC for more than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one level.
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. In the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, two cases (0.9%) of asymptomatic LVEF decrease were reported. 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.
Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. Permanently discontinue ENHERTU if LVEF of <40% or absolute decrease from baseline of >20% is confirmed. 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.
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 at least 7 months following the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months after the last dose of ENHERTU.