fam-trastuzumab deruxtecan

General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

Genetic Implications: Genetic Implications

Pronunciation:
fam tras-tu-zoo-mab de-rux-te-can


Trade Name(s)

  • Enhertu

Ther. Class.

antineoplastics

Pharm. Class.

monoclonal antibodies

enzyme inhibitors

Indications

  • Genetic implication Unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive (IHC 3+ or ISH+) breast cancer in patients who have previously received an anti-HER2-based regimens either in the metastatic setting or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 mo of completing therapy.
  • Genetic implication Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer in patients who have previously received chemotherapy in the metastatic setting or developed disease recurrence during or within 6 mo of completing adjuvant chemotherapy.
  • Genetic implication Locally advanced or metastatic HER2-positive (IHC 3+ or 2+/ISH+) gastric or gastroesophageal junction adenocarcinoma in patients who have previously received a trastuzumab-based regimen.
  • Genetic implication Unresectable or metastatic non-small cell lung cancer (NSCLC) in patients whose tumors have activating HER2 (ERBB2) mutations and who have received a prior systemic therapy.
  • Unresectable or metastatic HER2-positive (IHC 3+) solid tumors in patients who have received prior systemic treatment and have no satisfactory alternative treatment options.

Action

Acts as a HER2-directed antibody-drug conjugate composed of a humanized IgG1 monoclonal antibody (which has the same amino acid sequence as trastuzumab [and targets HER2]), a cleavable linker, and a topoisomerase I inhibitor (DXd) (the cytotoxic component that causes DNA damage and apoptosis).

Therapeutic Effect(s):

  • Regression of breast cancer and metastases.
  • Improved survival in gastric or gastroesophageal junction adenocarcinoma.
  • Decreased spread of NSCLC.

Pharmacokinetics

Absorption: IV administration results in complete bioavailability.

Distribution: Minimally distributed to extravascular tissues.

Protein Binding: 97%.

Metabolism and Excretion: Monoclonal antibody component is degraded into smaller peptides via catabolism. DXd primarily metabolized by the liver via CYP3A4 isoenzyme. Excretion pathway unknown.

Half-life: Fam-trastuzumab deruxtecan:  5.7 days;  DXd:  5.8 days.

TIME/ACTION PROFILE (plasma concentrations)

ROUTEONSETPEAKDURATION
IVunknownunknownunknown

Contraindication/Precautions

Contraindicated in:

  • OB:  Pregnancy;
  • Lactation: Lactation.

Use Cautiously in:

  • Severe renal impairment (CCr <30 mL/min);
  • Severe hepatic impairment (total bilirubin >3–10 times upper limit of normal [ULN] or AST > ULN);
  • Rep:  Women of reproductive potential and men with female partners of reproductive potential;
  • Pedi:  Safety and effectiveness not established in children;
  • Geri:  Older adults may have ↑ risk of adverse reactions.

Exercise Extreme Caution in:

Pre-existing cardiac dysfunction.

Adverse Reactions/Side Effects

CV: ↓ left ventricular ejection fraction (LVEF), HF

Derm: alopecia, rash

EENT: dry eye, epistaxis

F and E: hypokalemia

GI: ↑ liver enzymes, abdominal pain, constipation, diarrhea, dyspepsia, nausea, stomatitis, vomiting

GU: ↓ fertility (males)

Hemat: anemia, leukopenia, NEUTROPENIA, thrombocytopenia

Metabolic: ↓ appetite

Neuro: dizziness, fatigue, headache

Resp: cough, dyspnea, INTERSTITIAL LUNG DISEASE (ILD)/PNEUMONITIS, upper respiratory tract infection

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

None reported.

Route/Dosage

Do NOT substitute fam-trastuzumab deruxtecan with trastuzumab or ado-trastuzumab emtansine.

Metastatic Breast Cancer, Unresectable/Metastatic Non-Small Cell Lung Cancer, or Unresectable/Metastatic Solid Tumors

IV (Adults): 5.4 mg/kg every 3 wk. Continue until disease progression or unacceptable toxicity.

Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

IV (Adults): 6.4 mg/kg every 3 wk. Continue until disease progression or unacceptable toxicity.

Availability

Lyophilized powder for injection: 100 mg/vial

Assessment

  • Assess for signs and symptoms of ILD/pneumonitis (cough, dyspnea, fever, and/or any new or worsening respiratory symptoms) periodically during therapy. If asymptomatic (Grade 1), hold medication 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, ↓ dose one level. Consider corticosteroid therapy as soon as ILD/pneumonitis is suspected. If symptomatic ILD/pneumonitis occurs (≥Grade 2), discontinue therapy permanently and start corticosteroid therapy.
  • Assess for signs and symptoms of left ventricular dysfunction (LVEF) before starting and at regular intervals during therapy as clinically indicated. If LVEF >45% and absolute ↓ from baseline is 10–20%, continue with therapy. If LVEF is 40–45% and absolute ↓ from baseline is <10%, continue with therapy. Repeat LVEF assessment within 3 wk. If LVEF is 40–45% and absolute ↓ from baseline is 10–20%, hold therapy and repeat LVEF assessment within 3 wk. If LVEF has not recovered to within 10% from baseline, permanently discontinue therapy. If LVEF recovers to within 10% from baseline, resume therapy at the same dose. If LVEF <40% or absolute ↓ from baseline >20%, hold therapy and repeat LVEF assessment within 3 wk. If LVEF <40% or absolute ↓ from baseline >20% is confirmed, permanently discontinue therapy. If symptomatic HF occurs, discontinue therapy permanently.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.

  • Genetic implication Select patients for treatment of locally advanced or metastatic HER2-positive gastric cancer based on HER2 protein overexpression or HER2 gene amplification (IHC 3+ or IHC 2+/ISH+). Reassess HER2 status if it is feasible to obtain a new tumor specimen after prior trastuzumab-based therapy and before treatment with  Enhertu. Select patients for treatment of unresectable or metastatic HER2-low breast cancer based on HER2 expression (IHC 1+ or IHC 2+/ISH-). Select patients for treatment of unresectable or metastatic HER2-mutant NSCLC based on the presence of activating HER2 (ERBB2) mutations in tumor or plasma specimens. If no mutation is detected in a plasma specimen, test tumor tissue. Select patients for treatment of unresectable or metastatic solid tumors based on HER2-positive (IHC 3+) specimens. An FDA-approved test for the detection of HER2-positive (IHC 3+) solid tumors for treatment with  Enhertu  is not currently available. Information on FDA-approved tests available at: http://www.fda.gov/CompanionDiagnostics.
  • Monitor CBC prior to start of therapy and before each dose, and as clinically indicated.  If neutropenia of Grade 3 (absolute neutrophil count <1.0–0.5 × 109 /L) occurs,  hold therapy until resolved to ≤Grade 2, then resume at same dose.  If Grade 4 neutropenia (absolute neutrophil count < 0.5 × 109 /L) occurs,  hold therapy until resolved to ≤Grade 2; then ↓ dose by one level.  If febrile neutropenia (absolute neutrophil count <1.0 × 109 /L and temperature >38.3°C or a sustained temperature of ≥38°C for >1 hr),  hold therapy until resolved. ↓ dose by one level.  If Grade 3 thrombocytopenia (platelets <50 to 25 x 109 /L) occurs,  hold therapy until resolved to ≤Grade 1;, then maintain dose.  If Grade 4 thrombocytopenia (platelets <25 x 109 /L) occurs,  hold therapy until resolved to ≤Grade 1. Reduce dose by one level.

Implementation

  • Do not substitute fam-trastuzumab deruxtecan for or with trastuzumab or ado-trastuzumab.
  • Enhertu  is highly emetogenic and may cause delayed nausea and/or vomiting. Administer prophylactic antiemetic medications per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting.
  • Dose reduction schedule:

    Breast cancer, NSCLC, or solid tumors:  Starting dose 5.4 mg/kg. First dose reduction to 4.4 mg/kg. Second reduction to 3.2 mg/kg. If further dose reduction is needed, discontinue therapy. Do not re-escalate dose after dose reduction is made.

    • Gastric cancer:  Starting dose 6.4 mg/kg. First dose reduction to 5.4 mg/kg. Second reduction to 4.4 mg/kg. If further dose reduction is needed, discontinue therapy. Do not re-escalate dose after dose reduction is made.

IV Administration

  • Intermittent Infusion:   Reconstitution: Reconstitute immediately before dilution with 5 mL sterile water for injection for each 100 mg vial. Concentration: 20 mg/mL. Swirl gently to dissolve; do not shake. Solution is clear and colorless to light yellow; do not use if solution is cloudy, discolored, or contains particulate matter. Reconstituted solution is stable if refrigerated for 24 hr. Dilution:  Dilute in 100 mL of D5W; do not dilute with 0.9% NaCl. Gently invert to mix; do not shake. Cover infusion bag to protect from light. Diluted solution is stable for 4 hr at room temperature and up to 24 hr if refrigerated; do not freeze. Allow refrigerated solution to reach room temperature before infusion. Protect diluted solution from light.
  • Rate: Infuse 1st infusion over 90 min via an infusion set of polyolefin or polybutadiene and a 0.20 or 0.22 micron in-line polyethersulfone or polysulfone filter. If tolerated, subsequent infusions can be infused over 30 min. Slow rate or interrupt infusion if patient develops infusion-related symptoms. If reaction is severe, discontinue medication. Do not administer IV push or bolus.
  • Y-Site Incompatibility: Do not mix with other drugs or with other drugs in the same line.

Patient/Family Teaching

  • Explain purpose of therapy to patient. Advise patient to read  Medication Guide  before starting therapy.
  • Advise patient to notify health care professional immediately if signs and symptoms of lung problems (cough, trouble breathing or shortness of breath, fever, other new or worsening breathing symptoms [chest tightness, wheezing]), infection (fever, chills), or heart problems (new or worsening shortness of breath, coughing, feeling tired, swelling of ankles or legs, irregular heartbeat, sudden weight gain, dizziness or light-headedness, loss of consciousness) occur.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
  • Rep:  May cause fetal harm. Advise females of reproductive potential to use effective contraception and avoid breastfeeding during and for at least 7 mo after last dose. Advise males with female partners of reproductive potential to use effective contraception during and for at least 4 mo after last dose. May impair male fertility.

Evaluation/Desired Outcomes

  • Regression of breast cancer and metastases.
  • Improved survival in gastric or gastroesophageal junction adenocarcinoma.
  • Decreased spread of NSCLC.