General

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

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

•  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.
• Unresectable or metastatic hormone receptor-positive HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer that has progressed on ≥1 endocrine therapies in the metastatic setting.
•  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.
•  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.
•  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)

Contraindication/Precautions

Contraindicated in:

• OB:  Black Box:  Pregnancy;
• Lactation: Lactation.

Use Cautiously in:

• Severe renal impairment;
• Severe hepatic impairment (total bilirubin >3–10 times upper limit of normal [ULN] or AST > ULN);
• Rep:  Black Box:  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: ↓ appetite, ↑ liver enzymes, abdominal pain, constipation, diarrhea, dyspepsia, nausea, stomatitis, vomiting

GU: ↓ fertility (men)

Hemat: anemia, leukopenia, NEUTROPENIA, thrombocytopenia

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) periodically during therapy.  If asymptomatic,  hold until resolved to Grade 0; if resolved in <28 days, maintain dose. If resolved in >28 days, ↓ dose one level. Consider corticosteroid therapy as soon as ILD/pneumonitis is suspected.  If symptomatic ILD/pneumonitis occurs,  permanently discontinue fam-trastuzumab deruxtecan and start corticosteroid therapy.
• Assess for signs and symptoms of left ventricular dysfunction before starting and at regular intervals during therapy as clinically indicated.  If LVEF >45% and absolute ↓ from baseline is 10–20%,  continue therapy.  If LVEF is 40–45% and absolute ↓ from baseline is <10%,  continue therapy and repeat LVEF assessment in 3 wk.  If LVEF is 40–45% and absolute ↓ from baseline is 10–20%,  hold therapy and repeat LVEF assessment in 3 wk. If LVEF has not recovered to within 10% from baseline, permanently discontinue fam-trastuzumab deruxtecan. If LVEF recovers to within 10% from baseline, resume therapy at same dose.  If LVEF <40% or absolute ↓ from baseline >20%,  hold therapy and repeat LVEF assessment in 3 wk. If LVEF <40% or absolute ↓ from baseline >20% is confirmed, permanently discontinue fam-trastuzumab deruxtecan.  If symptomatic HF occurs, permanently discontinue fam-trastuzumab deruxtecan.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.

•  Select patients for treatment of: (1) 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 initiating treatment with fam-trastuzumab deruxtecan. (2) Unresectable or metastatic HER2-low or HER2-ultralow breast cancer based on HER2 expression (IHC 0, IHC 1+ or IHC 2+/ISH-). (3) 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. (4) Unresectable or metastatic HER2-positive solid tumor based on HER2-positive (IHC 3+) specimens. An FDA-approved test for detection of HER2-positive (IHC 3+) solid tumors for treatment with fam-trastuzumab deruxtecan is not currently available. Information on FDA-approved tests available at http://www.fda.gov/CompanionDiagnostics.
• Monitor CBC before starting therapy, before each dose, and as clinically indicated.  If Grade 3 neutropenia (ANC<1.0–0.5 × 10⁹ /L) occurs,  hold therapy until resolved to Grade ≤2; then resume at same dose.  If Grade 4 neutropenia (ANC < 0.5 × 10⁹ /L) occurs,  hold therapy until resolved to Grade ≤2; then ↓ dose by one level.  If febrile neutropenia (ANC <1.0 × 10⁹ /L and temperature >38.3°C or a sustained temperature of ≥38°C for >1 hr),  hold therapy until resolved; then ↓ dose by one level.  If Grade 3 thrombocytopenia (platelets <50–25 × 10⁹ /L) occurs,  hold therapy until resolved to Grade ≤1; then resume at same dose.  If Grade 4 thrombocytopenia (platelets <25 × 10⁹ /L) occurs,  hold therapy until resolved to Grade ≤1; then ↓ dose by one level.

Implementation

• Do not substitute fam-trastuzumab deruxtecan for or with trastuzumab or ado-trastuzumab.
• Fam-trastuzumab deruxtecan is highly emetogenic and may cause delayed nausea and/or vomiting. Administer prophylactic antiemetics per local institutional guidelines for prevention of chemotherapy-induced nausea and vomiting.
• Dose reduction schedule: Breast cancer, NSCLC, or solid tumors:  1st dose reduction: 4.4 mg/kg. 2nd dose reduction: 3.2 mg/kg. If further dose ↓ needed, discontinue fam-trastuzumab deruxtecan. Do not re-escalate dose after dose ↓ is made.  Gastric cancer:  1st dose reduction: 5.4 mg/kg. 2nd dose reduction: 4.4 mg/kg. If further dose ↓ needed, discontinue fam-trastuzumab deruxtecan. Do not re-escalate dose after dose ↓ is made.

Patient/Family Teaching

• Explain purpose of therapy to patient. Advise patient to read  Medication Guide  before starting therapy.
• Advise patient to notify health care provider immediately if signs and symptoms of lung problems (cough, trouble breathing, shortness of breath, fever) occur.
• Advise patient to notify health care provider immediately if signs and symptoms of 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 provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care provider before taking other medications.
• Rep:  Black Box:  May cause fetal harm. Advise women of reproductive potential to use effective contraception and avoid breastfeeding during therapy and for ≥7 mo after last dose. Advise men with female partners of reproductive potential to use effective contraception during and for ≥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.