fam-trastuzumab deruxtecan

High Alert

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 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 effects:

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/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)

ROUTE	ONSET	PEAK	DURATION
IV	unknown	unknown	unknown

Contraind./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.

Pre-existing cardiac dysfunction.

Adv. 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

Metab: ↓appetite

Neuro: dizziness, fatigue, headache

Resp: cough, dyspnea, interstitial lung disease (ILD)/pneumonitis, upper respiratory tract infection

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.
- 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. Diluent: 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.

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