Introduction
Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) approved for the treatment of HER2-positive and HER2-low metastatic breast cancer, as well as other HER2-expressing malignancies. This innovative therapeutic agent combines the humanized anti-HER2 monoclonal antibody trastuzumab with a potent topoisomerase I inhibitor payload (deruxtecan) via a stable tetrapeptide-based cleavable linker. T-DXd represents a significant advancement in targeted cancer therapy with its unique "bystander effect" that allows activity against heterogeneous tumors.
Mechanism of Action
T-DXd binds to HER2 receptors on cancer cell surfaces and undergoes internalization via receptor-mediated endocytosis. Intracellularly, the linker is cleaved by lysosomal enzymes, releasing the membrane-permeable payload (DXd), a derivative of exatecan. DXd inhibits topoisomerase I, causing DNA single-strand breaks and ultimately apoptotic cell death. The bystander effect occurs when the released payload diffuses into adjacent tumor cells regardless of their HER2 status, making T-DXd particularly effective against tumors with heterogeneous HER2 expression.
Indications
- HER2-positive metastatic breast cancer (previously treated with anti-HER2 therapy)
- HER2-low metastatic breast cancer (IHC 1+ or IHC 2+/ISH-negative)
- HER2-mutant metastatic non-small cell lung cancer (NSCLC)
- HER2-positive locally advanced or metastatic gastric cancer (previously treated)
Dosage and Administration
Standard dosing: 5.4 mg/kg administered intravenously every 3 weeks Infusion protocol: First infusion over 90 minutes; subsequent infusions over 30 minutes if tolerated Dose modifications: Required for hematologic and non-hematologic toxicities Special populations: No initial dose adjustment recommended for renal impairment or mild hepatic impairment; use with caution in moderate to severe hepatic impairmentPharmacokinetics
Absorption: IV administration only; complete bioavailability Distribution: Steady-state volume of distribution ~3.13 L; plasma protein binding of DXd ~97% Metabolism: Proteolytic cleavage releases DXd payload; DXd metabolized primarily by CYP3A4 Elimination: Half-life of T-DXd ~5.7 days; DXd half-life ~1.37 days; primarily hepatic eliminationContraindications
- History of hypersensitivity to trastuzumab deruxtecan or any component of the formulation
- Pregnancy (based on mechanism of action and animal data showing embryo-fetal toxicity)
Warnings and Precautions
Interstitial Lung Disease (ILD)/Pneumonitis: Can be severe and fatal; occurs in up to 12% of patients. Monitor patients for cough, dyspnea, fever. Immediately withhold and evaluate for ILD if suspected. Embryo-Fetal Toxicity: Can cause fetal harm; verify pregnancy status prior to initiation and advise effective contraception. Left Ventricular Dysfunction: Assess LVEF prior to initiation and at regular intervals during treatment. Neutropenia: Severe neutropenia including febrile neutropenia may occur; monitor blood counts. Thrombocytopenia: Monitor platelet counts; may require dose delay or reduction.Drug Interactions
Strong CYP3A inhibitors: May increase DXd exposure; consider alternative agents or monitor for increased toxicity Strong CYP3A inducers: May decrease DXd exposure; consider alternative agents Other myelosuppressive agents: May enhance myelosuppressive effects; monitor closelyAdverse Effects
Most common (≥20%): Nausea (79%), fatigue (59%), vomiting (47%), alopecia (46%), constipation (35%), decreased appetite (32%), anemia (31%), neutropenia (31%), diarrhea (29%), thrombocytopenia (26%) Serious adverse reactions: ILD/pneumonitis (12%), neutropenia (6.5%), left ventricular dysfunction (1.9%) Laboratory abnormalities: Decreased hemoglobin (97%), decreased lymphocytes (89%), decreased neutrophils (86%), decreased platelets (67%)Monitoring Parameters
- Baseline and periodic assessment of LVEF (echocardiogram or MUGA scan)
- Complete blood counts prior to each dose and as clinically indicated
- Signs and symptoms of ILD/pneumonitis (cough, dyspnea, fever, oxygen saturation)
- Liver function tests
- Pregnancy testing in patients of reproductive potential
- Clinical assessment for nausea/vomiting and other gastrointestinal toxicities
Patient Education
- Report immediately any new or worsening respiratory symptoms (cough, shortness of breath, fever)
- Use effective contraception during treatment and for at least 7 months after final dose
- Inform all healthcare providers about T-DXd treatment before any new medications
- Expect regular blood tests and cardiac monitoring throughout treatment
- Manage nausea with antiemetic medications as prescribed; report persistent vomiting
- Understand potential hair loss and other common side effects
- Seek immediate medical attention for signs of infection (fever, chills) or unusual bleeding/bruising
References
1. Modi S, Saura C, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2020;382(7):610-621. 2. Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. 2020;382(25):2419-2430. 3. Enhertu (trastuzumab deruxtecan) [package insert]. Daiichi Sankyo, Inc.; 2022. 4. Cortés J, Kim SB, Chung WP, et al. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med. 2022;386(12):1143-1154. 5. Li BT, Smit EF, Goto Y, et al. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer. N Engl J Med. 2022;386(3):241-251.