Introduction
Enhertu (fam-trastuzumab deruxtecan-nxki) is a groundbreaking antibody-drug conjugate (ADC) developed for targeted cancer therapy. Approved by the FDA in 2019, it represents a significant advancement in the treatment of HER2-positive cancers. This innovative therapy combines a humanized anti-HER2 monoclonal antibody with a potent topoisomerase I inhibitor payload, offering a targeted approach to cancer treatment with enhanced efficacy compared to traditional therapies.
Mechanism of Action
Enhertu operates through a sophisticated multi-step mechanism: 1. Target Binding: The trastuzumab component binds specifically to HER2 receptors on cancer cell surfaces 2. Internalization: The drug-receptor complex undergoes receptor-mediated endocytosis 3. Intracellular Processing: Lysosomal enzymes cleave the tetrapeptide-based linker 4. Payload Release: DXd (a derivative of exatecan) is released intracellularly 5. Cytotoxic Action: DXd inhibits topoisomerase I, causing DNA single-strand breaks and apoptosis 6. Bystander Effect: The membrane-permeable payload can affect adjacent tumor cells, including those with lower HER2 expression
Indications
FDA-approved indications include:
- HER2-positive unresectable or metastatic breast cancer after prior anti-HER2-based regimens
- HER2-low metastatic breast cancer (IHC 1+ or IHC 2+/ISH-negative) after prior chemotherapy
- HER2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma after prior trastuzumab-based regimen
- HER2-mutant metastatic non-small cell lung cancer (NSCLC)
Dosage and Administration
Standard dosing: 5.4 mg/kg administered intravenously every 3 weeks Administration guidelines:- Pre-medicate with corticosteroids, antipyretics, and antihistamines
- Infuse over 90 minutes (±15 minutes) for first infusion
- Subsequent infusions may be administered over 30 minutes if prior infusions were tolerated
- Do not administer as IV push or bolus
- ILD/pneumonitis: Permanently discontinue for Grade 2 or higher
- Neutropenia: Withhold until resolved to ≤Grade 1, then resume at same or reduced dose
- Thrombocytopenia: Withhold until resolved to ≤Grade 1, then resume at reduced dose
- Renal impairment: No dose adjustment recommended for mild to moderate impairment
- Hepatic impairment: Not recommended for total bilirubin >3 × ULN or AST >3 × ULN
- Geriatric: No dose adjustment required
Pharmacokinetics
Absorption: Administered intravenously, achieving complete bioavailability Distribution:- Steady-state volume of distribution: ~3.5 L
- Plasma protein binding: DXd is 92-96% bound
- Crosses blood-brain barrier to a limited extent
- Trastuzumab component: Proteolytic degradation
- DXd payload: Primarily metabolized by CYP3A4
- Half-life: ~5.7 days for trastuzumab deruxtecan
- Clearance: ~0.42 L/day
- Excretion: Primarily hepatic (feces), with minimal renal elimination
Contraindications
1. History of severe hypersensitivity reactions to fam-trastuzumab deruxtecan-nxki or any component 2. Pregnancy (based on mechanism of action and animal data) 3. Concurrent use with strong CYP3A4 inhibitors (unless absolutely necessary)
Warnings and Precautions
Boxed Warning:- Interstitial lung disease (ILD)/pneumonitis: Can be severe and fatal. Incidence: ~12%, with fatal cases occurring in 1.1% of patients
- Embryo-fetal toxicity: Can cause fetal harm
- Neutropenia: Grade 3-4 occurs in ~19% of patients
- Left ventricular dysfunction: Monitor LVEF at baseline and during treatment
- Nausea/vomiting: Prophylactic antiemetics recommended
Drug Interactions
Significant interactions:- Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin): May increase DXd exposure → avoid concurrent use
- Strong CYP3A4 inducers (e.g., rifampin, carbamazepine): May decrease DXd efficacy → monitor closely
- Other myelosuppressive agents: Additive bone marrow suppression → monitor blood counts
Adverse Effects
Most common (≥20%):- Nausea (79%)
- Fatigue (59%)
- Vomiting (47%)
- Alopecia (46%)
- Constipation (35%)
- Decreased appetite (32%)
- Anemia (31%)
- Neutropenia (29%)
- Diarrhea (29%)
- Thrombocytopenia (26%)
- ILD/pneumonitis (12%)
- Severe neutropenia (19%)
- Left ventricular dysfunction (2.1%)
- Severe nausea/vomiting (4%)
Monitoring Parameters
Baseline assessment:- HER2 status confirmation
- LVEF measurement (ECHO or MUGA scan)
- Complete blood count with differential
- Comprehensive metabolic panel
- Pregnancy test in women of reproductive potential
- CBC with differential: Prior to each dose
- LVEF: Every 3 months during treatment
- Pulmonary symptoms: Monitor continuously for cough, dyspnea, fever
- Liver function tests: Regularly during treatment
- Signs of infusion reactions: During and after infusion
- Continue cardiac monitoring for at least 4 months after last dose
- Monitor for delayed adverse effects
Patient Education
Key points to discuss:1. Pregnancy prevention: Use effective contraception during and for 7 months after treatment 2. Lung symptoms: Report immediately any new or worsening cough, shortness of breath, or fever 3. Infusion reactions: Understand potential symptoms and reporting procedures 4. Nausea management: Adhere to prescribed antiemetic regimen 5. Blood count monitoring: Understand importance of regular blood tests 6. Cardiac symptoms: Report chest pain, palpitations, or swelling in extremities 7. Fertility implications: Discuss fertility preservation options before treatment 8. Administration schedule: Maintain regular treatment appointments
Lifestyle considerations:- Maintain adequate hydration
- Practice good nutrition despite appetite changes
- Use sun protection (increased photosensitivity risk)
- Avoid grapefruit products (may affect drug metabolism)
References
1. FDA Prescribing Information: Enhertu (fam-trastuzumab deruxtecan-nxki). 2023 2. Modi S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2020;382(7):610-621 3. Shitara K, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. 2020;382(25):2419-2430 4. NCCN Guidelines: Breast Cancer Version 3.2023 5. Li BT, et al. Trastuzumab Deruxtecan in HER2-Mutant Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2022;386(3):241-251 6. American Society of Clinical Oncology (ASCO) Guidelines: Management of HER2-Positive Breast Cancer. 2022 7. European Society for Medical Oncology (ESMO) Guidelines: Metastatic Breast Cancer. 2021
Note: This monograph provides general information. Treatment decisions should be made in consultation with oncology specialists based on individual patient characteristics and current clinical guidelines.