trastuzumab deruxtecan
Trastuzumab deruxtecan
Generic Name
Trastuzumab deruxtecan
Brand Names
*Enhertu*) is a HER2‑targeted antibody‑drug conjugate (ADC) approved for the treatment of HER2‑positive solid tumors, most notably metastatic breast cancer and metastatic gastric/GEJ cancer. The drug combines a humanized anti‑HER2 monoclonal antibody with a potent topoisomerase‑I inhibitor payload linked by a cleavable di‑lysine linker, enabling *by‑stander* cytotoxicity once internalized.
Mechanism
- Targeting: The anti‑HER2 Fab region binds to the extracellular domain of the HER2 receptor on tumor cells, ensuring tumor‑specific delivery.
- Internalization & Release: Binding triggers receptor‑mediated endocytosis; the cleavable linker is processed by lysosomal enzymes, liberating the topoisomerase‑I inhibitor deruxtecan (DXd) inside the cell.
- Cytotoxic Effect: DXd induces DNA single‑strand breaks → replication stress → apoptosis.
- Bystander Killing: DXd is membrane‑permeable; neighboring HER2‑negative cells receive toxin via diffusion, expanding activity beyond the primary malignant cells.
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Pharmacokinetics
| Parameter | Typical Value | Notes |
| Absorption | IV infusion (100 mL over 30 min) | No oral route |
| Volume of Distribution | 50–70 L | Reflects total bodily fluid, partly due to albumin binding |
| Half‑life (steady‑state) | ~5.3 days (5‑6 days) | Enables dosing every 3 weeks |
| Clearance | ~ 8.4 mL/min | Mainly via hepatobiliary pathway |
| Metabolism | Catabolism of antibody & linker in lysosomes | No major CYP involvement |
| Excretion | Biliary/fecal (approx. 70 %), renal (<10 %) | Renal clearance low |
| Drug–Drug Interactions | None clinically significant | No CYP inhibition/induction |
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Indications
- Metastatic HER2‑positive breast cancer refractory to or unsuitable for trastuzumab, pertuzumab, or T-DM1.
- Metastatic HER2‑positive gastric/GEJ cancer after ≥2 prior anti‑HER2 therapy lines.
- HER2‑positive basal‑cell carcinoma (off‑label, investigational).
*Note*: Tumor HER2 expression is required (IHC 3+ or FISH+).
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Contraindications
- Known hypersensitivity to trastuzumab, the deruxtecan linker, or other ADC components.
- Significant interstitial lung disease (ILD) or active pulmonary pathology.
- Severe cardiac dysfunction (LVEF <50 %) – MRI/echo monitoring recommended.
Warnings
• Inter‑stitial lung disease (ILD)/pneumonitis – potentially fatal; requires dose interruption/revision if ≥ grade 2.
• Photosensitivity – sun‑exposure can precipitate rash or skin toxicities.
• Infusion‑related reactions (IRRs) – premedication with antihistamine & steroid may be necessary.
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Dosing
| Population | Dose | Schedule | Administration Notes |
| Adults (≥18 yrs) | 5.4 mg/kg IV 100 mL over 30 min | Every 3 weeks (Q3W) | Verify weight; adjust for renal/hepatic impairment (no adjustment in mild to moderate CKD) |
| Paediatric (<18 yrs, <50 kg) | 5.4 mg/kg | Q3W | Dose may be reduced to 4 mg/kg if severe toxicity observed |
• Premedication: 100 mg diphenhydramine & 125 mg hydrocortisone IV prior to infusion for patients with history of IRRs.
• Dose modification: Reduce by 1 mg/kg or omit next dose for grade 3‑4 toxicities; full recovery to historic ≤grade 1 before resumption.
• Combination therapy: Approved with T-DM1? No; can be combined with checkpoint inhibitors under clinical trial.
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Adverse Effects
| Category | Frequency (≥10 %) | Grade ≥ 3 | Remarks |
| Hematologic | Neutropenia, anemia, thrombocytopenia | 10‑20 % | Monitor CBC qweek; consider G-CSF if ANC <1.0×10⁹/L |
| Pulmonary | General respiratory symptoms (dyspnea, cough) | 15–20 % | ILD; urgent evaluation if grade 2 on a baseline CT |
| Dermatologic | Rash, photosensitivity | 20–30 % | Grade 3 rash in 5 % |
| GI | Nausea, vomiting, diarrhea | 10–15 % | Antiemetics should be proactive |
| Cardiac | Chest pain, heart failure exacerbation | ≤3 % | LVEF monitoring pre‑treatment and after each cycle |
| Allergic | Hypersensitivity reaction | 5 ×ULN |
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Monitoring
- Baseline: CBC, CMP, liver enzymes, chest X‑ray/CT, LVEF (echo/MUGA), skin photosensitivity assessment.
- During Therapy:
- CBC & CMP every 3 weeks.
- LVEF every 3 cycles.
- Chest images (CT) every 3 cycles to screen for ILD.
- Patient diary for any coughing or dyspnea.
- Adverse event grading per CTCAE V5.0.
- Post‑Treatment: Sufficient recovery of CBC/chemistries before continuation; yearly cardiac review.
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Clinical Pearls
- “By‑stander killing” matters: Even low HER2‑expression tumors can respond because DXd diffuses to adjacent cells, broadening the therapeutic window.
- ILDS are often late: On average they present after 2–3 cycles; maintain a high index of suspicion even if initial scans are normal.
- Avoid combined ACE inhibitors: They may worsen cardiac IRRs; monitor LVEF carefully.
- Cytokine‑like symptoms: Sarcoid‑like lymphadenopathy can mimic disease progression; a biopsy clarifies.
- Premedication strategy: A single 30‑min infusion without premedication is tolerable in most; heavily reactive patients benefit from hydrocortisone + antihistamine pre‑infusion.
- Photosensitivity: Recommend SPF ≥ 50+ sunscreen during days 1‑3 of infusion—reduces rash risk by 30 %.
> Key takeaway: Trastuzumab deruxtecan offers durable responses in heavily pre‑treated HER2‑positive cancers, but its life‑threatening ILD risk mandates vigilant pulmonary monitoring and patient education.
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