Fam-trastuzumab deruxtecan-nxki (Enhertu)
Pharmacologic Class
- Antibody–drug conjugate (ADC)
- Antibody: Trastuzumab (anti-HER2 monoclonal antibody).
- Linker: Cleavable tetrapeptide-based linker.
- Payload: Deruxtecan (a topoisomerase I inhibitor, similar to irinotecan’s SN-38).
Indications (FDA-Approved)
- HER2-positive metastatic breast cancer (after ≥1 prior anti-HER2 regimens).
- HER2-low breast cancer (IHC 1+ or 2+/ISH–) after prior chemotherapy.
- HER2-positive gastric or gastroesophageal junction adenocarcinoma (after trastuzumab).
- HER2-mutant NSCLC (locally advanced or metastatic, previously treated).
- Other solid tumors with activating HER2 mutations (tumor-agnostic, 2024 approval).
Mechanism of Action
- Trastuzumab component: Binds to HER2 receptor, blocking signaling and mediating ADCC.
- Deruxtecan payload: Potent topoisomerase I inhibitor → DNA damage → apoptosis.
- Bystander effect: Payload is membrane-permeable → can kill neighboring HER2-negative cells in a heterogeneous tumor.
Dosing
- Breast, NSCLC, and other solid tumors:
- 5.4 mg/kg IV q3 weeks (until progression or unacceptable toxicity).
- Gastric/GEJ cancer:
- 6.4 mg/kg IV q3 weeks.
No renal/hepatic adjustments specified, but use caution in moderate/severe impairment.
Key Adverse Effects
- Interstitial lung disease (ILD)/pneumonitis → potentially fatal (boxed warning).
- Myelosuppression → neutropenia, anemia, thrombocytopenia.
- GI toxicity → nausea, vomiting, constipation, decreased appetite.
- Fatigue.
- Alopecia.
- Cardiac dysfunction (rare, but trastuzumab component warrants LVEF monitoring).
Monitoring
- Pulmonary symptoms: cough, dyspnea → hold drug and evaluate for ILD.
- CBC: baseline and before each cycle.
- LVEF: baseline and periodically (trastuzumab effect).
- Liver function: baseline and periodically.
Drug Interactions
- Minimal CYP interactions.
- Avoid combination with strong topoisomerase I inhibitors (additive toxicity).
- Caution with myelosuppressive drugs.
Clinical Pearls
- Boxed Warning: ILD/pneumonitis (any grade in ~10–15% of patients; grade ≥3 in ~3–4%; fatal in ~1–2%).
- Early recognition of ILD is critical → permanent discontinuation for ≥Grade 2 ILD.
- More effective than T-DM1 (trastuzumab emtansine) in the DESTINY-Breast03 trial (improved PFS and OS).
- HER2-low approval makes it a practice-changing agent, expanding HER2-targeted therapy beyond HER2-positive disease.
- Premedication for nausea is often required (moderate-to-high emetogenic risk).
Summary:
Enhertu is a HER2-targeted ADC with a potent topoisomerase I payload, now approved across multiple tumor types. Its most serious risk is ILD, which requires aggressive monitoring and early intervention.