Fam-trastuzumab deruxtecan-nxki

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.

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