Zenocutuzumab — Drug Monograph

Brand names: Bizengri

Drug class: Monoclonal Antibody

Mechanism of Action

Zenocutuzumab is a bispecific monoclonal antibody (IgG1 format) that simultaneously binds HER2 and HER3, blocking the binding of neuregulin-1 (NRG1) to HER3. In NRG1-rearranged tumors, oncogenic gene fusions produce NRG1 ligand that constitutively activates HER3 by binding its EGF-like domain, triggering HER2:HER3 heterodimerization and downstream PI3K/AKT/mTOR and RAS/MAPK signaling. By occupying HER3's NRG1-binding domain while simultaneously engaging HER2, zenocutuzumab sterically blocks NRG1-driven heterodimerization and abrogates the oncogenic signaling cascade. This mechanism is…

FDA Indications

• Advanced, unresectable or metastatic non-small cell lung cancer (NSCLC) harboring an NRG1 gene fusion — adults with disease progression on or after prior systemic therapy (FDA accelerated approval 2023, eNRGy trial; ORR 33%, median DOR 7.4 months)
• Advanced, unresectable or metastatic pancreatic ductal adenocarcinoma (PDAC) harboring an NRG1 gene fusion — adults with disease progression on or after prior systemic therapy (FDA accelerated approval 2023, eNRGy trial; ORR 40%, median DOR 9.1 months)
• Advanced, unresectable or metastatic cholangiocarcinoma harboring an NRG1 gene fusion — adults with disease progression on or after prior systemic therapy (FDA approved May 8, 2026, eNRGy trial; ORR 36.8%, DOR range 2.8–12.9 months)

Common Side Effects

• Diarrhea
• Musculoskeletal pain
• Fatigue
• Nausea
• Infusion-related reactions (IRR)
• Dyspnea
• Rash
• Constipation
• Vomiting
• Abdominal pain
• Edema

Clinical Pearl

NRG1 gene fusions are rare — present in ~0.2% of all solid tumors — but are enriched in NSCLC (especially invasive mucinous adenocarcinoma, ~30%), PDAC (~1%), and now cholangiocarcinoma. These fusions produce an NRG1 ligand protein that constitutively drives HER3 signaling, creating a targetable oncogenic dependency. Critically, NRG1-rearranged tumors are typically HER2 non-amplified and negative by IHC — zenocutuzumab's activity is NRG1-fusion driven, not HER2-copy-number driven. Standard…

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