zanidatamab — Drug Monograph
Zanidatamab (Ziihera) — Biparatopic HER2 Bispecific Overview
Zanidatamab (Ziihera) is a HER2-directed biparatopic bispecific antibody for HER2-amplified biliary tract cancer (BTC). It simultaneously binds two non-overlapping HER2 epitopes — domain II (the pertuzumab-binding, dimerization domain) and domain IV (the trastuzumab-binding domain) — driving potent HER2 clustering, receptor internalization, and enhanced ADCC/ADCP beyond single-epitope HER2 antibodies. This monograph covers zanidatamab dosing (20 mg/kg IV every 2 weeks), HER2-expressing biliary tract cancer indications, the biparatopic antibody binding mechanism, LVEF monitoring, and infusion-related reaction management.
Indications (FDA / NCCN)
- HER2-amplified (IHC 3+ or 2+/ISH+) biliary tract cancer after prior gemcitabine-containing chemotherapy (HERIZON-BTC-01)
- FDA accelerated approval (November 2024)
- HER2 overexpression/amplification confirmed by IHC or ISH before starting
Dosing
- Standard dose: 20 mg/kg IV every 2 weeks
- First infusion over ≥60 min; may shorten to 30 min if tolerated
- Premedicate (antihistamine, antipyretic, corticosteroid) for first and second infusions
- Hepatitis B screening required before initiation
Monitoring
- LVEF by ECHO or MUGA at baseline and periodically (HER2 class cardiotoxicity)
- Infusion-related reactions, including anaphylaxis
- Avoid additive cardiotoxicity with anthracyclines
- HER2 status confirmation
Brand names: Ziihera
Drug class: Other
Mechanism of Action
HER2-directed bispecific antibody that simultaneously binds two distinct and non-overlapping epitopes of the HER2 receptor: domain II (the pertuzumab-binding domain, which blocks HER2 dimerization) and domain IV (the trastuzumab-binding domain, which blocks ligand-independent signaling and promotes receptor downregulation). This dual-epitope engagement results in potent HER2 clustering and receptor internalization, enhanced antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP), collectively providing superior antitumor activity compared to…
FDA Indications
- HER2-amplified (IHC 3+ or IHC 2+/ISH+) biliary tract cancer (BTC), including intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer, after prior gemcitabine-containing chemotherapy (FDA accelerated approval November 2023, HERIZON-BTC-01: 41.3% ORR)
Common Side Effects
- Diarrhea
- Infusion-related reactions
- Nausea
- Fatigue
- Abdominal pain
- Vomiting
- Decreased appetite
- Anemia
- Elevated liver enzymes (AST/ALT)
Clinical Pearl
Zanidatamab targets two non-overlapping HER2 epitopes simultaneously — this dual-epitope binding drives potent receptor clustering, internalization, and degradation, as well as enhanced ADCC. BTC is a rare HER2-driven cancer with limited treatment options; HER2 amplification occurs in ~5–20% of BTCs. Zanidatamab is being evaluated in earlier lines in the HERIZON-GEA-01 trial (HER2-positive gastric/GEJ cancer) in combination with chemotherapy.