Zanidatamab

Zanidatamab is a humanised IgG1 bispecific antibody made in Chinese hamster ovary cells by recombinant DNA technology. It is directed against HER2, a receptor tyrosine kinase that, once activated, switches on intracellular signalling pathways (such as the MAPK pathway) controlling cell proliferation, differentiation and cell death. Disturbed HER2 function contributes to several cancers, including biliary tract cancer.

Mechanism of Action

• Dual HER2 binding: zanidatamab binds extracellular domains 2 and 4 of HER2 at the same time, on two separate HER2 molecules (binding in trans).
• Blocked signalling: HER2 signalling relies on the receptor forming dimers; by occupying two distinct sites, zanidatamab prevents HER2 from dimerising.
• Internalisation: binding leads to internalisation of the receptor and so to less HER2 on the cell surface.
• Immune effector activity: zanidatamab induces complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. Together with the effects above, these inhibit tumour growth and cause tumour cell death.
• HER2 status: in a phase 2 study the antibody was more effective in HER2-positive than in HER2-negative patients, and the EU indication is limited to tumours scoring 3+ by immunohistochemistry.
• Immunogenicity: anti-drug antibodies were rarely detected (1.2%; 1 of 85 evaluable patients in Study 203). No effect on pharmacokinetics, efficacy or safety was seen, but the data are limited.
• Cardiac electrophysiology: no effect on the QTc interval, and no relationship between exposure and change in QTc.

Pharmacokinetics

• Absorption: given by intravenous infusion, so it reaches the circulation directly. Kinetics are non-linear between 5 and 30 mg/kg, with faster clearance at low doses: after the first dose Cmax rises in proportion to dose, while total exposure rises more than proportionally. At 20 mg/kg every 2 weeks in biliary tract cancer (Study 203), the geometric mean Cmax was 455 µg/mL after the first dose and 600 µg/mL at steady state (cycle 4 or later), with trough concentrations of 68.3 and 178 µg/mL and areas under the curve over the dosing interval of 2,280 and 3,980 days·µg/mL. The trough accumulation ratio is about 2.4.
• Distribution: elimination from the circulation is biphasic. In the population analysis for biliary tract cancer, the typical volume of the central compartment is 3.22 L and of the peripheral compartment 3.20 L.
• Metabolism: probably broken down by catabolic pathways into smaller peptides and amino acids. As an antibody it is not expected to affect cytochrome P450 enzymes.
• Elimination: typical clearance 0.0110 L/h and half-life about 19 days at steady state. With repeated dosing, steady state takes about 3.2 months (five half-lives) to reach.
• Special populations: population analysis found no clinically significant differences by age (24 to 88 years), sex, race (White, Black, Asian) or body weight (35.4 to 128 kg), nor in mild or moderate renal impairment (eGFR 30 to 89 mL/min) or mild hepatic impairment. The pharmacokinetics in severe renal impairment, end-stage renal disease and moderate or severe hepatic impairment are unknown; because IgG antibodies are not mainly cleared by the kidney or the liver, changes in renal or hepatic function are not expected to alter exposure.

Ziihera was authorised in the EU in June 2025 under a conditional marketing authorisation (granted on less complete data than usual, with further data to be provided) and is an orphan medicine.

• Biliary tract cancer (BTC): as monotherapy for adults with unresectable locally advanced or metastatic HER2-positive (IHC3+) biliary tract cancer previously treated with at least one prior line of systemic therapy.
• Patient selection: the tumour must have documented HER2-positive status, defined as a score of 3+ by immunohistochemistry (IHC) assessed with a CE-marked in vitro diagnostic medical device with the corresponding intended purpose. If no CE-marked device is available, another validated test should be used.

• Hypersensitivity to zanidatamab or to any of the excipients (see Composition).

The safety profile comes from 233 patients who received 20 mg/kg as a single agent in two single-arm trials; 39% were treated for 6 months or longer and 17% for more than a year. Serious adverse reactions occurred in 8.2% of patients, most often diarrhoea (1.7%) and fatigue (1.3%). The most common reactions were diarrhoea (48.5%), infusion-related reaction (30.5%), fatigue (26.2%), anaemia (21.9%) and rash (21.5%).

Very common (≥1/10): anaemia, decreased appetite, diarrhoea, abdominal pain, nausea, vomiting, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), rash, fatigue, infusion-related reaction.

Common (≥1/100 to <1/10): decreased left ventricular ejection fraction.

Uncommon (≥1/1,000 to <1/100): pneumonitis.

In the SmPC table, abdominal pain includes upper abdominal pain; rash includes acneiform dermatitis, maculo-papular rash, pruritic rash and urticaria; fatigue includes asthenia and malaise.

Important reactions described in the SmPC (pooled population of 233 patients):

• Diarrhoea: 48.5%; grade 3 in 5.2%, no grade 4 or 5. Median time to first onset 10 days, to resolution 3 days. The dose was reduced in 1.3% and held or delayed in 2.6%; no patient stopped treatment because of it.
• Infusion-related reactions: 30.5%; grade 3 in 0.4%. Median onset and resolution 1 day. The infusion was interrupted in 25.3% and treatment stopped in 0.4%.
• Left ventricular dysfunction: 12 events of decreased ejection fraction in 10 patients (4.3%), one considered serious; grade 3 in 1.3%. Median onset 171 days, median resolution 27 days. The dose was reduced in 1 patient, held or delayed in 5 and stopped in 2.
• Anaemia and liver enzymes: anaemia 21.9% (grade 3 in 9.9%, grade 4 in 0.4%); raised ALT 12.4% (grade 3 in 1.7%, grade 4 in 0.4%) and raised AST 11.6% (grade 3 in 1.3%, grade 4 in 0.9%).
• Pneumonitis: reported in 0.4% of patients.

No dedicated clinical drug interaction studies have been done with zanidatamab, and the SmPC names no specific interacting medicine.

• Cytochrome P450: as an antibody, zanidatamab is not expected to affect cytochrome P450 enzymes.
• Other medicines: zanidatamab is not known to act on mechanisms linked to pro-inflammatory cytokines, so it is not expected to change the pharmacokinetics of medicines taken at the same time.

Treatment must be started by a physician experienced in the diagnosis and treatment of biliary tract cancer. Ziihera is given by a qualified healthcare professional, with appropriate resuscitation equipment available. It is given only as an intravenous infusion and must not be given as an intravenous push or a rapid single bolus injection. Before treatment, the tumour must be shown to be HER2-positive (IHC 3+) with a CE-marked in vitro diagnostic device or, if none is available, another validated test.

Recommended Dose

• 20 mg/kg as an intravenous infusion every 2 weeks (every 14 days), until disease progression or unacceptable toxicity.
• Premedication: 30 to 60 minutes before each infusion, a corticosteroid, an antihistamine and an antipyretic are recommended to prevent infusion-related reactions.
• Infusion time: the first and second infusions run for 120–150 minutes; the third and fourth for 90 minutes and later ones for 60 minutes, in each case if the previous infusions were well tolerated.
• Preparation: the powder is reconstituted and then diluted; the diluted solution must have a final concentration of 0.4 to 6 mg/mL. The SmPC (section 6.6) gives the preparation steps.

Dose Modifications

• Left ventricular dysfunction: left ventricular function is assessed before treatment and at regular intervals. If the LVEF falls by an absolute 16 percentage points or more from baseline, or falls below 50% with an absolute decrease of 10 percentage points or more below baseline, treatment is withheld for at least 4 weeks and the LVEF is checked again within 4 weeks. Treatment can resume within 4 to 8 weeks if the LVEF is back within normal limits and the absolute decrease is 15 percentage points or less from baseline; otherwise it is stopped permanently.
• Infusion-related reactions, grade 1 (mild): reduce the infusion rate by 50%. Later infusions start at the reduced rate and may be sped up gradually, as tolerated.
• Grade 2 (moderate): hold the infusion at once and treat; resume at 50% of the previous rate once symptoms resolve. Later infusions may be sped up gradually, as tolerated.
• Grade 3 (severe): hold the infusion at once and treat promptly; resume at the next scheduled dose at 50% of the previous rate once symptoms resolve. Stop permanently if grade 3 symptoms recur.
• Grade 4 (life-threatening): hold the infusion at once, treat promptly and stop permanently.
• Pneumonitis: stop permanently for confirmed grade 2 or higher pneumonitis.

Special Populations

• Renal impairment: no adjustment in mild or moderate impairment (eGFR 30 to 89 mL/min). It has not been evaluated in severe impairment or end-stage renal disease, with or without dialysis, but because renal processes play a minor part in clearance, no adjustment is recommended.
• Hepatic impairment: no adjustment in mild impairment. It has not been evaluated in moderate or severe impairment, but because hepatic processes play a minor part in clearance, no adjustment is recommended.
• Elderly: no adjustment at 65 years and over.
• Children and adolescents: patients under 18 were not included in trials; safety, efficacy and pharmacokinetics have not been established.

Missed Dose

Give the scheduled dose as soon as possible and adjust the schedule so that a 2-week interval between doses is kept.

Traceability

To keep biological medicines traceable, the name and batch number of the product given must be clearly recorded.

Embryo-Foetal Toxicity and Contraception

Zanidatamab may cause foetal harm when given to a pregnant woman. After marketing, other HER2-directed antibodies used in pregnancy were reported to cause oligohydramnios, which showed as pulmonary hypoplasia, skeletal abnormalities and neonatal death. A pregnancy test is needed before treatment starts, patients should avoid becoming pregnant during treatment, and women who can become pregnant must use effective contraception during treatment and for 4 months after the last dose.

Left Ventricular Dysfunction

Decreased LVEF has been reported with medicines that block HER2, including zanidatamab. LVEF must be assessed by echocardiogram or MUGA scan before treatment and at regular intervals, and treatment is stopped as set out under Dose Modifications. Zanidatamab has not been studied in patients with a pre-treatment LVEF below 50%, a myocardial infarction or unstable angina in the previous 6 months, troponin levels consistent with myocardial infarction, or clinically significant cardiac disease such as ventricular arrhythmia needing treatment, uncontrolled hypertension or any history of symptomatic congestive heart failure.

Infusion-Related Reactions

Infusion-related reactions are very common. Premedication is given before every dose, patients are monitored during the infusion and as clinically indicated afterwards, and emergency medicines and equipment to treat these reactions must be available for immediate use.

Pneumonitis

Pneumonitis has been reported with HER2-blocking medicines, including Ziihera (0.4% of 233 patients given 20 mg/kg as a single agent). Patients are monitored for signs and symptoms, and treatment is stopped permanently for confirmed grade 2 or higher pneumonitis.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: not recommended during pregnancy or in women who can become pregnant and are not using contraception. There are no human or animal data on use in pregnancy. Women who received it during pregnancy, or within 4 months before conception, should be monitored for oligohydramnios; if it occurs, foetal testing suited to the gestational age and to local standard of care should be done.
• Breastfeeding: it is not known whether zanidatamab passes into human milk or what effect it has on a breast-fed child or on milk production. A decision is made whether to stop breastfeeding or stop treatment, weighing the benefit of breastfeeding for the child and the benefit of treatment for the woman, and taking the 4-month washout period into account.
• Fertility: fertility studies have not been performed.

Excipients: Sodium and Polysorbate 20

Each dose contains less than 1 mmol (23 mg) of sodium, so it is essentially sodium-free. Each vial contains 0.63 mg of polysorbate 20 (0.105 mg/mL), which can cause allergic reactions.

Effect on Driving

Zanidatamab has a minor influence on the ability to drive and use machines. Fatigue has been reported, so patients should take care when driving or operating machines.

Store the unopened vials in a refrigerator at 2–8 °C. Do not freeze. The cold chain must be kept during transport and handling. The vial is a 20 mL type I glass vial with a chlorobutyl stopper and flip-off cap; packs hold 1 or 2 vials, and not all pack sizes may be marketed. For the reconstituted and diluted solutions, see Shelf Life.

• Unopened vial: 3 years.
• Reconstituted solution: chemical and physical in-use stability has been shown for up to 6 hours at room temperature (18–24 °C) and up to 24 hours at 2–8 °C. From a microbiological point of view, unless reconstitution rules out the risk of microbial contamination, it should be used immediately; if not, in-use times and conditions are the user’s responsibility and should not exceed 4 hours at room temperature or in the refrigerator.
• Diluted solution: chemical and physical in-use stability has been shown for up to 24 hours at room temperature (18–24 °C) and at 2–8 °C. From a microbial point of view it should be used immediately; if not, in-use times and conditions are the user’s responsibility and should not exceed 12 hours at room temperature or 24 hours in the refrigerator at 2–8 °C. These times start from the time of reconstitution.

Prescription only (Rx): a medicinal product subject to restricted medical prescription. Treatment is started by a physician experienced in the diagnosis and treatment of biliary tract cancer. Ziihera is an intravenous infusion given by a qualified healthcare professional, so it is supplied to the hospital or clinic that administers it, under cold-chain conditions (2–8 °C).