What Is Zanidatamab-hrii (Zııhera)? FDA Approval, Licensing and Reimbursement in Türkiye

• FDA Approval: Yes (first approval date: November 20, 2024)
• Brand Name: Zııhera
• Active Ingredient: Zanidatamab-hrii
• Route of Administration: Intravenous infusion (IV)
• Class: Bispecific HER2-targeted monoclonal antibody
• Category: Antineoplastic / targeted biological agent
• Manufacturer: Jazz Pharmaceuticals
• Distribution in Türkiye: Not yet licensed in Türkiye; access may be possible through special importation
• Approved Cancers: Previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer

What Is Zııhera and How Does It Work?

Ziihera (active ingredient: zanidatamab-hrii) is a bispecific monoclonal antibody used to treat HER2 (human epidermal growth factor receptor 2)-positive cancers. It was developed particularly as a targeted treatment for metastatic or unresectable biliary tract cancer.

How Does It Work?

Zanidatamab, Ziihera's active component, is a bispecific antibody that recognizes and binds two different regions of the HER2 receptor simultaneously. This structure provides stronger and more versatile activity than conventional HER2 antibodies:

• Dual-Epitope Binding: Zanidatamab simultaneously binds domains 2 and 4 of the HER2 receptor, increasing clustering and internalization of the receptor at the cell surface. This suppresses HER2 signaling.
• Blocking Signal Transmission: HER2 activates proliferation pathways such as PI3K/AKT and MAPK. Zanidatamab prevents HER2 homodimer and heterodimer formation, blocking these pathways and suppressing tumor-cell growth.
• Antibody-Dependent Cellular Cytotoxicity: HER2-positive cells bound by zanidatamab are recognized and killed by immune cells, particularly NK cells. This immune-mediated effect contributes to treatment.
• Preventing Receptor Recycling: Once HER2 receptors are internalized, their return to the surface is prevented, reducing cell-surface HER2 density.

FDA (US Food and Drug Administration) Approval History

• November 20, 2024: The FDA granted Ziihera (zanidatamab-hrii) accelerated approval for HER2-positive biliary tract cancer.
• September 16, 2024: Jazz Pharmaceuticals presented updated phase 2 findings showing improved median progression-free survival (mPFS) in HER2-positive metastatic gastroesophageal adenocarcinoma.
• June 1, 2024: Jazz Pharmaceuticals presented overall survival (OS) and longer follow-up findings from HERIZON-BTC-01 in previously treated HER2-positive biliary tract cancer.
• May 29, 2024: Zanidatamab received FDA Priority Review for HER2-positive metastatic biliary tract cancer.
• April 2, 2024: Jazz Pharmaceuticals completed the biologics license application (BLA) process for zanidatamab in previously treated HER2-positive metastatic biliary tract cancer.
• June 2, 2023: Jazz Pharmaceuticals and Zymeworks presented positive pivotal phase 2b findings for zanidatamab in HER2-amplified biliary tract cancer at ASCO 2023.

Licensing and Reimbursement in Türkiye

Ziihera (zanidatamab-hrii) has not yet been licensed by Türkiye's Ministry of Health Turkish Medicines and Medical Devices Agency (TİTCK) or included in reimbursement. Access is possible through special importation under overseas medicine procurement. The process begins with a physician's report documenting the need for treatment and the required applications.

Mechanisms of Resistance

• Reduced or Lost HER2 Expression: During treatment, tumor cells may reduce or lose HER2 receptors. Zanidatamab then cannot bind HER2 and becomes ineffective, a process described as secondary resistance.
• Structural Mutations in the HER2 Receptor: HER2 gene mutations may structurally alter antibody-binding regions, particularly domains 2 or 4, preventing Ziihera from binding HER2 and exerting its effect.
• Activation of Alternative Signaling Pathways: Mutations in PI3K/AKT/mTOR or MAPK/ERK pathways, such as PIK3CA mutations or PTEN loss, may sustain intracellular proliferation signals despite HER2 blockade. These bypass mechanisms cause nonresponse.
• Recycling of the Antibody–Antigen Complex: Ziihera aims to internalize and degrade HER2, but some cells may allow the complex to escape lysosomal degradation and return to the surface. This maintains receptor levels and reduces therapeutic effect.
• Immune-System Factors: Zanidatamab's ADCC (antibody-dependent cellular cytotoxicity) may decrease with low NK activity, immunosuppression, or increased PD-L1 expression in the tumor microenvironment, limiting immune-mediated tumor-cell elimination.
• Increased HER2 Heterodimer Formation: Increased heterodimerization between HER2 and other ErbB-family members such as EGFR (HER1) or HER3 may make Ziihera's inhibitory effect on HER2 insufficient.
• Tumor Heterogeneity: Uneven HER2 expression across tumor tissue, high in some cells and low in others, may produce a heterogeneous treatment response.

Absorption

• Because Ziihera is administered by IV infusion, there is no conventional gastrointestinal absorption.
• It enters the systemic circulation directly after administration.
• The absorption rate depends on the administration duration, such as a 30–90-minute infusion, and dosing schedule.

Distribution

• As a large monoclonal antibody, Ziihera has limited tissue distribution and remains mainly in the intravascular space.
• Volume of distribution (Vd): approximately 0.05 – 0.1 L/kg, with slow transfer between plasma and lymph
• It may accumulate through target-mediated disposition in tumor tissue with high HER2 expression.
• Ability to cross the blood–brain barrier is very low.

Metabolism

• Ziihera is not metabolized through conventional enzyme pathways such as CYP450.
• Its antibody structure allows breakdown through the reticuloendothelial system (RES):
• Monocytes, macrophages, and dendritic cells recognize it and perform lysosomal degradation.
• After binding HER2, the receptor–antibody complex is internalized and degraded within the cell.

Elimination

• Elimination is slow, generally through intracellular protein breakdown.
• Conventional urinary or biliary excretion is negligible.
• Half-life (t1/2): approximately 7–10 days according to clinical findings, varying with dose and HER2 expression.
• Accumulation may occur with repeated doses, so the interval is generally set at 2–3 weeks.

Dose Range

• Dose: 30 mg/kg
• Route: intravenous infusion
• Frequency: every three weeks (every 21 days)
• Infusion duration: generally 90 minutes for the first dose, shortened to 30–60 minutes for subsequent doses if tolerated.
• If a severe infusion reaction occurs, such as fever, chills, or hypotension, treatment is stopped or slowed. Premedication, such as an antihistamine or corticosteroid, may be added.
• Mild to moderate adverse reactions generally do not require dose changes.
• Severe adverse events, such as grade ≥3 toxicity, may require temporary interruption. Depending on clinical response, the interval may be extended or treatment discontinued.

Drug Interactions

• Interactions with the CYP450 Enzyme System: Ziihera is not metabolized in the liver, and direct pharmacokinetic interactions with drugs processed by enzymes such as CYP3A4 or CYP2D6 are not expected. It can therefore be used safely with azole antifungals, macrolide antibiotics, anticonvulsants, warfarin, and similar drugs.
• Combination with Chemotherapy: In clinical trials, Ziihera is often given with chemotherapy such as capecitabine, cisplatin, gemcitabine, or FOLFOX. Additive toxicity rather than pharmacokinetic interaction is important in these combinations: neutropenia, diarrhea, and mucositis may increase, requiring dose modification when necessary.
• Use with Immunosuppressive or Immunotherapeutic Agents: When used with corticosteroids, PD-1/PD-L1 inhibitors, or other immune modulators, Ziihera's antibody-dependent cellular cytotoxicity may be suppressed, potentially reducing efficacy, particularly in patients with a weak immune response.
• Vaccines: Use with live attenuated vaccines, such as yellow fever or BCG, is not recommended. Altered immunity may reduce vaccine effectiveness or increase vaccine-related complications. Inactivated vaccines, such as influenza or COVID-19 vaccines, are generally safe but should be assessed with the oncology team.
• Antihistamines and Premedication: Antihistamines, acetaminophen, or low-dose steroids may be given before initial infusions. No significant effect of these agents on Ziihera efficacy has been demonstrated.

Points Requiring Attention

• Confirming HER2 Positivity: Ziihera is effective only in HER2 IHC 3+ or ISH-positive tumors. HER2 expression should be confirmed in tumor tissue before treatment using an appropriate FDA-approved IHC or FISH/ISH test.
• Infusion Reactions: IV Ziihera may cause acute infusion reactions such as chills, fever, hypotension, or dyspnea. These are more frequent with the first dose. Premedication with an antihistamine, acetaminophen ± steroid is recommended. If a reaction occurs, stop the infusion; it may subsequently be resumed more slowly.
• Monitoring Response and Resistance: Nonresponse, such as HER2 loss or progression, warrants repeat biological profiling. Secondary resistance may develop with long-term use.
• Insufficient Immune Response / Immunosuppression: Immune-mediated mechanisms such as ADCC (antibody-dependent cellular cytotoxicity) may be ineffective in immunocompromised patients, including older patients or those receiving concurrent immunosuppressive treatment.
• Pregnancy and Breastfeeding: Monoclonal antibodies may cross the placenta and pose a fetal-toxicity risk. Do not use during pregnancy (pregnancy category: probably D). Use during breastfeeding is not recommended.
• Liver and Kidney Impairment: Although clinical data are limited, less dose adjustment may be needed because monoclonal antibodies are not eliminated through CYP enzymes or the kidneys. Careful clinical monitoring is nevertheless recommended.
• Laboratory and Clinical Monitoring: HER2 expression, tumor dimensions, blood counts, and liver function tests should be monitored regularly during treatment.
• Live Vaccines: Live attenuated vaccines, such as measles or yellow fever vaccines, should not be administered during Ziihera treatment. Inactivated vaccines are generally safe but should be given under medical supervision.

Adverse Reactions

• Diarrhea 48%
• Nausea 38%
• Vomiting 29%
• Fatigue (asthenia) 27%
• Abdominal pain 25%
• Mouth sores (stomatitis / mucositis) 22%
• Loss of appetite (anorexia) 21%
• Rash 18%
• Itching (pruritus) 15%
• Dry skin 13%
• Fever 12%
• Weakness 12%
• Headache 11%
• Infusion reactions 10%
• Constipation 10%
• Neutropenia 9%
• Elevated liver enzymes (ALT / AST) 9%
• Thrombocytopenia 7%
• Febrile neutropenia 5%
• Mild allergic reactions (urticaria, redness) 4%
• Pulmonary complications (dyspnea, cough) 3%
• Severe infusion reaction 1–2%
• Anaphylaxis (rare) <1%