Zanidatamab-hrii

Overview

Zanidatamab-hrii (Ziihera®) is a novel Targeted Therapy designed to treat specific cancers that overexpress the human epidermal growth factor receptor 2 (HER2) protein. It is the first bispecific antibody approved for the treatment of biliary tract cancer. As a bispecific antibody, it is engineered to bind to two distinct regions of the HER2 receptor simultaneously, providing a more comprehensive blockade of tumor growth signals than traditional therapies.

• Generic Name: Zanidatamab-hrii
• US Brand Name: Ziihera®
• Drug Class: Bispecific HER2-Directed Antibody
• Route of Administration: Intravenous (IV) Infusion
• FDA Approval Status: Accelerated Approval (November 2024)

What Is It and How Does It Work? (Mechanism of Action)

Zanidatamab-hrii is a biparatopic, bispecific antibody, meaning it targets two different epitopes (binding sites) on the same HER2 receptor. Traditional HER2 therapies (like trastuzumab or pertuzumab) typically bind to only one site.

Molecular Mechanism:

• Dual Binding: The antibody binds to both the extracellular domain 4 (ECD4) and the dimerization domain (ECD2) of the HER2 receptor.
• Receptor Clustering and Internalization: This dual binding causes HER2 receptors to cluster together on the tumor cell surface. This clustering triggers the cell to internalize (absorb) the receptors, effectively removing them from the surface where they would otherwise receive growth signals.
• Signal Blockade: By removing HER2 from the cell surface and preventing it from pairing with other receptors (dimerization), the drug shuts down downstream signaling pathways (such as PI3K/AKT and MAPK) that drive uncontrolled cell proliferation.

The drug also engages the patient’s immune system through mechanisms called Antibody-Dependent Cellular Cytotoxicity (ADCC) and Complement-Dependent Cytotoxicity (CDC). It acts as a flag, recruiting immune cells (such as natural killer cells) to attack and destroy the cancer cells it has bound to.

FDA Approved Clinical Indications

Zanidatamab-hrii is currently FDA-approved for the following oncological use:

• Biliary Tract Cancer (BTC): Treatment of adult patients with previously treated, unresectable (cannot be removed by surgery) or metastatic HER2-positive (IHC 3+) biliary tract cancer. This includes cancers of the gallbladder and bile ducts (cholangiocarcinoma).

Note: This indication was granted under accelerated approval based on tumor response rate and duration of response. Continued approval may be contingent upon verification of clinical benefit in confirmatory trials.

• Non-oncological uses: None.

Dosage and Administration Protocols

Zanidatamab-hrii is administered by a healthcare professional in a clinical setting equipped to manage infusion reactions.

Clinical Efficacy and Research Results

The FDA approval of Zanidatamab-hrii was based on the pivotal HERIZON-BTC-01 Phase 2b clinical trial (NCT04466891). Results published in 2024 and presented at major oncology conferences demonstrated significant activity in patients who had already progressed on standard chemotherapy.

• Objective Response Rate (ORR): In the primary efficacy cohort (HER2-positive/IHC 3+), approximately 52% of patients achieved a confirmed objective response (defined as> 50% reduction in tumor size).
• Duration of Response (DOR): Responses were durable, with a median duration of approximately 14.9 months.
• Overall Survival (OS): Updated data from 2024 showed a median OS of 15.5 months, representing a meaningful improvement in this historically difficult-to-treat setting, where survival is often limited to less than a year after first-line therapy fails.

Safety Profile and Side Effects

BLACK BOX WARNING: EMBRYO-FETAL TOXICITY

Exposure to Zanidatamab-hrii during pregnancy can cause embryo-fetal harm, including oligohydramnios (low amniotic fluid) and skeletal abnormalities. Verify pregnancy status in females of reproductive potential prior to initiating treatment. Advise patients to use effective contraception during treatment and for 4 months after the last dose.

Common Side Effects (>10%)

• Gastrointestinal: Diarrhea (can be severe), nausea, vomiting, abdominal pain.
• Infusion-Related: Infusion-related reactions (chills, fever, flushing, breathing difficulties).
• General: Fatigue, decreased appetite.
• Skin: Rash.

Serious Adverse Events

• Left Ventricular Dysfunction: The drug can weaken the heart muscle, leading to a decrease in Left Ventricular Ejection Fraction (LVEF). Regular cardiac monitoring is required.
• Severe Diarrhea: Grade 3 or higher diarrhea can occur, requiring aggressive management with anti-diarrheal medications and fluid replacement.
• Infusion-Related Reactions (IRRs): Severe reactions, including anaphylaxis, can occur, typically during the first infusion.
• Pneumonitis/Interstitial Lung Disease: Inflammation of the lungs has been reported and can be severe.

Management Strategies:

• For Diarrhea: Initiate anti-diarrheal therapy (e.g., loperamide) at the first sign of loose stools. Increase fluid intake.
• For Heart Function: Perform cardiac monitoring (Echocardiogram or MUGA scan) at baseline and every 3 months during treatment. Withhold dosing if LVEF drops significantly.

Research Areas

Zanidatamab-hrii is currently being investigated in other HER2-expressing solid tumors beyond biliary tract cancer.

• Gastroesophageal Cancers: Ongoing Phase 3 trials (e.g., HERIZON-GEA-01) are evaluating its combination with chemotherapy and immunotherapy (PD-1 inhibitors) in first-line gastric and gastroesophageal junction cancers.
• Breast Cancer: Studies are exploring its use in HER2-positive breast cancer, potentially in combination with other agents to overcome resistance to standard therapies like trastuzumab.
• Colorectal Cancer: Early-phase research has shown promise in HER2-amplified colorectal cancer.

Note: There is currently no established standard protocol combining Zanidatamab-hrii with stem cell regenerative therapies.

Patient Management and Practical Recommendations

Pre-treatment Tests:

• HER2 Testing: Confirmation of HER2-positive status (IHC 3+) via an FDA-approved test is mandatory.
• Cardiac Assessment: Baseline Echocardiogram (ECHO) or MUGA scan to assess heart function (LVEF).
• Pregnancy Test: Required for women of childbearing potential.
• Liver Function Tests: To establish a baseline for monitoring potential toxicity.

Precautions During Treatment:

• Heart Health: Report any new shortness of breath, ankle swelling, or palpitations immediately, as these may be signs of heart failure.
• Reproductive Health: Use effective contraception during treatment and for 4 months after the final dose. Do not breastfeed during this period.

Do’s and Don’ts List:

• DO: Take your premedications (Tylenol, antihistamine, steroid) exactly as prescribed before your infusion appointment.
• DO: Monitor your weight daily; sudden weight gain may indicate fluid retention related to heart function.
• DON’T: Miss your infusion appointments. The drug works best when sustained levels are maintained in the body.
• DON’T: Ignore diarrhea. If it persists for more than 24 hours, contact your oncology team immediately for management instructions.

Legal Disclaimer

The information provided in this guide is for educational and informational purposes only and is intended for international patients and healthcare professionals. It does not constitute medical advice, diagnosis, or treatment. Zanidatamab-hrii (Ziihera®) is a prescription medication; its use must be determined by a qualified oncologist based on individual patient history and genetic profiling. Dosing, protocols, and approval status may vary by country and regulatory jurisdiction. Always consult with a healthcare provider regarding specific medical conditions and treatment options.