Zanidatamab (Ziihera®): A Comprehensive Monograph on a First-in-Class Bispecific HER2-Directed Antibody

Executive Summary

Zanidatamab represents a significant advancement in the field of targeted oncology, establishing a new class of therapy as a biparatopic, human epidermal growth factor receptor 2 (HER2)-directed antibody. Marketed under the brand name Ziihera®, this engineered biologic possesses a novel mechanism of action that distinguishes it from prior generations of HER2-targeted agents. By simultaneously engaging two distinct, non-overlapping epitopes on the HER2 receptor, zanidatamab induces unique receptor clustering, leading to rapid internalization, downregulation, and a multi-pronged, immune-mediated attack on tumor cells that includes potent complement-dependent cytotoxicity (CDC)—a mechanism largely absent in its predecessors.

The clinical value of this unique pharmacology was definitively established in the pivotal HERIZON-BTC-01 trial, a global Phase 2b study in patients with previously treated, unresectable or metastatic HER2-positive biliary tract cancer (BTC). The trial demonstrated compelling and durable clinical activity, particularly in the subgroup of patients with high HER2 expression (immunohistochemistry [IHC] 3+), with an objective response rate exceeding 50% and a median overall survival of over 18 months. These results, coupled with a manageable and tolerable safety profile devoid of chemotherapy-associated toxicities, address a profound unmet medical need in a patient population with historically poor outcomes.

Based on the strength of these data, zanidatamab secured Accelerated Approval from the U.S. Food and Drug Administration (FDA) and Conditional Marketing Authorisation from the European Medicines Agency (EMA) for the treatment of previously treated, unresectable or metastatic HER2-positive (IHC 3+) BTC. Its development is supported by a robust and ambitious clinical program aimed at expanding its use into the first-line settings for both BTC and gastroesophageal adenocarcinoma (GEA), as well as into other HER2-expressing solid tumors such as breast and colorectal cancer. This strategic pipeline positions zanidatamab not only as a new standard of care in its initial indication but also as a potential cornerstone therapy across a broad spectrum of HER2-driven malignancies. The global development and commercialization are managed through a strategic partnership between Zymeworks, the innovator, Jazz Pharmaceuticals (U.S., Europe, Japan), and BeiGene (Asia-Pacific).

Introduction and Molecular Profile

Zanidatamab is an innovative antineoplastic agent that has emerged as a first-in-class targeted therapy for HER2-expressing cancers. Its development marks a significant step forward in protein engineering, designed to overcome limitations of existing HER2-targeted therapies by employing a novel bispecific binding mechanism.

Drug Identification and Classification

Zanidatamab is the internationally recognized nonproprietary name (INN) for the molecule.[1] In the United States, it is formally identified by the nonproprietary name zanidatamab-hrii, with the four-letter, non-meaningful suffix "-hrii" used by the FDA to distinguish it from other potential future biologic products.[1] The "-hrii" suffix is a regulatory convention specific to the U.S. market, designed to enhance pharmacovigilance and ensure accurate product tracing, but it is not part of the global INN. During its development, the compound was known by the code ZW25.[1] Commercially, it is marketed under the brand name Ziihera®.[1]

From a classification standpoint, zanidatamab is a biotech therapeutic, specifically categorized as a humanized, bispecific HER2-directed monoclonal antibody.[1] Its therapeutic function places it in the pharmacologic class of antineoplastic agents. The World Health Organization has assigned it the Anatomical Therapeutic Chemical (ATC) code L01FD07.[1]

Structural and Physicochemical Characteristics

Zanidatamab is a complex protein therapeutic produced through recombinant DNA technology in Chinese Hamster Ovary (CHO) cells, a standard mammalian cell line for the production of therapeutic antibodies.[1] It is a humanized antibody, meaning the protein sequences were originally derived from a murine (mouse) source and subsequently modified to more closely resemble human antibodies, thereby reducing the potential for immunogenicity in patients.[1]

Structurally, zanidatamab is an IgG1-like bispecific antibody.[6] Its sophisticated architecture is a product of advanced protein engineering, specifically the Azymetric™ platform. It is assembled from two distinct half-antibodies, resulting in an asymmetric molecule with the structure Fab-h-CH2-CH3 x scFv-h-CH2-CH3.[7] This engineered asymmetry is fundamental to its unique biological activity, enabling it to bind two different epitopes on the HER2 receptor and, critically, to engage two separate HER2 molecules simultaneously—a capability not found in naturally occurring antibodies or conventional monoclonal antibody therapies.

The molecular formula for zanidatamab is C5553​H8526​N1482​O1726​S36​, with a calculated molar mass of approximately 124,818.10 g·mol−1, or 124.8 kDa.[1] Other sources report a molecular weight of approximately 148.28 kDa, a variation that can arise from different calculation methods or post-translational modifications such as glycosylation.[6]

Table 1: Zanidatamab Drug Profile Summary

Characteristic	Value
International Nonproprietary Name (INN)	zanidatamab 1
US Adopted Name (USAN)	zanidatamab-hrii 1
Brand Name	Ziihera® 1
Development Code	ZW25 1
Drug Type	Biotech, Protein-Based Therapy 1
Drug Class	Antineoplastic, Bispecific HER2-Directed Antibody 1
ATC Code	L01FD07 1
DrugBank ID	DB15471 1
CAS Number	2169946-15-8 1
Source	Humanized (from mouse), produced in CHO cells 1
Molecular Formula	C5553​H8526​N1482​O1726​S36​ 1
Molar Mass	124,818.10 g·mol−1 1

Preclinical Pharmacology and Mechanism of Action (MoA)

The therapeutic efficacy of zanidatamab is rooted in its unique and multifaceted mechanism of action, which is a direct consequence of its engineered bispecific design. It targets the human epidermal growth factor receptor 2 (HER2, also known as ERBB2), a receptor tyrosine kinase that is a well-established oncogenic driver in a variety of solid tumors, including biliary tract, breast, and gastric cancers.[5] Aberrant HER2 signaling, typically resulting from gene amplification and subsequent protein overexpression, promotes uncontrolled cell proliferation, survival, and differentiation.[5] Zanidatamab was designed to inhibit HER2 signaling more effectively than existing agents by engaging the receptor in a novel manner.

Biparatopic Engagement of the HER2 Receptor

Zanidatamab is a biparatopic antibody, meaning it is engineered to simultaneously bind two distinct and non-overlapping epitopes on the extracellular domain (ECD) of the HER2 protein.[1] This dual engagement is a key point of differentiation from monospecific antibodies. Specifically, zanidatamab targets:

1. The Dimerization Domain (ECD2): This is the same domain targeted by the monoclonal antibody pertuzumab.[6]
2. The Juxtamembrane Domain (ECD4): This is the same domain targeted by the monoclonal antibody trastuzumab.[6]

By binding to both of these critical sites, zanidatamab can physically obstruct the receptor's ability to dimerize with other HER family members, a crucial step for the activation of downstream signaling pathways.[5]

Unique Receptor Dynamics: Trans-Binding, Clustering, and Capping

The most innovative aspect of zanidatamab's mechanism is not just its dual-epitope targeting but how it engages these epitopes. Preclinical structural and biophysical studies, including surface plasmon resonance (SPR) and cryo-electron microscopy, have demonstrated that zanidatamab binds to HER2 in trans.[7] This means that a single zanidatamab molecule crosslinks two adjacent HER2 molecules on the cell surface by binding to ECD2 on one receptor and ECD4 on the other. This mode of binding is a consequence of its engineered structure, which creates a spatial constraint that prevents it from binding to two epitopes on the same HER2 molecule (

cis-binding).[9]

This trans-binding action forces a novel reorganization of HER2 receptors on the tumor cell surface. It induces the formation of large, high-order HER2 clusters and promotes the migration of these clusters into polarized "caps" on the cell surface.[7] This dramatic alteration of receptor topography is a unique feature of zanidatamab and is not observed with treatment by trastuzumab, pertuzumab, or even the combination of the two.[9]

Downstream Consequences: Internalization, Downregulation, and Signal Blockade

The formation of these large HER2-zanidatamab complexes serves as a potent signal for the cell's endocytic machinery. This leads to the rapid and superior internalization of the HER2 receptor from the cell surface into the cell's interior, followed by trafficking to lysosomes for degradation.[5] The consequence is a profound depletion and downregulation of total HER2 protein levels on and within the tumor cell.[2] By physically removing the oncogenic driver from the cell surface, zanidatamab achieves a durable blockade of downstream signaling pathways, such as the MAPK pathway, thereby inhibiting tumor cell growth and promoting apoptosis.[5]

Potentiation of Immune-Mediated Cytotoxicity

Beyond direct signal blockade, zanidatamab's IgG1 Fc domain is fully functional and engineered to recruit the patient's immune system to attack the tumor. The unique receptor clustering induced by zanidatamab creates an ideal platform for immune effector functions, leading to several forms of immune-mediated cell death:

• Complement-Dependent Cytotoxicity (CDC): The high-density HER2 clusters formed by zanidatamab create an optimal geometry for the binding and activation of C1q, the initiating protein of the classical complement cascade. This triggers a lytic cascade that results in the formation of the membrane attack complex and subsequent tumor cell lysis. This is a crucial mechanistic differentiator, as preclinical studies have shown that zanidatamab elicits potent CDC, whereas trastuzumab and pertuzumab are inactive in this regard.[7] The ability to harness the complement system, a powerful component of innate immunity, provides an additional and potent killing mechanism that may be effective even in tumors that have developed resistance to other immune-mediated pathways.
• Antibody-Dependent Cellular Cytotoxicity (ADCC): Zanidatamab's Fc region effectively binds to Fcγ receptors on immune effector cells, such as Natural Killer (NK) cells, flagging the tumor cell for destruction.[7]
• Antibody-Dependent Cellular Phagocytosis (ADCP): Similarly, zanidatamab mediates the engulfment and destruction of tumor cells by macrophages through ADCP.[7]

The convergence of these multiple, synergistic mechanisms—direct signal blockade via receptor downregulation and a multi-pronged immune attack—underpins the potent anti-tumor activity of zanidatamab. This multi-modal approach may be particularly effective at overcoming the mechanisms of resistance that can limit the efficacy of monospecific antibodies like trastuzumab.[9] It is also important to note that zanidatamab is not a T-cell engager and therefore does not activate cytotoxic T-cells in a way that leads to cytokine release syndrome (CRS), a significant safety advantage over some other classes of bispecific antibodies.[13]

Clinical Pharmacokinetics (PK) and Dosing

The pharmacokinetic profile of zanidatamab is characteristic of a large protein therapeutic, defined by intravenous administration, limited distribution, slow clearance, and a long half-life, which collectively support a convenient dosing schedule for patients.

Absorption, Distribution, Metabolism, and Elimination (ADME)

• Administration and Absorption: Zanidatamab is administered exclusively as an intravenous (IV) infusion, resulting in 100% bioavailability.[1] Following IV administration, pharmacokinetic parameters show that the maximum concentration ( Cmax​) is dose-proportional. However, the total systemic exposure, as measured by the area under the concentration-time curve (AUC), is greater than dose-proportional. This suggests that at higher concentrations, the drug's clearance mechanisms may become saturated, leading to a disproportionately larger increase in overall exposure with increasing doses.[5]
• Distribution: Population pharmacokinetic analysis indicates a volume of distribution (Vd​) of approximately 7.5 liters.[5] This relatively small Vd​ suggests that the distribution of zanidatamab is primarily confined to the blood plasma and the interstitial fluid of well-perfused tissues, which is typical for large molecules like monoclonal antibodies that do not readily cross cellular membranes.
• Metabolism: As a protein-based therapeutic, zanidatamab is not metabolized by the hepatic cytochrome P450 (CYP450) enzyme system. Instead, it is expected to be degraded through general protein catabolism into smaller peptides and individual amino acids, which are then recycled by the body.[5] This metabolic pathway minimizes the risk of drug-drug interactions with small-molecule drugs that are substrates, inhibitors, or inducers of CYP450 enzymes.
• Elimination and Half-Life: Zanidatamab exhibits slow clearance, with an estimated clearance rate of 0.012 L/h based on population PK analysis.[5] This slow clearance contributes to a long terminal elimination half-life, estimated to be approximately 21 days.[5] This extended half-life is a key pharmacokinetic feature, ensuring that therapeutic concentrations are maintained in the body over a prolonged period. This property is of significant clinical and commercial utility, as it enables a less frequent, bi-weekly dosing regimen, which is more convenient for patients compared to weekly or more frequent infusions. This reduction in the burden of treatment can improve patient quality of life and adherence, particularly in the context of long-term therapy for metastatic disease.

Dosing and Administration

Based on clinical trial data, the recommended dosage of zanidatamab is 20 mg/kg administered as an intravenous infusion every two weeks until disease progression or unacceptable toxicity.[15] To mitigate the risk of infusion-related reactions (IRRs), a common adverse event with monoclonal antibody therapies, premedication is recommended. Patients should receive acetaminophen, an antihistamine (e.g., diphenhydramine), and a corticosteroid (e.g., dexamethasone) approximately 30 to 60 minutes prior to each infusion.[18]

Clinical Development and Efficacy in Biliary Tract Cancer (BTC)

The regulatory approvals for zanidatamab were primarily based on the compelling efficacy and safety data from the HERIZON-BTC-01 study, a pivotal trial that established a new standard of care for a specific, biomarker-defined population of patients with advanced biliary tract cancer.

The HERIZON-BTC-01 Pivotal Trial (NCT04466891)

HERIZON-BTC-01 was a global, multicenter, open-label, single-arm, Phase 2b clinical trial designed to evaluate the efficacy and safety of zanidatamab monotherapy.[1] The study enrolled patients with HER2-amplified, unresectable, locally advanced, or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder cancer) who had experienced disease progression after receiving at least one prior gemcitabine-containing chemotherapy regimen.[1] This represents a patient population with a high unmet medical need and historically poor prognosis.

A total of 87 patients were enrolled and assigned to one of two cohorts based on centrally confirmed HER2 protein expression levels as determined by immunohistochemistry (IHC):

• Cohort 1: Patients with HER2-positive tumors (IHC 2+ or IHC 3+), comprising 80 individuals. This cohort was the primary focus for the efficacy analysis.[15]
• Cohort 2: Patients with low or negative HER2 expression (IHC 0 or IHC 1+), comprising 7 individuals, who served as a control group for exploratory analysis.[15]

The primary endpoint of the study was the confirmed objective response rate (cORR) in Cohort 1, as assessed by an independent central review (ICR) according to RECIST v1.1 criteria.[15]

Efficacy Results in HER2-Positive BTC (Cohort 1, n=80)

The HERIZON-BTC-01 trial successfully met its primary endpoint, demonstrating robust and durable anti-tumor activity. With a median follow-up of 21.9 months, the key efficacy results for the overall HER2-positive population (Cohort 1) were as follows:

• Objective Response Rate (cORR): The cORR was 41.3% (95% CI: 30.4-52.8). This included 2 patients (2.5%) who achieved a complete response (CR) and 31 patients who achieved a partial response (PR).[15]
• Duration of Response (DOR): The responses were highly durable, with a median DOR of 14.9 months (95% CI: 7.4-not reached).[22]
• Disease Control Rate (DCR): The DCR, which includes patients with a complete response, partial response, or stable disease, was 68.8% (95% CI: 57.4-78.7).[25]
• Overall Survival (OS): Zanidatamab treatment resulted in a median OS of 15.5 months (95% CI: 10.4-18.5).[23]
• Progression-Free Survival (PFS): The median PFS was 5.5 months (95% CI: 3.6-7.3).[22]
• Time to Response: The anti-tumor activity was rapid, with a median time to first response of just 1.8 months.[26]

Efficacy in the High HER2-Expressing Subgroup (IHC 3+, n=62)

A pre-specified subgroup analysis revealed that the clinical benefit of zanidatamab was most pronounced in patients with the highest level of HER2 expression (IHC 3+). This finding is of paramount clinical significance, as it validates the drug's mechanism of action, which is dependent on a high density of HER2 targets on the tumor cell surface. The efficacy in this subgroup of 62 patients was markedly superior:

• cORR: The cORR was 51.6% (95% CI: 38.6-64.5), as reported in European regulatory filings, or 52% (95% CI: 39-65) in other reports.[3]
• DOR: The median DOR remained durable at 14.9 months (95% CI: 7.4-not estimable).[3]
• OS: The median OS was an impressive 18.1 months (95% CI: 12.2-23.2).[16] In stark contrast, the median OS for the small number of patients with IHC 2+ tumors was only 5.2 months, underscoring the critical importance of the IHC 3+ biomarker.[22]
• PFS: The median PFS was 7.2 months (95% CI: 5.4-9.4).[22]

These data strongly support the use of the companion diagnostic test to select patients most likely to derive substantial benefit from zanidatamab, justifying the specific labeling granted by regulatory authorities for the IHC 3+ population. When benchmarked against historical controls for second-line chemotherapy in BTC, which typically yield response rates in the single digits (around 5-8%) and a median OS of only 6 to 9 months, the results for zanidatamab in the IHC 3+ population represent a paradigm shift in treatment and a major clinical advancement.[16] This substantial improvement over available therapy provided the rationale for the FDA's Breakthrough Therapy designation and the subsequent accelerated approval.

Patient-Reported Outcomes

Beyond objective tumor measurements, the clinical benefit of zanidatamab was also reflected in patient-reported outcomes from the HERIZON-BTC-01 trial. Patients who achieved a response (CR or PR) to zanidatamab generally reported clinically meaningful improvements in pain scores and less interference from pain with their daily activities compared to baseline. Furthermore, these responders had a significantly lower rate of increased opioid use (3.1%) compared to patients whose disease progressed (34.8%), indicating a tangible improvement in quality of life.[30]

Table 2: Summary of Efficacy Results from the HERIZON-BTC-01 Trial

Efficacy Endpoint	All HER2-Positive (Cohort 1, n=80)	IHC 3+ Subgroup (n=62)
Confirmed Objective Response Rate (cORR)	41.3% 15	51.6% - 52% 3
Median Duration of Response (DOR)	14.9 months 22	14.9 months 3
Median Overall Survival (OS)	15.5 months 24	18.1 months 16
Median Progression-Free Survival (PFS)	5.5 months 22	7.2 months 22

Comprehensive Safety and Tolerability Profile

The safety profile of zanidatamab has been well-characterized through its clinical development program, particularly in the HERIZON-BTC-01 trial. The overall assessment is that the drug is generally well-tolerated, with a manageable safety profile consistent with the class of HER2-targeted therapies.[12] A key advantage is the absence of chemotherapy-associated toxicities, such as significant myelosuppression, peripheral neuropathy, or alopecia, making it an attractive option for patients who have already been exposed to cytotoxic regimens.[25]

Overview of Adverse Events

• Most Common Adverse Reactions: The most frequently reported adverse reactions, occurring in at least 20% of patients who received zanidatamab-hrii, were diarrhea, infusion-related reactions (IRR), abdominal pain, and fatigue.[1]
• Treatment-Related Adverse Events (TRAEs): In the HERIZON-BTC-01 study population (N=87), TRAEs of any grade occurred in 72% of patients. The most common TRAEs reported in 10% or more of patients were diarrhea (37%) and IRR (33%).[20] Other frequently observed adverse events included various laboratory abnormalities such as decreased hemoglobin, increased liver enzymes (AST/ALT), and electrolyte imbalances, as well as gastrointestinal symptoms like nausea and vomiting, and dermatologic events like rash.[34]
• Grade 3 or Higher TRAEs: Severe (Grade ≥3) TRAEs were relatively infrequent, occurring in approximately 18% to 21% of patients.[15] The most common Grade 3 TRAEs were diarrhea (4.6%), decreased ejection fraction (3.4%), and anemia (3.4%).[15] Grade 4 TRAEs were rare, and importantly, no treatment-related deaths were reported across the clinical trials.[15] The overall rate of treatment discontinuation due to TRAEs was low, at 2.3%.[22]

Boxed Warning and Key Precautions

The prescribing information for Ziihera includes several important warnings and precautions that require careful monitoring and management by healthcare professionals.

• Boxed Warning - Embryo-Fetal Toxicity: The U.S. prescribing information carries a boxed warning for the risk of embryo-fetal toxicity.[1] Based on the mechanism of action of HER2-directed antibodies and literature reports, administration during pregnancy can cause fetal harm, including oligohydramnios (deficient amniotic fluid) and subsequent complications such as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Pregnancy status must be verified before initiating treatment. Females of reproductive potential must be advised to use effective contraception during therapy and for at least 4 months following the final dose.[13]
• Left Ventricular Dysfunction (LVD): Treatment with zanidatamab can lead to a decrease in left ventricular ejection fraction (LVEF), a known class effect of HER2-targeted therapies. In a pooled safety analysis, LVEF declined by >10% to a value <50% in 4.3% of patients. The median time to the first occurrence of LVD was 5.6 months. Assessment of LVEF is mandatory prior to starting treatment and at regular intervals during therapy. The drug should be withheld or permanently discontinued based on the severity of LVD.[13]
• Infusion-Related Reactions (IRR): IRRs are common, reported in approximately 31-35% of patients, with the majority being Grade 1 or 2 in severity.[28] These reactions, which can include symptoms like fever, chills, flushing, and dyspnea, typically occur during or shortly after the first infusion and resolve within one day. Prophylactic premedication is required to minimize their incidence and severity.[14]
• Severe Diarrhea: Diarrhea is the most common adverse event, reported in up to 50% of patients, with Grade 3 events occurring in approximately 5-6%.[34] Prompt management with antidiarrheal agents is necessary. For severe or persistent cases, dose interruption or reduction may be required.[14]
• Pneumonitis: Although rare, non-infectious pneumonitis has been reported. Patients presenting with new or worsening pulmonary symptoms should be evaluated, and zanidatamab should be permanently discontinued for confirmed Grade 2 or higher pneumonitis.[14]

Management of Adverse Events

The management of zanidatamab-related adverse events is generally supportive and follows established clinical practice guidelines.

• IRRs are managed with mandatory premedication. If a reaction occurs, the infusion rate should be slowed or the infusion temporarily held. For severe reactions, the infusion should be stopped, and permanent discontinuation may be necessary.[14]
• LVD requires diligent cardiac monitoring. Treatment should be withheld for significant LVEF declines and may be resumed if LVEF recovers. Permanent discontinuation is warranted for symptomatic heart failure or persistent cardiac dysfunction.[13]
• Diarrhea should be treated with standard antidiarrheal medications (e.g., loperamide) and supportive care. Dose modifications are considered for severe (Grade ≥3) or persistent cases.[14]

Table 3: Summary of Common and Serious Treatment-Related Adverse Events (HERIZON-BTC-01, N=87)

Adverse Event	Incidence (All Grades, %)	Incidence (Grade ≥3, %)
Diarrhea	37% - 40% 26	4.6% - 5% 15
Infusion-Related Reaction	33% - 35% 26	1.1% 25
Fatigue	24% 35	2.3% 21
Abdominal Pain	29% 35	Not specified
Decreased Ejection Fraction	10.3% 17	3.4% 25
Nausea	9.2% - 18% 25	1.1% 25
Increased AST	6.9% - 47% 25	2.3% 25
Increased ALT	6.9% - 46% 25	1.1% - 2.3% 21

Global Regulatory Landscape

Zanidatamab has successfully navigated the regulatory pathways in major global markets, achieving landmark approvals based on the strength of its pivotal clinical data and its potential to address a significant unmet medical need. The parallel use of expedited programs in the United States and Europe highlights a global regulatory consensus on the drug's favorable risk-benefit profile for its initial indication. This strategy allows for earlier patient access while the company completes a confirmatory Phase 3 trial to secure full approval.

U.S. Food and Drug Administration (FDA)

• Approval Status: The FDA granted Accelerated Approval to zanidatamab-hrii on November 20, 2024.[1]
• Indication: The approved indication is for the treatment of adult patients with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer, as detected by an FDA-approved test.[1] The specificity of the label to the IHC 3+ population directly reflects the clinical trial data showing the most profound benefit in this subgroup.
• Special Designations: The zanidatamab development program received several expedited designations from the FDA, underscoring its therapeutic potential. These included Breakthrough Therapy designation, Fast Track designation, and Orphan Drug designation for biliary tract cancer.[8]
• Companion Diagnostic: Concurrent with the drug's approval, the FDA also approved the Ventana Pathway anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody (Roche Diagnostics) as a companion diagnostic device. This test is essential for identifying patients with IHC 3+ BTC who are eligible for treatment with Ziihera.[3]
• Post-Marketing Requirement: As a condition of the Accelerated Approval, continued approval for this indication is contingent upon the verification and description of clinical benefit in a confirmatory clinical trial. The ongoing HERIZON-BTC-302 study is intended to fulfill this requirement.[8]

European Medicines Agency (EMA)

• Approval Status: The European Commission granted Conditional Marketing Authorisation for zanidatamab on June 27, 2025.[1] This decision followed a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) adopted on April 25, 2025.[17]
• Indication: The European indication is as a monotherapy for the treatment of adults with unresectable locally advanced or metastatic HER2-positive (IHC3+) biliary tract cancer who have been previously treated with at least one prior line of systemic therapy.[16]
• Special Designations: During its development, zanidatamab received Orphan Drug designation from the EMA for the treatment of both biliary tract cancer and gastric cancer.[23] Following its approval, the medicine is placed under "additional monitoring" status within the EU to encourage the collection of further safety data.[37]
• Post-Marketing Requirement: Similar to the FDA's requirement, the conditional authorization is contingent upon the submission of data from the confirmatory Phase 3 HERIZON-BTC-302 trial to verify its clinical benefit.[16]

Status in Other Jurisdictions

The global reach of zanidatamab is expanding beyond the U.S. and Europe. A marketing application was submitted to China's National Medical Products Administration (NMPA), and conditional approval was granted in May 2025 for the treatment of previously treated HER2-positive BTC.[8] Full market availability in China, managed by BeiGene, is anticipated in the latter half of 2025.[8]

The Evolving Role of Zanidatamab: Ongoing Trials and Future Directions

With initial approvals secured for second-line biliary tract cancer, the developers of zanidatamab have embarked on a highly ambitious and strategic clinical development program. This program is designed not only to confirm its benefit in BTC but also to expand its use into earlier lines of therapy and into a broad range of other HER2-expressing solid tumors. The overarching goal is to establish zanidatamab as a foundational therapy for HER2-driven cancers, potentially displacing existing standards of care.

Confirmatory Trial in Biliary Tract Cancer (HERIZON-BTC-302, NCT06282575)

This ongoing, global, randomized, open-label Phase 3 trial is the mandatory confirmatory study required by both the FDA and EMA. It is evaluating the efficacy and safety of zanidatamab in combination with standard-of-care (SoC) therapy (cisplatin and gemcitabine, with or without a PD-1/L1 inhibitor) versus SoC therapy alone in the first-line setting for patients with advanced HER2-positive BTC.[8] A positive outcome in this trial would secure full regulatory approval and potentially move zanidatamab into the first-line treatment paradigm.

Expansion into Gastroesophageal Adenocarcinoma (HERIZON-GEA-01, NCT05152147)

This is a large-scale, global, randomized, open-label Phase 3 trial expected to enroll approximately 900 patients. It is designed to directly challenge the current standard of care, trastuzumab. The study is evaluating zanidatamab plus chemotherapy against trastuzumab plus chemotherapy as a first-line treatment for patients with HER2-positive advanced or metastatic gastroesophageal adenocarcinoma (GEA), which includes stomach, gastroesophageal junction, and esophageal cancers.[40] A third experimental arm is investigating the triplet combination of zanidatamab, chemotherapy, and tislelizumab (an anti-PD-1 antibody), exploring the potential synergy of dual HER2 blockade with immune checkpoint inhibition.[41] This trial leverages the corporate partnership with BeiGene, the developer of tislelizumab, and if successful, could establish a new, potentially superior standard of care in a major oncology indication.

Investigational Use in Breast Cancer

Zanidatamab is being actively investigated in HER2-positive breast cancer, a setting with multiple established therapies but still significant unmet needs.

• EMPOWHER-303 (NCT06435429): This global Phase 3 trial is evaluating zanidatamab plus physician's choice of chemotherapy compared to trastuzumab plus chemotherapy. It is specifically enrolling patients with metastatic HER2-positive breast cancer whose disease has progressed following treatment with the antibody-drug conjugate trastuzumab deruxtecan (T-DXd), a growing area of unmet need.[39]
• I-SPY TRIAL (NCT01042379): Zanidatamab is also being studied within the innovative I-SPY adaptive platform trial, which evaluates novel agents in the neoadjuvant (pre-surgical) setting for high-risk, early-stage breast cancer.[42]

Pan-Tumor Development (DiscovHER PAN-206, NCT06695845)

Reflecting a modern, biomarker-driven approach to oncology, the DiscovHER PAN-206 trial is a Phase 2 "basket" study. It is designed to evaluate the efficacy of zanidatamab monotherapy across a wide range of locally advanced or metastatic solid tumors that are HER2-positive (defined as IHC 3+), with the exception of BTC. This includes, but is not limited to, colorectal, endometrial, non-small cell lung, ovarian, urothelial, and pancreatic cancers.[39] Success in this trial could support a tumor-agnostic approval, significantly broadening zanidatamab's potential patient population based solely on the presence of the HER2 IHC 3+ biomarker.

Table 4: Overview of Major Ongoing Clinical Trials for Zanidatamab

Trial Name (NCT ID)	Phase	Indication	Setting	Comparator(s)	Strategic Goal
HERIZON-BTC-302 (NCT06282575)	3	Biliary Tract Cancer	1st Line	Standard of Care (Chemo +/- PD-1/L1) 40	Convert accelerated/conditional approval to full approval; establish 1L standard of care.
HERIZON-GEA-01 (NCT05152147)	3	Gastroesophageal Adenocarcinoma	1st Line	Trastuzumab + Chemo 41	Displace trastuzumab as 1L standard of care; explore synergy with PD-1 inhibition.
EMPOWHER-303 (NCT06435429)	3	Breast Cancer	Metastatic (Post-T-DXd)	Trastuzumab + Chemo 40	Address unmet need in patients progressing on modern ADCs.
DiscovHER PAN-206 (NCT06695845)	2	Pan-Tumor (Solid Tumors)	Previously Treated	Single-Arm	Establish broad, tumor-agnostic activity in HER2 IHC 3+ cancers for label expansion.

Synthesis and Expert Analysis

Positioning in the Therapeutic Armamentarium

Zanidatamab has firmly established itself as a practice-changing therapy and the undisputed standard of care for adult patients with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer. Its unique biparatopic mechanism of action translates into superior preclinical activity and clinically meaningful outcomes in a patient population with a dire prognosis and limited therapeutic options. The combination of a high objective response rate, durable responses, a significant overall survival benefit, and a manageable, chemotherapy-free safety profile provides a compelling clinical rationale for its use. The convenient bi-weekly dosing schedule further enhances its attractiveness for both clinicians and patients.

The future role and ultimate commercial success of zanidatamab will be defined by the outcomes of its ambitious Phase 3 clinical development program. Success in the HERIZON-GEA-01 or EMPOWHER-303 trials would be transformative, elevating zanidatamab from a successful drug for a rare cancer into a major oncology product capable of challenging long-standing standards of care in much larger indications. The pan-tumor strategy of the DiscovHER PAN-206 trial also holds the potential to unlock significant value by establishing a biomarker-driven, tumor-agnostic label.

Corporate and Commercial Landscape

The global strategy for zanidatamab is managed through a tripartite corporate structure that leverages the strengths of each partner. Zymeworks serves as the innovator and licensor of the core technology. Jazz Pharmaceuticals has secured the development and commercialization rights for the major markets of the United States, Europe, and Japan, and has successfully guided the drug through its initial regulatory approvals.[8] BeiGene holds the exclusive rights for development and commercialization in key Asia-Pacific territories, including China, Australia, and New Zealand, and is also a strategic partner in the combination study with its PD-1 inhibitor, tislelizumab.[8] This collaborative framework ensures a coordinated global development strategy and broad market access.

Unmet Needs and Remaining Questions

Despite the clear success of zanidatamab, several important questions remain that will be addressed through ongoing research and long-term follow-up. A primary focus will be understanding the mechanisms of acquired resistance that will inevitably emerge. Identifying biomarkers of response and resistance beyond HER2 IHC status will be crucial for optimizing patient selection and developing rational next-line combination strategies. The long-term durability of responses and the ultimate impact on survival will continue to be monitored in all ongoing trials. Finally, the exploration of zanidatamab in combination with other novel agents, such as antibody-drug conjugates (ADCs), other targeted therapies, or next-generation immunotherapies, will be essential to further improve outcomes and fully define zanidatamab's legacy in the comprehensive treatment of HER2-positive cancers.

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