Zanidatamab Receives Accelerated FDA Approval in HER2-Positive Advanced Biliary Tract Cancer

First Approval

On 20 November 2024, the United States Food and Drug Administration (FDA) granted accelerated approval to zanidatamab-hrii (Ziihera, Jazz Pharmaceuticals, Inc.), a HER2-directed bispecific antibody, for patients with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer.

This approval of zanidatamab-hrii (Ziihera) is the first FDA approval specifically directed at HER2-positive biliary tract cancer.

On the same day, the FDA approved the VENTANA PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody (Ventana Medical Systems, Inc./Roche Diagnostics) as a companion diagnostic to help identify patients with biliary tract cancer who may be eligible for Ziihera.

Biliary tract cancer is challenging, particularly because treatment options are limited in advanced disease. Developing new treatments for patients with HER2 (human epidermal growth factor receptor 2)-positive tumors is therefore particularly important.

What Proportion of Biliary Tract Cancers Are HER2-Positive?

HER2 (Human Epidermal Growth Factor Receptor 2) is a receptor that can stimulate cell growth and division in many cancers. HER2 overexpression or gene amplification (an increased number of gene copies in DNA) occurs in various cancers, especially breast and stomach cancers.

HER2 positivity is less common in bile duct cancers but is present in a subset of patients. HER2 mutations or gene amplifications occur in 17.4% to 18.5% of extrahepatic biliary tract cancers, 19.1% to 31.3% of gallbladder cancers, and 3.7% to 4.8% of intrahepatic biliary tract cancers.

These rates indicate the potential applicability of HER2-targeted treatments in bile duct cancers.

How Does Zanidatamab Work?

Zanidatamab is a bispecific antibody targeting human epidermal growth factor receptor 2 (HER2). Bispecific antibodies can recognize two different targets simultaneously. Zanidatamab binds two distinct antigen-binding regions on its selected HER2 receptor: the HER2 dimerization domain and the extracellular juxtamembrane domain.

This distinctive structure helps zanidatamab form cross-links between HER2 molecules and cluster receptors on the cell surface. This promotes receptor internalization and reduces HER2 signaling. The process controls cancer cell growth and proliferation because HER2 stimulates cell growth and division in certain cancers.

Zanidatamab also activates immune mechanisms called Antibody Dependent Cellular Cytotoxicity (ADCC), Antibody Dependent Cellular Phagocytosis (ADCP), and Complement Dependent Cytotoxicity (CDC).

ADCC describes antibodies' ability to kill target cells through specialized cells such as natural killer cells. Zanidatamab directs the immune system's natural killer cells to destroy target cells, in this case cancer cells overexpressing HER2. ADCP describes antibody-mediated engulfment of target cells, generally involving cells such as macrophages and dendritic cells. CDC describes antibodies' ability to kill target cells through specialized proteins belonging to the complement system.

In preclinical studies, zanidatamab demonstrated greater antitumor activity than trastuzumab alone or trastuzumab combined with pertuzumab. It is therefore a potential candidate for treating HER2-positive cancers.

FDA Approval Based on HERIZON-BTC-01

The FDA approval was based on HERIZON-BTC-01, an open-label, multicenter, single-arm clinical trial.

The study evaluated 62 patients with unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer who had received at least one prior line of gemcitabine-containing treatment.

Results:

Independent central review using RECIST v1.1 criteria reported an

• objective response rate of 52% (95% CI: 39, 65).
• Median duration of response was 14.9 months (95% CI: 7.4, not estimable).

In other arms of the same study, zanidatamab's efficacy was quite limited in patients without HER2 IHC 3+ expression (IHC 0, 1+, or 2+).

Side Effects and Warnings

The most common side effects of zanidatamab include diarrhea, infusion-related reactions, abdominal pain, and fatigue. Its prescribing information includes an embryo-fetal toxicity warning; patients who are pregnant or planning pregnancy should therefore be cautious.

Dosage and Administration

The recommended zanidatamab dose is 20 mg/kg by intravenous infusion every two weeks until disease progression or unacceptable toxicity.

Conclusion and Future Prospects

The ongoing phase 3 HERIZON-BTC-302 study is testing zanidatamab in patients with advanced or metastatic HER2-positive biliary tract cancer (BTC) as a standard regimen alongside first-line treatment. The bispecific antibody is also being developed for advanced/metastatic HER2-positive gastroesophageal adenocarcinoma.

Accelerated FDA approval of zanidatamab is a promising development for patients with HER2-positive advanced biliary tract cancer. It offers a new option to a group with previously limited treatments. Continued accelerated approval, however, will depend on further studies confirming clinical benefit. More comprehensive research into zanidatamab's efficacy and safety is therefore important.