Zanidatamab, a HER2-targeted bispecific antibody, has achieved significant milestones in the treatment of HER2-positive biliary tract cancer (BTC). It has been included as a category 2A treatment option in the National Comprehensive Cancer Network (NCCN) guidelines and has received FDA approval for a companion diagnostic to identify eligible patients. These developments mark a significant advancement in the treatment landscape for this challenging cancer.
The FDA's accelerated approval of zanidatamab in November 2024 was based on the results of the HERIZON-BTC-01 clinical trial. This phase 2b open-label, multicenter study enrolled 62 patients with HER2+ BTC who had previously received at least one gemcitabine-containing chemotherapy regimen. The study demonstrated a 52% objective response rate (ORR) and a median duration of response (DOR) of 14.9 months.
Sustained Outcomes in HERIZON-BTC-01 Trial
Updated results from the HERIZON-BTC-01 trial, presented at the 2024 ASCO Meeting, showed sustained outcomes with a median overall survival (OS) of 15.5 months (95% CI, 10.4-18.5). Notably, higher OS rates were observed in patients with HER2 immunohistochemistry (IHC) 3+ (18.1 months; 95% CI, 12.2-23.2) compared to IHC 2+ (5.2 months; 95% CI, 3.1-10.2).
James J. Harding, MD, director of Early Drug Development at Memorial Sloan Kettering Cancer Center, noted the importance of this approval, stating it marks the first HER2-targeted therapy specifically for biliary tract cancer. He highlighted the pivotal HORIZON BTC-01 trial findings and zanidatamab's potential to transform care for patients with this challenging disease.
Companion Diagnostic Approval
In addition to the NCCN guideline update, the FDA approved the PATHWAY anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody test as a companion diagnostic. This test will aid in assessing HER2-positive status in patients with BTC, ensuring that zanidatamab is prescribed to those most likely to benefit. Jill German, head of the Pathology Lab at Roche Diagnostics, emphasized that this test is a step forward in furthering access to personalized medicine, potentially improving clinical outcomes for patients with limited treatment options.
Mechanism of Action and Safety Profile
Zanidatamab's mechanism of action involves binding to two extracellular sites on the HER2 receptor, leading to tumor growth inhibition and cell death through complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis. The most common adverse events (AEs) observed in the study included diarrhea, infusion-related reactions, abdominal pain, and fatigue. Serious AEs occurred in 53% of patients, with biliary obstruction and biliary tract infections being the most frequently observed.
Ongoing Research and Future Directions
An ongoing, confirmatory phase 3 trial, HERIZON-BTC-302 (NCT06282575), is evaluating frontline zanidatamab plus standard-of-care (SOC) therapy versus SOC therapy alone in patients with HER2-positive biliary tract cancer. This trial aims to further validate the clinical benefits of zanidatamab and potentially expand its use to earlier stages of the disease. Zanidatamab is also being explored in combination with other therapies, offering hope for more effective treatment regimens for patients with HER2-amplified cancers. As Dr. Harding noted, there is active research assessing zanidatamab's activity in combination with chemotherapy and immunotherapy in the treatment-naive setting.
