Zanidatamab in HER2-Positive Advanced Biliary Tract Cancer

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In the phase IIb HERIZON-BTC-01 trial reported in The Lancet Oncology, James J. Harding, MD, and colleagues found that zanidatamab—a bispecific antibody targeting two distinct HER2 epitopes—showed activity in previously treated patients with HER2-positive advanced biliary tract cancer.

Study Details

In the trial, 87 patients with unresectable locally advanced or metastatic disease with disease progression on gemcitabine-based therapy were enrolled from sites in Canada, Chile, China, France, Italy, South Korea, Spain, the United Kingdom, and the United States between September 2020 and March 2022. Patients were divided into two cohorts based on HER2 immunohistochemistry (IHC) score: cohort 1 (n = 80; IHC 2+ or 3+ = HER2-positive) and cohort 2 (n = 7; IHC 0 or 1+). A total of 65% of patients in cohort 1 were Asian. The number of patients who had tumors with HER2 IHC 0 or 1+ was lower than expected, and cohort 2 enrollment was stopped when cohort 1 was completely enrolled. Patients received zanidatamab at 20 mg/kg every 2 weeks. The primary endpoint was confirmed objective response rate in cohort 1 as assessed by independent central review.


At data cutoff in October 2022, median follow-up was 12.4 months (interquartile range = 9.4–17.2 months). Objective responses were observed in 33 (41.3%, 95% confidence interval [CI] = 30.4%–52.8%) of 80 patients in cohort 1, with complete response seen in 1 (1.3%). An additional 22 patients (27.5%) had stable disease, yielding a disease control rate of 68.8%. Median time to response was 1.8 months (95% CI = 1.7–2.0 months). Median duration of response was 12.9 months (95% CI = 6.0 months to not estimable), with 16 responses (49%) ongoing at the time of data cutoff. Median progression-free survival was 5.5 months (95% CI = 3.7–7.2 months). 

Overall survival data were not mature, but overall survival at 9 months was 69.9% (95% CI = 57.8%–79.1%).

No objective responses were observed among the seven patients in cohort 2. Median progression-free survival was 1.9 months (95% CI = 1.2 months to not estimable), and median overall survival was 5.5 months (95% CI = 1.2–10.1 months).   

Adverse Events

Among all 87 patients, the most common treatment-related adverse events of any grade were diarrhea (37%), infusion-related reactions (33%), increased ejection fraction (9%), and nausea (9%). Treatment-related grade 3 adverse events (no grade 4 or 5 events were observed) occurred in 16 patients (18%), most commonly diarrhea (5%) and decreased ejection fraction (3%). Serious treatment-related adverse events of any grade occurred in 8% of patients. Treatment-related adverse events led to discontinuation of treatment in two patients, consisting of decreased ejection fraction and pneumonitis.

The investigators concluded, “Zanidatamab demonstrated meaningful clinical benefit with a manageable safety profile in patients with treatment-refractory, HER2-positive biliary tract cancer. These results support the potential of zanidatamab as a future treatment option in HER2-positive biliary tract cancer.”

Dr. Harding, of Memorial Sloan Kettering Cancer Center, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Zymeworks, Jazz, and BeiGene. For full disclosures of the study authors, visit

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