Zanidatamab Shows Potential to Enter the Armamentarium for HER2+ BTC


Based on the largest clinical trial of patients with HER2-amplified biliary tract cancer, a novel anti-HER bispecific antibody may be the next option.

Mohamedtaki Tejani of AdventHealth statement to Targeted Oncology about zanidatamab

Mohamedtaki A. Tejani, MD

Substantial clinical benefit has been exhibited in the phase 2b HERIZON-BTC-01 study (NCT04466891), which is investigating treatment with zanidatamab (ZW25) in patients with HER2-positive biliary tract cancer (BTC).1

"This is a powerful study which demonstrates a HER2-targeted therapy is effective in this rare tumor type. The benefit seen with zanidatamab in terms of tumor responses is clinically meaningful in this subset of patients with limited treatment options. The key takeaway from this study is that it is critical for patients with biliary tract cancer to have molecular tumor profiling right at diagnosis. Patients cannot benefit from targeted therapy if their tumor-specific biomarker is not known, Mohamedtaki A. Tejani, MD, hematologist/oncologist at AdventHealth told Targeted OncologyTM.

Findings also showed that zanidatamab dosed at 20 mg/kg and administered intravenously every 2 weeks displayed a manageable safety profile when administered to patients with HER2-positive BTC in the study. The results were consistent with preliminary efficacy data from the phase 1 study of zanidatamab in patients with HER2-amplifed BTC in which the objective response rate (ORR) was 38%.

In 87 patients followed for a median of 12.4 months (interquartile range IQR, 58-77), the confirmed ORR was 41.3% (95% CI, 30.4%-52.8%). One percent of patients had complete responses to zanidatamab, while the remainder had partial responses (40%), stable disease (28%), and progressive disease (1%), Only 1 patient was not evaluable for response, and the disease control rate was 68.8% (95% CI, 57.4%-78.7%). According to the study investigators, the ORR shown with zanidatamab in HERIZON-BTC-01 is a seven-fold improvement, compared with historical data (NIFTY; NCT03524508).2

Biliary tract in gi tract | Image Credit: © Matthieu -

Biliary tract in gi tract | Image Credit: © Matthieu -

The median time to first response with zanidatamab in HERIZON-BTC-01 was only 1.8 months (range, 1.7-2.0 months). The percentage of patients with duration of response ≥ 16 was 81.8% (95% CI, 64.5%-93.0%).1

In terms of other secondary end points, treatment with zanidatamab led to a median progression-free survival (PFS) of 5.5 months (95% CI, 3.7-7.2 months). Overall survival follow-up was still ongoing at the time of data cutoff, but results show that 32 patients died by that timepoint. The median OS was determined to be 5.5 months (95% CI, 1.2-10.1 months).

Safety findings revealed that 97% of patients in the study experienced at least 1 treatment-emergent adverse event (AE), and 72% of patients had an AE determined by investigators to be zanidatamab-related.

The most common treatment-related AEs (TRAEs) observed during the study were diarrhea (37%), and infusion-related reactions (33%). Most of the diarrhea cases were low-grade and were resolved quickly. The grade 3 TRAEs observed were diarrhea (5%), decrease in ejection fraction (3%), and anemia (2%). There were no cases of grade 4/5 TRAEs.

Dose delays from TRAEs occurred in 6% of patients in the study, and dose reductions were required in 35 of patients. Treatment with zanidatamab was discontinued in 2 patients because of TRAEs.

Investigators noted serious TRAEs occurred in 8% of patients. In addition, TRAEs of special interest included infusion-related reactions (97%), like chills, pyrexia, and hypertension. The TRAEs of special interest were all low grade.

"Zanidatamab is safe, tolerable, and is associated with durable responses in patients with HER2-overexpressed BTC," Shubham Pant, MD, MBBS, associate professor, Department of Gastrointestinal Medical Oncology and Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center told Targeted Oncology.

The global, multicenter, single-arm study included patients who were treated at 32 different sites in North America, South America, Asia, and Europe. All patients involved in the study were at least 18 years of age with an ECOG performance score of 0 or 1.

Based on the study findings, investigators noted that zanidatamab is a potential new therapy for HER2-amplified BTC. Further, another study of zanidatamab has been announced. The study is a randomized, multicenter, phase 3 study (NCT05152147) investigating the use of zanidatamab in combination with chemotherapy, with or without tislelizumab in the HER2-positive, unresectable, locally advanced or metastatic gastroesophageal adenocarcinoma population.

"The results from this study are quite compelling. We do not have FDA approval to use zanidatamab for this patient population yet, but I believe it will be a treatment option in the near future. Our next hope is to make this treatment option available earlier in the course of patients’ disease trajectory," said Tejani.


1. Harding JJ, Fan J, Oh D, et al. Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study. Lancet Oncol. 2023;24(7):772-782. doi: 10.1016/S1470-2045(23)00242-5

2. Yoo C, Kim K, Jeong JH, et al. Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): a multicentre, open-label, randomised, phase 2b study. Lancet Oncol. 2021;22(11):1560-1572. doi: 10.1016/S1470-2045(21)00486-1

Related Videos
Experts on GI cancer
Experts on GI cancer
Experts on CRC
Experts on GI Cancer
Experts on GI cancer
Related Content