Safety and Initial Efficacy of Zanidatamab (ZW25) in HER2-Overexpressing Biliary Tract Cancer

Web Exclusives — December 20, 2021

Approximately 5% to 19% of all biliary tract cancers (BTCs) show overexpression/amplification of HER2. The bispecific HER2-targeted antibody zanidatamab was evaluated in a first-in-human, 3-part, phase 1 study ( Identifier: NCT02892123; ZWI-ZW25-101) in HER2-overexpressing cancers, including BTCs. Results of the expansion cohort of this phase 1 study were presented at the 2021 American Society of Clinical Oncology Annual Meeting.

The BTC cohort of this phase 1 study included patients with BTC that was centrally confirmed HER2-overexpressing (ie, immunohistochemistry [IHC] 3+ or IHC 2+/fluorescence in situ hybridization [FISH]+), showed disease progression after standard-of-care therapy, and had measurable disease per RECIST version 1.1. Eligible patients were treated with zanidatamab 20 mg/kg every 2 weeks. Tumor assessments were performed every 8 weeks. The data cutoff date was July 28, 2020.

In the dose-escalation part 1 of the study, the recommended dose of zanidatamab monotherapy was determined to be 10 mg/kg weekly and 20 mg/kg every 2 weeks. In the expansion part 2 of the study, a total of 21 patients with BTC were enrolled and received the recommended dose of 20 mg/kg every 2 weeks. The median age of the expansion cohort was 63 years. The majority of the participants were females, and the median number of prior systemic therapies was 2.5, including 5 patients who had received prior trastuzumab. In the BTC cohort, 11 participants had gallbladder cancer, 5 had intrahepatic cholangiocarcinoma, and 4 had extrahepatic cholangiocarcinoma.

Of the 20 patients in the safety population, 14 (70%) individuals experienced zanidatamab-related adverse events (AEs). The most common treatment-related AEs were diarrhea (45%) and infusion-related reactions (30%). No grade ≥3 zanidatamab-related AEs were reported.

Of the 17 patients who were evaluable for response, the confirmed overall response rate was 47% (n = 8), all of which were partial responses. Five additional patients achieved stable disease, for a disease control rate of 65% (n = 11). The median duration of response was 6.6 months.

Based on these results, the researchers concluded that zanidatamab is well-tolerated and active in patients with HER2-overexpressing BTC. An ongoing global phase 2b study ( Identifier: NCT04466891; HERIZON-BTC-01) is further evaluating zanidatamab in patients with advanced HER2-positive BTC who have progressed after treatment with a gemcitabine-containing regimen.


Meric-Bernstam F, Hanna DL, El-Khoueiry AB, et al. Zanidatamab (ZW25) in HER2-positive biliary tract cancers (BTCs): results from a phase I study. J Clin Oncol. 2021;39(suppl_3):299-299.

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