Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study

HERIZON-BTC-01 study group, James J. Harding, Jia Fan, Do Youn Oh, Hye Jin Choi, Jin Won Kim, Heung Moon Chang, Lequn Bao, Hui Chuan Sun, Teresa Macarulla, Feng Xie, Jean Phillippe Metges, Jie'er Ying, John Bridgewater, Myung Ah Lee, Mohamedtaki A. Tejani, Emerson Y. Chen, Dong Uk Kim, Harpreet Wasan, Michel DucreuxYuanyuan Bao, Lisa Boyken, Jiafang Ma, Phillip Garfin, Shubham Pant, Ghassan Abou-Alfa, Jorge Adeva Alfonso, Massimo Aglietta, Ari Baron, Muhammad Beg, Paula Carrasco Aguirre, Eric Chen, Ying Cheng, Antonio Cubillo Gracián, Laetitia Dahan, Filippo De Braud, Elisabetta Fenocchio, Olumide Gbolohon, Roopinder Gillmore, Marine Jary, Milind Javle, Yixing Jiang, Jung Hun Kang, Gentry George King, Madappa Kundranda, Laura Layos, Daneng Li, Tingbo Liang, Sara Lonardi, Omkar Marathe, Sebastian Mondaca, Andrés J.Muñoz Martin, Joon Oh Park, Roberto Pazo Cid, Paula Ribera Fernandez, Lorenza Rimassa, Rosa Rodriguez Alonso, Saeed Sadeghi, Aaron Scott, Benjamin Tan, David Tougeron, Qiang Yan, Xiaoyu Yin, Haitao Zhao

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Abstract

Background: HER2 is overexpressed or amplified in a subset of biliary tract cancer. Zanidatamab, a bispecific antibody targeting two distinct HER2 epitopes, exhibited tolerability and preliminary anti-tumour activity in HER2-expressing or HER2 (also known as ERBB2)-amplified treatment-refractory biliary tract cancer. Methods: HERIZON-BTC-01 is a global, multicentre, single-arm, phase 2b trial of zanidatamab in patients with HER2-amplified, unresectable, locally advanced, or metastatic biliary tract cancer with disease progression on previous gemcitabine-based therapy, recruited at 32 clinical trial sites in nine countries in North America, South America, Asia, and Europe. Eligible patients were aged 18 years or older with HER2-amplified biliary tract cancer confirmed by in-situ hybridisation per central testing, at least one measurable target lesion per Response Evaluation Criteria in Solid Tumours (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were assigned into cohorts based on HER2 immunohistochemistry (IHC) score: cohort 1 (IHC 2+ or 3+; HER2-positive) and cohort 2 (IHC 0 or 1+). Patients received zanidatamab 20 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response rate in cohort 1 as assessed by independent central review. Anti-tumour activity and safety were assessed in all participants who received any dose of zanidatamab. This trial is registered with ClinicalTrials.gov, NCT04466891, is ongoing, and is closed to recruitment. Findings: Between Sept 15, 2020, and March 16, 2022, 87 patients were enrolled in HERIZON-BTC-01: 80 in cohort 1 (45 [56%] were female and 35 [44%] were male; 52 [65%] were Asian; median age was 64 years [IQR 58–70]) and seven in cohort 2 (five [71%] were male and two [29%] were female; five [71%] were Asian; median age was 62 years [IQR 58–77]). At the time of the data cutoff (Oct 10, 2022), 18 (21%) patients (17 in cohort 1 and one in cohort 2) were continuing to receive zanidatamab; 69 (79%) discontinued treatment (radiographic progression in 64 [74%] patients). The median duration of follow-up was 12·4 months (IQR 9·4–17·2). Confirmed objective responses by independent central review were observed in 33 patients in cohort 1 (41·3% [95% CI 30·4–52·8]). 16 (18%) patients had grade 3 treatment-related adverse events; the most common were diarrhoea (four [5%] patients) and decreased ejection fraction (three [3%] patients). There were no grade 4 treatment-related adverse events and no treatment-related deaths. Interpretation: 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. Funding: Zymeworks, Jazz, and BeiGene.

Original languageEnglish
Pages (from-to)772-782
Number of pages11
JournalThe Lancet Oncology
Volume24
Issue number7
DOIs
StatePublished - Jul 2023

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