%0 Journal Article
%@ 0004-637X
%A Harding, James J
%A Fan, Jia
%A Oh, Do-Youn
%A Choi, Hye Jin
%A Kim, Jin Won
%A Chang, Heung-Moon
%A Bao, Lequn
%A Sun, Hui-Chuan
%A Macarulla, Teresa
%A Xie, Feng
%A Metges, Jean-Phillippe
%A Ying, Jie'er
%A Bridgewater, John
%A Lee, Myung-Ah
%A Tejani, Mohamedtaki A
%A Chen, Emerson Y
%A Kim, Dong Uk
%A Wasan, Harpreet
%A Ducreux, Michel
%A Bao, Yuanyuan
%A Boyken, Lisa
%A Ma, Jiafang
%A Garfin, Phillip
%A Pant, Shubham
%A HERIZON-BTC-01 study group
%D 2023
%F discovery:10173106
%I Elsevier
%J The Lancet Oncology
%K HERIZON-BTC-01 study group
%N 7
%P 772-782
%T Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study
%U https://discovery.ucl.ac.uk/id/eprint/10173106/
%V 24
%X 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.
%Z This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.