Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study
- PMID: 37276871
- DOI: 10.1016/S1470-2045(23)00242-5
Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study
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.
Copyright © 2023 Elsevier Ltd. All rights reserved.
Conflict of interest statement
Declaration of interests JJH reports support from Zymeworks to self (uncompensated), and research support to institution for this work; grants or contracts from Bristol Myers Squibb, Boehringer Ingelheim, CytomX, Debiopharm, Eli Lilly, Genoscience, Incyte, Loxo@Lilly, Novartis, Polaris, Pfizer, Zymeworks, and Yiviva outside of this work; consulting fees or advisory board from Adaptimmune, AstraZeneca, Bristol Myers Squibb, Exelexis, Elevar, Eisai, Genoscience (uncompensated), Hepion, Imvax, Merck, Medivir, QED, Tyra, and Zymeworks (uncompensated) outside of this work. D-YO reports grants or contracts from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, and Handok to institution outside of this work; and participation on advisory boards for AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, and IQVIA outside of this work. HJC reports consulting fees to self from Roche and AstraZeneca outside of this work. JWK reports grants or contracts from Inno.N and Jeil Pharm outside of this work; and consulting fees from AstraZeneca, Beyond Bio, Eisai, MSD, BeiGene, Bristol Myers Squibb/Celgene, GC Cell, ONO, Sanofi-Aventis, Servier, and TCUBEit outside of this work. H-MC reports funding for clinical trial from Zymeworks to institution for this work. HC-S reports consulting fees from TopAlliance outside of this work; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from TopAlliance and AstraZeneca outside of this work. J-PM reports payment or honoraria for lectures from MSD, BMS, Bayer, Astellas, and Merck outside of this work. JB reports consultancy fees from Taiho, Incyte, Servier, BMS outside of this work; grants or contracts for research from Incyte outside of this work; and payment or honoraria as a speaker from Incyte and Servier outside of this work. MAT reports payment or honoraria as a speaker from Natera and Caris outside of this work. HW reports support from Zymeworks for this work; consulting fees from Oncosil outside of this work; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Servier, Pierre Fabre, Incyte, Bayer, Merck KGaA, Amgen, Roche/Genentech/FM, SIRTEX Medical, BMS (Celgene), BTG, and Seagen outside of this work; payment for expert testimony from Oncosil outside of this work; support for attending meetings and/or travel from Pierre Fabre, Servier, and Merck KGaA outside of this work; participation on a DSMB or advisory board from Incyte, Bayer, Merck KGaA, Amgen, Roche/Genentech/FM, SIRTEX Medical, Erytech Pharma, BMS (Celgene), BTG, and Seagen outside of this work; and leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Pfizer and Zymeworks (trial steering committee for both) outside of this work. MD reports participation on advisory boards from Roche, Merck Serono, Amgen, Bayer, Servier, Pierre Fabre, BeiGene, AstraZeneca, Daiichi Sankyo, Merck-Sharp-Dohme, and Boehringer Ingelheim outside of this work; speaker in symposia from Roche, Merck Serono, Bayer, Merck-Sharp-Dohme, Servier, Pierre Fabre, and Daiichi Sankyo outside of this work; institutional research funding from Roche, Merck Serono, and Keocyt outside of this work; and participation in independent data monitoring committees for Roche and Pancan outside of this work. MD's spouse is head of the oncology business unit at Sandoz France. YB reports employment by BeiGene at the time of the study and ownership of BeiGene stock or stock options outside of this work. LB reports employment by Zymeworks at the time of the study and ownership of Zymeworks stock or stock options outside of this work. JM reports ownership of stock or stock options of BeiGene as an employee. PG reports employment by Zymeworks at the time of the study; support for attending meetings and/or travel from Zymeworks Inc outside of this work; and ownership of Zymeworks and Seagen stock or stock options outside of this work. SP reports advisory/consultancy fees to self from Zymeworks, Ipsen, Novartis, Janssen, Boehringer Ingelheim, and AskGene Pharma outside of this work; and a research grant or funding to their institution from Mirati Therapeutics, Lilly, Xencor, Novartis, Rgenix, Bristol-Myers Squibb, Astellas Pharma, Framewave, 4D Pharma, Boehringer Ingelheim, NGM Biopharmaceuticals, Janssen, Arcus Biosciences, Elicio Therapeutics, BioNtech, Ipsen, Zymeworks, Pfizer, ImmunoMET, Immuneering, Amal Therapeutics outside of this work. JF, LeB, TM, FX, JY, M-AL, EYC, and DUK declare no competing interests.
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