Abstract CT253: HERIZON-BTC-302: A phase 3 trial of zanidatamab with standard-of-care therapy vs SOC alone for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced/metastatic biliary tract cancer

Abstract Background: Zanidatamab, a dual HER2-targeted bispecific antibody, received accelerated approval from the United States Food and Drug Administration for adults with previously treated, unresectable, or metastatic HER2-positive (immunohistochemistry [IHC] 3+) biliary tract cancer (BTC) based on the results from the single-arm, phase 2 HERIZON-BTC-01 trial. This phase 3 trial is assessing zanidatamab plus standard-of-care (SOC) therapy vs SOC alone for the first-line treatment of patients with HER2-positive advanced/metastatic BTC. Methods: This ongoing, global, phase 3, randomized, open-label trial (NCT06282575) is investigating the efficacy and safety of zanidatamab with cisplatin and gemcitabine (CisGem) vs CisGem alone ± a programmed cell death protein-1/ligand 1 (PD-1/L1) inhibitor (pembrolizumab or durvalumab at physician’s discretion if locally approved) as first-line treatment for patients with advanced/metastatic HER2-positive BTC. HER2-positive BTC is defined by an IHC score of 3+ or an IHC score of 2+ with HER2 gene amplification by in situ hybridization. Additional eligibility criteria include ≥18 years of age; locally advanced, unresectable, or metastatic BTC and Eastern Cooperative Oncology Group performance status ≤1. Patients may have received ≤2 cycles of a gemcitabine-based regimen ± pembrolizumab or durvalumab. Prior HER2-targeted therapy is not allowed except for patients who completed it for breast cancer >5 years prior to BTC diagnosis. Eligible patients will be randomized to receive zanidatamab (flat 2-tiered dosing: 1800 mg intravenous [IV; body weight <70 kg] or 2400 mg IV [body weight ≥70 kg] every 3 weeks) + a standard dose of CisGem ± a PD-1/L1 inhibitor or CisGem alone ± a PD-1/L1 inhibitor (≤8 cycles). The primary endpoint is progression-free survival (PFS) in patients with IHC 3+ tumors. Secondary/exploratory endpoints include overall survival (IHC 3+ subgroup; overall population), PFS (overall population), cORR, incidence and severity of adverse events, and patient-reported outcomes. The trial is currently recruiting patients. Citation Format: James J. Harding, Teresa Macarulla, Xiaotian Wu, Phillip M. Garfin, Takuji Okusaka, Shubham Pant. HERIZON-BTC-302: A phase 3 trial of zanidatamab with standard-of-care therapy vs SOC alone for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced/metastatic biliary tract cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT253.