Clinical trialPhase 2bBile duct and gallbladder cancer (biliary tract cancer)

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

Lancet Oncol · 202387 patients (80 in cohort 1 with IHC 2+ or 3+; 7 in cohort 2 with IHC 0 or 1+)

Harding JJ, Fan J, Oh DY, et al. Lancet Oncol. 2023. 24:772-782

Study type: Clinical trial
Study name: HERIZON-BTC-01
Phase: Phase 2b
Design: Global, multicentre, single-arm trial at 32 sites in 9 countries in North America, South America, Asia and Europe
Sample size: 87 patients (80 in cohort 1 with IHC 2+ or 3+; 7 in cohort 2 with IHC 0 or 1+)
Source: Lancet Oncol · 2023
Trial registration: NCT04466891

In plain words

People with advanced bile duct cancer with a change in the HER2 gene, whose disease had grown after chemotherapy, received zanidatamab by drip every 2 weeks. The tumour shrank in about 4 in 10 patients, and in about half of those whose HER2 was very strong (‎3+‎). Severe side effects were uncommon, the most frequent being diarrhoea; heart function also needs to be checked.

Key results

41.3%

Confirmed objective response (cohort 1)

33 of 80; 95% CI 30.4–52.8; median follow-up 12.4 months

14.9 months

Final analysis: median duration of response

Follow-up 33.4 months (JAMA Oncol 2026)

15.5 months

Final analysis: median overall survival

95% CI 10.4–18.7

Response 51.6%

IHC 3+ (62 patients)

Median overall survival 18.1 months; progression-free survival 7.2 months

Response 5.6%

IHC 2+ (18 patients)

1 partial response; median overall survival 5.2 months

Dose and schedule cards

Zanidatamab (HER2 IHC 3+)

Unresectable or metastatic, previously treated, HER2-positive (IHC 3+) biliary tract cancer (FDA, accelerated approval)Cycle length: Every 14 daysOn the page “Bile duct and gallbladder cancer (biliary tract cancer)” · After progression on first line: chemotherapy and targeted therapy

Unresectable or metastatic, previously treated, HER2-positive (IHC 3+) biliary tract cancer (FDA, accelerated approval)

Drug	Dose	Route	Schedule
Zanidatamab	20 mg/kg (first infusion 120, second 90 and then 60 minutes if tolerated)	IV	Every 2 weeks

Cycle length: Every 14 days
Duration: Until progression or unacceptable toxicity

Dose source: FDA label. Premedication 30–60 minutes before each dose: paracetamol (acetaminophen), an antihistamine (such as diphenhydramine) and a corticosteroid (such as hydrocortisone). Dose reduction: 15 mg/kg every 2 weeks; intolerance → permanent discontinuation. LVEF before starting and periodically; an absolute decrease of 16 percentage points or more, or LVEF below 50% with a decrease of 10 points or more → withhold for at least 4 weeks. In HERIZON-BTC-01, treatment-related grade 3 adverse events occurred in 18% (diarrhoea 5%, decreased ejection fraction 3%).

On the page “Bile duct and gallbladder cancer (biliary tract cancer)” · After progression on first line: chemotherapy and targeted therapy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Zanidatamab

Zanidatamab 20 mg/kg intravenously every 2 weeks (in 28-day cycles).

Source of the regimen details: Abstract of the paper (Lancet Oncol 2023), the research letter with the final analysis (JAMA Oncol 2026; PMC12635922) and the FDA label for Ziihera

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 18 or older with unresectable locally advanced or metastatic biliary tract cancer with HER2 amplification confirmed by in-situ hybridisation in central testing, progression during or after previous gemcitabine-based therapy, at least one measurable target lesion (RECIST 1.1) and ECOG 0 or 1. Cohort 1: IHC ‎2+‎ or ‎3+‎ (HER2-positive); cohort 2: IHC 0 or ‎1+‎.

Endpoints

Primary endpoint: confirmed objective response in cohort 1 by independent central review. Secondary endpoints: duration of response, disease control, progression-free survival, overall survival and safety; the final analysis also assessed patient-reported worst pain (BPI-SF).

Safety and side effects

In the first report, 16 patients (18%) had treatment-related grade 3 adverse events, most often diarrhoea (4 patients, 5%) and decreased ejection fraction (3 patients, 3%); there were no treatment-related grade 4 events or deaths. In the final analysis, 76% had at least one treatment-related adverse event; grade 3 events in more than 2 patients were diarrhoea (5.0%), decreased ejection fraction (3.8%) and anaemia (3.8%), and 3% stopped treatment because of adverse events.

Clinical significance and place in guidelines

HERIZON-BTC-01 was the basis of FDA accelerated approval of zanidatamab, a bispecific antibody against HER2, for previously treated HER2-positive (IHC ‎3+‎) biliary tract cancer; it has also received conditional authorisation in the European Union and China. ESMO 2025 recommends it for previously treated HER2-positive disease [III, A; ESCAT I-C]. The phase 3 HERIZON-BTC-302 trial is testing zanidatamab with standard first-line treatment.

Limitations

A single-arm trial without a comparison group. Benefit was much smaller with IHC ‎2+‎, and the comparison of the IHC ‎3+‎ and ‎2+‎ subgroups was post hoc. Most patients were Asian (65% in cohort 1).

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.