In a global, multicentre, single-arm, phase IIb HERIZON-BTC-01 study, zanidatamab showed meaningful activity, including rapid and durable responses, with a favourable safety profile in the treatment of patients with HER2-positive biliary tract cancer with disease progression on previous gemcitabine-based therapy. It is the largest clinical study reported to date for HER2-amplified biliary tract cancer. The confirmed objective response rate (ORR) by independent central review in patients with HER2-positive tumours was 41.3%.

Antitumour activity observed for zanidatamab in patients with HER2-positive biliary tract cancer compares favourably to historic controls. The findings are reported at 2023 ASCO Annual Meeting on 2 June in Chicago, IL, US along with a simultaneous publication in The Lancet Oncology by Dr. Shubham Pant of the MD Anderson Cancer Center in Houston, TX, US, and Dr. James J Harding of the Memorial Sloan Kettering Cancer Center in New York, NY, US, and study colleagues.

Most patients with biliary tract cancer present with incurable, locally advanced or metastatic disease. In the first-line setting, patients can be treated with palliative cisplatin-gemcitabine or cisplatin-gemcitabine plus durvalumab, which results in improved overall survival (OS) compared with cisplatin-gemcitabine alone. For patients with locally advanced/metastatic biliary tract cancer who progress after first-line treatment, standard treatment offers limited clinical benefit with modest improvement in survival. Therapies targeting FGFR2 or IDH1 alterations are beneficial for select patients with these specific molecular subtypes of biliary tract cancer.

The authors also explained in the background that molecular profiling has identified that HER2 is mutated, amplified, or overexpressed in 19.1–31.3% of cases with gallbladder cancer, 17.4–18.5% of extrahepatic cholangiocarcinoma, and 3.7–4.8% of intrahepatic cholangiocarcinoma. Findings from early clinical studies of small sample sizes suggest that targeting HER2 alterations with various agents in biliary tract cancer leads to clinical benefit.

In preclinical studies, a HER2-targeted bispecific antibody, zanidatamab exhibited antitumour activity in HER2-driven neoplasia that was superior to both trastuzumab monotherapy and trastuzumab combined with pertuzumab. A phase I study with zanidatamab demonstrated manageable safety with antitumour activity in multiple HER2-expressing or HER2-amplified tumour types. The phase I study included a cohort of patients with biliary tract cancer where treatment with 20 mg/kg zanidatamab once every 2 weeks elicited a confirmed ORR of 38%.

The HERIZON-BTC-01 study tests the hypothesis that zanidatamab is an active therapy for patients with HER2-amplified biliary tract cancer. Patients were recruited at 32 sites in 9 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 RECIST v1.1, and an ECOG 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 ORR in cohort 1 as assessed by independent central review. Antitumour activity and safety were assessed in all participants who received any dose of zanidatamab. This study is ongoing, and is closed to recruitment.

Between 15 September 2020 and 16 March 2022, 87 patients were enrolled in HERIZON-BTC-01; 80 in cohort 1 from whom 45 (56%) were female and 35 (44%) were male, 52 (65%) were Asian, median age was 64 years and 7 patients were included in cohort 2 of whom 5 (71%) were male and 2 (29%) were female, 5 (71%) were Asian, median age was 62 years. At the time of the data cut-off on 10 October 2022, 18 patients (21%) of whom 17 in cohort 1 and 1 in cohort 2 were continuing to receive zanidatamab. A total, 69 patients (79%) discontinued treatment, of whom 64 (74%) due to radiographic progression.

The median duration of follow-up was 12.4 months. Confirmed objective responses by independent central review were observed in 33 patients in cohort 1 (41.3%, 95% confidence interval [CI] 30.4–52.8). Among the 33 responders at the data cut-off, 49% had ongoing responses and 82% had a duration of response of ≥16 weeks. Median time to first response was 1.8 month (range, 1.6-5.5). Progression-free survival and OS are being evaluated.

In both cohorts, treatment-related adverse events (TRAEs) occurred in 72% of patients; TRAEs in ≥10% of patients were diarrhoea (37%) and infusion-related reaction (33%). In total, 16 patients (18%) had grade 3 TRAEs; the most common were diarrhoea (4.6%) and decreased ejection fraction (3.4%). There was no grade 4 TRAEs and no treatment-related deaths. Two patients (2.3%) discontinued zanidatamab due to an adverse event (decreased ejection fraction and non-infectious pneumonitis).

Continued development of zanidatamab is currently ongoing for the treatment of HER2-positive biliary tract cancer in combination with standard first-line cisplatin–gemcitabine. Additionally, zanidatamab is being evaluated for other HER2-expressing solid tumours, including in a phase III study for first-line treatment of gastro-oesophageal adenocarcinoma.

This study was funded by Zymeworks, Jazz Pharmaceuticals, and BeiGene.