Zanidatamab Shows Meaningful Benefit in HER2+ Biliary Tract Cancer

Treatment with zanidatamab-hrii (Ziihera) produced clinically meaningful benefits among patients with HER2-amplified, locally advanced or metastatic, previously treated biliary tract cancer (BTC), according to final results from the phase 2 HERIZON-BTC-01 trial (NCT04466891) published in JAMA Oncology.¹

Data showed a confirmed objective response rate (ORR) of 41.3% (95% CI, 30.4%-52.8%) along with a median duration of response (DOR) of 14.9 months (95% CI, 7.4-24.0). Additionally, the median overall survival (OS) was 15.5 months (95% CI, 10.4-18.7).

Among 62 patients with immunohistochemistry (IHC) tumors of 3+, zanidatamab elicited a confirmed ORR of 51.6% (95% CI, 38.6%-64.5%) and a median OS of 18.1 months (95% CI, 12.2-22.9). Regarding 18 patients with IHC 2+ status, 1 patient experienced a partial response for a confirmed ORR of 5.6% (95% CI, 0.1%-27.3%); the median OS was 5.2 months (95% CI, 3.1-10.2).

“The observed [ORR], prolonged [DOR], and consistent activity in IHC 3+ tumors underscores HER2 as a valid therapeutic target in biliary tract cancer and support the emerging role of zanidatamab in the treatment paradigm,” lead study investigator Shubham Pant, MD, MBBS, a professor in the Department of Gastrointestinal Medical Oncology with a joint appointment in the Department of Investigational Cancer Therapeutics (Phase I Center) at The University of Texas MD Anderson Cancer Center, stated in a press release.²

In the multicenter, open-label, single-arm HERIZON-BTC-01 trial, 80 patients with HER2-amplified, locally advanced, or metastatic BTC and disease progression on or after prior gemcitabine-based treatment were assigned to receive zanidatamab at 20 mg/kg intravenously every 2 weeks in each 28-day cycle.²

The trial’s primary end point was the confirmed ORR per independent central review using RECIST v1.1 criteria. Secondary end points included DOR, disease control rate, progression-free survival (PFS), OS, incidence of adverse effects (AEs), and incidence of laboratory abnormalities.

Patients 18 years and older with histologically or cytologically confirmed BTC; locally advanced or metastatic disease not eligible for curative resection, transplantation, or ablative treatment; and receipt of 1 or more prior gemcitabine-based regimens for advanced disease were eligible for enrollment on the trial. Additional requirements for enrollment on the trial included having an ECOG performance status of 0 or 1, adequate organ function, and adequate cardiac function.

The median age was 64 years (range, 32-79), and most patients were female (56%). After a median follow-up of 33.4 months (range, 28.0-45.0), 44% of patients received subsequent anti-cancer therapy following discontinuation of zanidatamab.

At least 1 treatment-related AE (TRAE) occurred in 76% of patients. Grade 3 or higher TRAEs included diarrhea (5.0%), decreased ejection fractions (3.8%), and anemia (3.8%). Investigators reported no treatment-related deaths, and 3% of patients discontinued treatment following TRAEs.

The investigators noted that assessment of zanidatamab plus standard-of-care frontline treatment among patients with HER2-positive BTC is currently underway in the phase 3 HERIZON-BTC-302 trial (NCT06282575). Standard-of-care therapy will consist of cisplatin/gemcitabine with or without durvalumab (Imfinzi) or pembrolizumab (Keytruda).⁴

The trial’s primary end point is PFS among patients with IHC 3+ tumors. Secondary end points include OS, confirmed ORR, DOR, treatment-emergent AEs, and time to deterioration for those with IHC 3+ tumors.

Patients 18 years and older with histologically or cytologically confirmed BTC, including gallbladder cancer, intrahepatic cholangiocarcinoma, or extrahepatic cholangiocarcinoma are eligible for enrollment on the study. Other eligibility criteria include having no more than 2 prior cycles of systemic therapy with cisplatin/gemcitabine with or without a PD-(L)1 inhibitor for advanced unresectable or metastatic disease, evaluable disease per RECIST v1.1 guidelines, an ECOG performance status of 0 or 1, and adequate organ function.

References

1. Pant S, Fan J, Oh D-Y. Zanidatamab in HER2-positive metastatic biliary tract cancer final results from HERIZON-BTC-01. JAMA Oncol. Published online November 20, 2025. doi:10.1001/jamaoncol.2025.4736
2. HER2-targeted therapy shows promising results in rare bile duct cancers. News release. The University of Texas MD Anderson Cancer Center. November 25, 2025. Accessed November 26, 2025. https://tinyurl.com/2p9sfear
3. A study of ZW25 (Zanidatamab) in subjects with advanced or metastatic HER2-amplified biliary tract cancers (HERIZON-BTC-01). ClinicalTrials.gov. Updated September 15, 2025. Accessed November 26, 2025. https://tinyurl.com/wrvyhwte
4. Efficacy and safety of zanidatamab with standard-of-care therapy against standard-of-care therapy for advanced HER2-positive biliary tract cancer. ClinicalTrials.gov. Updated November 21, 2025. Accessed November 25, 2025. https://tinyurl.com/3hvaw8wt