Optimizing Zanidatamab Dosing in Patients With HER2-Positive Biliary Tract Cancer

Zanidatamab, a dual HER2-targeted bispecific antibody, has shown promise in treating HER2-positive biliary tract cancer (BTC) by binding to 2 distinct HER2 domains, leading to receptor clustering, HER2 internalization and degradation, reduction of HER2 dimerization, and ultimately promoting immune-mediated effects. Recently, zanidatamab received accelerated approval for the treatment of patients with previously treated unresectable or metastatic BTC, based on results of the HERIZON-BTC-01 trial. To determine the optimal dosage of zanidatamab, a study was conducted combining data from the phase 1 ZWI-ZW25-101 study (NCT02892123), the phase 2 HERIZON-BTC-01 study (NCT04466891), and in vitro analysis of ligand-dependent growth inhibition (LDGI) in HER-expressing human cancer cell lines. Results of this study were presented at the 2025 ASCO Gastrointestinal Cancers Symposium.

ZWI-ZW25-101 was a phase 1 dose-escalation and dose-expansion expansion study that investigated zanidatamab in previously treated patients with locally advanced or metastatic HER-expressing solid tumors at doses from 5 to 30 mg/kg every week (QW), every 2 weeks (Q2W), and every 3 weeks. HERIZON-BTC-01 was a global, single-arm, phase 2 study that investigated zanidatamab at 20 mg/kg Q2W in previously treated patients with locally advanced/metastatic HER2-amplified BTC. In the LDGI study, cancer cells were cultured in media supplemented with 50 ng/mL epidermal growth factor and treated with zanidatamab at concentrations ranging from 0.002 to 37.454 μg/mL.

The results of this analysis suggest that 20 mg/kg Q2W is the optimal dose for zanidatamab. The study found that the 5-mg/kg QW dose was below the IC90 for LDGI and showed no confirmed responses, whereas doses of 10 mg/kg QW and 20 mg/kg Q2W showed similar response rates of 25% and 29%, respectively, and were above the IC90 for LDGI. Clearance simulations indicated that target-mediated elimination was saturated at the 20-mg/kg Q2W dose, with clearance comparable to that of a higher dose of 30 mg/kg Q2W. Furthermore, clinical utility analysis using data from HERIZON-BTC-01 showed that the majority of patients had an exposure range on the plateau of the efficacy curve at the 20-mg/kg Q2W dose regimen.

The analysis concludes that zanidatamab at 20 mg/kg Q2W is the optimal dose for patients with HER2-positive BTC. This dosage provides the best balance of safety and efficacy, ensuring target exposure and saturating the target-mediated elimination pathway, without the need for higher, potentially more toxic, doses.

Source:

Trueman S, Wu L, Girgis S, et al. Zanidatamab dose optimization in patients with HER2-positive biliary tract cancer. Presented at: ASCO Gastrointestinal Cancers Symposium. January 23-25, 2025; San Francisco, CA; Virtual. Poster 546.