The FDA has granted accelerated approval to zanidatamab-hrii (Ziihera) for the treatment of adult patients with previously treated, unresectable or metastatic HER2-positive (HER2+) biliary tract cancer (BTC). This approval marks a significant advancement as the first HER2-targeted therapy specifically approved for this disease. The decision is based on data from the phase 2b HERIZON-BTC-01 trial, highlighting the drug's efficacy in a patient population with limited treatment options.
HERIZON-BTC-01 Trial Results
The approval is primarily supported by the results from cohort 1 of the open-label, multicenter, global phase 2b HERIZON-BTC-01 trial. The study included 62 patients with HER2+ BTC who had previously received at least one gemcitabine-containing chemotherapy regimen for advanced disease. The median age of patients was 64 years (range, 38-79).
The trial demonstrated an objective response rate (ORR) of 52% (95% CI, 39%-65%) per independent central review (ICR). This included 30 patients achieving a partial response and 2 patients experiencing a complete response. The median duration of response (DOR) was 14.9 months (95% CI, 7.4-not reached).
Updated findings presented at the 2024 ASCO Annual Meeting, with a median follow-up of 21.9 months (range, 16-34), confirmed the ORR remained consistent with the primary analysis. The median overall survival (OS) was 15.5 months (95% CI, 10.4-18.5), with a 12-month OS rate of 56.2% (95% CI, 44.3%-66.5%).
Survival Outcomes Based on IHC Status
Further analysis of overall survival based on immunohistochemistry (IHC) status revealed notable differences. In patients with IHC 2+, the median OS was 5.2 months (95% CI, 3.1-10.2), with a 6-month OS rate of 41.7% (95% CI, 17.5%-64.4%) and a 12-month OS rate of 20.8% (95% CI, 5.1%-43.7%). For those with IHC 3+, the median OS was 18.1 months (95% CI, 12.2-23.2), and the 6- and 12-month OS rates were 90.1% (95% CI, 79.2%-95.4%) and 65.0% (95% CI, 51.6%-75.6%), respectively.
Safety Profile
The prescribing label for zanidatamab indicates that common adverse events (AEs) occurring in at least 20% of patients included diarrhea, infusion-related reactions, abdominal pain, and fatigue. Serious AEs (SAEs) were reported in 53% of patients, with the most frequent being biliary obstruction (15%), biliary tract infection (8%), and sepsis (8%). Discontinuation of zanidatamab due to AEs occurred in 2.5% of patients, and one patient experienced a fatal AE.
Ongoing Research
The ongoing, international, phase 3 HERIZON-BTC-02 trial (NCT06282575) is currently evaluating zanidatamab as a first-line treatment in combination with standard cisplatin/gemcitabine, with or without a PD-1/PD-L1 inhibitor, for patients with advanced HER2+ biliary tract cancer. This trial aims to further establish the role of zanidatamab in the treatment paradigm for this aggressive cancer.
According to Dr. James Harding, an investigator in the trial, zanidatamab represents a new option for patients with HER2-positive biliary tract cancer, addressing a significant unmet need. He looks forward to continued drug development for biliary tract cancer.
