Zanidatamab for HER2-Amplified Advanced Biliary Tract Cancer

Next-generation sequencing of advanced biliary tract cancers has identified targetable genomic abnormalities, including HER2, IDH1, and FGFR. In a prior phase 1 study, zanidatamab, a bispecific antibody targeting two epitopes of HER2, elicited an objective response in patients with HER2-amplified or HER2-expressing biliary tract cancer (Lancet Oncol 2022; 23:1558.

Investigators now report results of an industry-sponsored, international, single-arm, phase 2b trial of zanidatamab in 80 patients with advanced biliary cancers. Patients had HER2-amplified cancers centrally confirmed by fluorescence in-situ hybridization and immunohistochemistry (IHC) assays; 78% had tumors with an IHC score of 3+, and 23% had tumors with an IHC score of 2+. Half of patients (51%) had gallbladder primaries, 29% had extrahepatic cholangiocarcinoma, and 20% had extrahepatic cholangiocarcinoma. All patients had disease progression while receiving at least one prior gemcitabine-containing chemotherapy regimen. Patients were administered zanidatamab (20 mg/kg) on days 1 and 15 every 28 days; 63% were treated in Asia.

At a median follow-up of 12.4 months, the objective response rate (the primary endpoint) was 41.3%, and the disease control rate was 68.8%. The median duration of response was 12.9 months, median progression-free survival was 5.5 months, and overall survival at 9 months was 69.9%. Three patients (18%) had grade 3 treatment-related adverse events including diarrhea (5%) and ejection fraction decrease (3%). A separate cohort of 7 patients with IHC scores of 0 or 1+ had no response to zanidatamab.