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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.
Zanidatamab appears to have substantial single-agent antitumor activity in HER2-positive cholangiocarcinoma, with minimal treatment-related toxicity. This and other studies validate HER2 as highly targetable in cholangiocarcinoma and underscore the need to perform next-generation sequencing on all patients with metastatic disease.
Harding JJ et al.
Title: Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): A multicentre, single-arm, phase 2b study.
Source: Lancet Oncol 2023 Jun 2; [e-pub]. (Abstract/FREE Full Text)