The bispecific antibody zanidatamab in HER2 expressing solid tumors

Several types of HER2-targeted drugs with different mechanisms of action have been approved for therapeutic use in patients with HER2 overexpressing breast tumors, gastric or gastro-oesophageal junction tumors, or both types of cancer. Other cancers exhibit HER2 expression or amplification, suggesting that HER2-targeted agents can have broader therapeutic impact: now a first-in-human trial, recently published in The Lancet Oncology, shows that HER2 is an actionable target in various cancer histologies, including biliary tract cancer and colorectal cancer.

This multicentre, phase 1, dose-escalation and expansion trial included patients aged 18 years and older, with a life expectancy of at least 3 months, with locally advanced or metastatic HER2-expressing or HER2-amplified solid tumors of any kind who had received all available approved therapies. The aim was to evaluate the safety and anti-tumor activity of zanidatamab, a humanised, bispecific monoclonal antibody directed against two non-overlapping domains of HER2, across a range of solid tumors with HER2 expression or amplification. Different intravenous doses (from 5 mg/kg to 30 mg/kg) and intervals (every 1, 2, or 3 weeks) were tested, to identify the maximum tolerated dose, optimal biological dose, or recommended dose of the drug as well as its the safety and tolerability as monotherapy in solid tumors. Results show that zanidatamab is well tolerated and has encouraging activity in patients with heavily pretreated, advanced, HER2-overexpressing tumours, including biliary tract cancer and colorectal cancer, and who have progressed after standard therapies. «These data support that HER2 is an actionable target for the treatment of biliary tract cancer, colorectal cancer, and other cancers with HER2 expression or amplification. Furthermore, the preliminary evidence from this study suggests that single-agent targeting of both the extracellular domain and the dimerisation domain of HER2 by a bispecific antibody might provide unique mechanisms to achieve anti-tumor activity in patients who are pretreated, including those who have received previous HER2-targeted therapy. The evaluation of zanidatamab in combination with chemotherapy is ongoing», authors conclude.