The HER2-targeted bispecific antibody zanidatamab demonstrated durable responses in patients with treatment-refractory HER2-positive biliary tract cancer, according to research presented by Shubham Pant, MD, and colleagues at the 2023 ASCO Annual Meeting (Abstract 4008). The results were also simultaneously published in The Lancet Oncology.
Shubham Pant, MD
In the first cohort of the global phase II HERIZON-BTC-01 trial, which included 80 patients with HER2-positive tumors, the confirmed objective response rate was 41%, with a median duration of response of 12.9 months at a median follow-up of 12.4 months. Among the 33 responders, 49% had ongoing responses, and 82% had a response lasting more than 16 weeks. According to the researchers, this is the largest study of a HER2-targeted drug in patients with biliary tract cancer.
“Chemotherapy for patients with biliary tract cancers [whose disease has] progressed on first-line therapy is usually associated with a 5% response rate,” said global trial lead Dr. Pant, Professor of Gastrointestinal Medical Oncology and Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center. “These results provide evidence that zanidatamab can achieve durable responses and may offer a new treatment opportunity for patients who previously had limited options.”
Patients with advanced biliary tract cancer whose disease progresses after first-line treatment are offered standard-of-care therapies, which may result in limited clinical benefit and only modest improvement in survival. HER2-targeted therapies have improved survival in HER2-positive breast and gastric cancers, but there currently is no approved HER2-targeted therapy for biliary tract cancer.
Zanidatamab was first evaluated in a phase I trial, and its results—published by Meric-Bernstam in The Lancet Oncology in November 2022—supported HER2 as an actionable target in various cancer types, including biliary tract cancer. Based on those results, researchers advanced zanidatamab into this phase II trial for patients with biliary tract cancer.
Key Results
This open-label, single-arm trial evaluated the antitumor activity of zanidatamab in patients with HER2-amplified advanced biliary tract cancer, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer. The trial was conducted at 67 sites; patients were divided into two cohorts based on HER2 expression (positive or low/negative) by tumor immunohistochemistry. The primary endpoint was confirmed objective response rate in the HER2-positive cohort.
The study enrolled 80 patients in the HER2-positive cohort and 7 patients in the HER2-low/negative cohort. All patients had received one previous line of gemcitabine-containing therapy. The median patient age was 64 years, and 65.5% of the patients were Asian, 28.7% were White, and 5.7% were another race. Of the trial participants, 52% had gallbladder cancer, 30% had intrahepatic cholangiocarcinoma, and 18% had extrahepatic cholangiocarcinoma.
There were no responses to zanidatamab observed in the HER2-low/negative cohort.
Across both cohorts, grade 3 treatment-related adverse events occurred in 18% of patients. Two patients (2.3%) discontinued zanidatamab because of an adverse event. No grade 4 or 5 treatment-related adverse events were reported.
“Given these data, we believe strongly there should be continued efforts to explore zanidatamab as a viable treatment option for HER2-positive biliary tract cancer,” said Dr. Pant. “We are encouraged by the potential impact of zanidatamab on improving patient outcomes."
Dr. Pant and his team still are evaluating progression-free survival and overall survival in these patients. Additionally, clinical trials are underway to further investigate the therapeutic potential of zanidatamab as a monotherapy and in combination with first-line chemotherapy for HER2-positive biliary tract cancer.
Disclosure: This study was funded by Zymeworks BC Inc. and BeiGene Ltd. For full disclosures of the study authors, visit coi.asco.org.
