The U.S. Food and Drug Administration (FDA) has granted accelerated approval to Ziihera® (zanidatamab-hrii) for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC). This approval marks a significant advancement in the treatment landscape for BTC, offering the first dual HER2-targeted bispecific antibody and chemotherapy-free option for these patients.
Clinical Trial Data
The approval of Ziihera is based on data from the HERIZON-BTC-01 trial, a Phase 2b clinical trial evaluating zanidatamab as a single agent in patients with previously treated HER2-positive BTC. The trial demonstrated a 52% objective response rate (ORR) as determined by independent central review (ICR), with a median duration of response (DOR) of 14.9 months. These results were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2023 and published in The Lancet Oncology.
Mechanism of Action
Zanidatamab-hrii is a bispecific HER2-directed antibody that binds to two distinct extracellular sites on HER2, leading to receptor internalization and reduction on the tumor cell surface. This unique binding mechanism induces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP), resulting in tumor growth inhibition and cell death.
Ongoing Clinical Development
While the current approval is based on accelerated data, continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial. The ongoing Phase 3 HERIZON-BTC-302 trial is evaluating zanidatamab in combination with standard-of-care therapy versus standard-of-care therapy alone in the first-line setting for patients with HER2-positive BTC. Zanidatamab is also being investigated in Phase 3 trials for gastroesophageal adenocarcinomas (GEAs) and metastatic breast cancer (mBC).
Safety Information
The prescribing information for Ziihera includes a Boxed Warning for embryo-fetal toxicity, advising patients of the risk and need for effective contraception. Common adverse reactions reported in clinical trials include diarrhea (48%), infusion-related reactions (31%), abdominal pain (29%), and fatigue (24%).
Company Statements
"The FDA’s accelerated approval of Ziihera marks the culmination of more than a decade of research and development at Zymeworks," said Paul Moore, Ph.D., Chief Scientific Officer at Zymeworks. Kenneth Galbraith, Chair and Chief Executive Officer of Zymeworks, added, "Our strategic collaboration with Jazz provided the optimal ‘partner of choice’ to continue the rapid advancement of zanidatamab."
