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, providing the first and only dual HER2-targeted bispecific antibody for this patient population.
The approval of Ziihera, a bispecific HER2-directed antibody, 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) and a median duration of response (DOR) of 14.9 months, as determined by independent central review (ICR).
Clinical Efficacy and Safety
The HERIZON-BTC-01 trial, the largest Phase 2b clinical trial to date specifically for this patient population, achieved its primary endpoint of confirmed objective response rate (cORR) by ICR. These results were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2023 and published in The Lancet Oncology. Longer follow-up data, showing improvement upon previously reported DOR, were reported at the ASCO Annual Meeting 2024.
Ziihera's approval comes with a boxed warning for embryo-fetal toxicity, advising patients of the risk and need for effective contraception. Common adverse reactions reported in clinical studies include diarrhea (50%), infusion-related reactions (35%), abdominal pain (29%), and fatigue (24%). Serious adverse reactions occurred in 53% of patients, including biliary obstruction (15%), biliary tract infection (8%), and sepsis (8%).
Mechanism of Action
Zanidatamab-hrii binds to two extracellular sites on HER2, leading to internalization and a reduction of the receptor on the tumor cell surface. It also induces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP), resulting in tumor growth inhibition and cell death in vitro and in vivo.
Ongoing and Future Studies
The Phase 3 HERIZON-BTC-302 confirmatory trial is ongoing to evaluate 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).
Financial Implications
Under the terms of the Jazz license and collaboration agreement, Zymeworks has earned a milestone payment of $25 million based on the FDA approval in BTC. Zymeworks is also eligible to receive up to a further $500 million in regulatory milestone payments and $862.5 million in commercial milestone payments, as well as tiered royalties of 10% to 20% of net sales by Jazz.
About Biliary Tract Cancer
Biliary tract cancers (BTC), including gallbladder cancer and intrahepatic and extrahepatic cholangiocarcinoma, account for less than 1% of all adult cancers globally and are often associated with a poor prognosis. The human epidermal growth factor receptor 2 (HER2) is a well-validated target for antitumor therapy in other cancers. Approximately 12,000 people are diagnosed with HER2+ BTC annually across the U.S., Europe, and Japan.
