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 was based on data from the HERIZON-BTC-01 clinical trial, a Phase 2b study that evaluated zanidatamab as a single agent in patients with HER2-positive BTC who had previously undergone treatment. 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.
Clinical Efficacy and Safety
The HERIZON-BTC-01 trial is the largest Phase 2b clinical trial to date specifically for this patient population. Longer follow-up data presented at the ASCO Annual Meeting 2024 showed improvement upon previously reported DOR. The accelerated approval is contingent upon verification and description of clinical benefit in a confirmatory trial.
Common adverse reactions observed in patients treated with Ziihera in clinical studies included diarrhea (50%), infusion-related reactions (35%), abdominal pain (29%), and fatigue (24%). Serious adverse reactions occurred in 53% of patients, with biliary obstruction (15%), biliary tract infection (8%), and sepsis (8%) being the most frequent.
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 dual targeting 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 and Future Studies
The Phase 3 HERIZON-BTC-302 confirmatory trial is currently underway 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 (GEA) and metastatic breast cancer (mBC).
Financial Implications for Zymeworks
Zymeworks entered into a license and collaboration agreement with Jazz Pharmaceuticals in late 2022 for the exclusive development and commercialization rights to zanidatamab in the United States, Europe, Japan, and other territories. With this FDA approval, Zymeworks will receive a $25 million milestone payment from Jazz Pharmaceuticals. Additionally, Zymeworks is eligible to receive up to $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, 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. 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.
