The U.S. Food and Drug Administration (FDA) has granted accelerated approval to Ziihera® (zanidatamab-hrii) for the treatment of adult patients 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 decision was announced by Zymeworks Inc. and Jazz Pharmaceuticals.
Ziihera received accelerated approval based on data from the HERIZON-BTC-01 clinical trial, which 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). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Clinical Efficacy and Safety
The FDA approval of Ziihera is based on compelling data from the HERIZON-BTC-01 trial, the largest Phase 2b clinical trial to date specifically for this patient population. The trial evaluated zanidatamab as a single agent in previously treated HER2-positive BTC. Key findings from the trial include:
- A confirmed objective response rate (cORR) of 52% by independent central review (ICR).
- A median duration of response (DOR) of 14.9 months.
The safety profile of Ziihera was also evaluated in the trial. Common adverse reactions (≥20%) included diarrhea (50%), infusion-related reaction (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 extracellular sites on HER2, leading to internalization and reduction of the receptor 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 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 for Zymeworks
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.
Biliary Tract Cancer (BTC) Context
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. The human epidermal growth factor receptor 2 (HER2) is a well-validated target for antitumor therapy in other cancers. Across the U.S., Europe, and Japan, approximately 12,000 people are diagnosed with HER2+ BTC annually.
