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, developed by Zymeworks in collaboration with Jazz Pharmaceuticals, is based on data from the HERIZON-BTC-01 clinical trial. This 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). These results offer new hope for patients with limited treatment options and few approved therapies.
Clinical Efficacy and Safety
The HERIZON-BTC-01 trial, the largest Phase 2b clinical trial to date specifically for this patient population, evaluated zanidatamab as a single agent in previously treated HER2-positive BTC. The trial met its primary endpoint of confirmed objective response rate (cORR) by ICR. Longer follow-up data presented at the ASCO Annual Meeting 2024 showed improvement upon previously reported DOR.
Common adverse reactions observed in patients treated with Ziihera 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
Ziihera (zanidatamab-hrii) is a bispecific HER2-directed antibody that binds to two extracellular sites on HER2, leading to receptor internalization and a reduction of HER2 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
While this approval is based on accelerated approval, continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 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 other tumor types, including Phase 3 trials in gastroesophageal adenocarcinomas (GEAs) and metastatic breast cancer (mBC).
