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 this rare and aggressive cancer, offering a new chemotherapy-free option for patients with limited alternatives. Ziihera, developed by Jazz Pharmaceuticals in collaboration with BeiGene, is a bispecific HER2-directed antibody.
The approval was based on data from the HERIZON-BTC-01 trial, a phase 2b study that evaluated zanidatamab as a single agent in patients with HER2-positive BTC who had received prior gemcitabine-containing therapy. The trial enrolled 62 patients with HER2 IHC 3+ BTC and demonstrated a 52% objective response rate (ORR) with a 95% confidence interval (CI) of 39% to 65%, as determined by independent central review (ICR). The Kaplan-Meier estimated median duration of response (DOR) was 14.9 months (95% CI: 7.4 months – not estimable) by ICR.
Clinical Efficacy and Safety
The HERIZON-BTC-01 trial is the largest phase 2b clinical trial to date specifically for this patient population. The study's primary endpoint was confirmed objective response rate (cORR) by independent central review (ICR). Key findings from the trial, initially presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2023 and later updated at the ASCO Annual Meeting 2024, underscored the drug's potential to provide meaningful clinical benefit. The efficacy of Ziihera was evaluated based on ORR and DOR as determined by ICR according to RECIST v1.1.
Mechanism of Action
Ziihera (zanidatamab-hrii) is a bispecific HER2-directed antibody that binds to two extracellular sites on HER2, leading to internalization and a reduction of the receptor on the tumor cell surface. This 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.
Expert Commentary
"BTC is a devastating disease with a poor prognosis and five-year survival rates under five percent in the metastatic setting," said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development, and chief medical officer of Jazz Pharmaceuticals. "The approval of Ziihera...is an important advance and offers the first and only dual HER2-targeted bispecific antibody and chemotherapy-free treatment for patients living with BTC."
Dr. James Harding, associate attending, Gastrointestinal Oncology and Early Drug Development Services, at Memorial Sloan Kettering Cancer Center, added, "Zanidatamab has demonstrated antitumor activity and is now a new option for patients with HER2-positive biliary tract cancer. I look forward to continued and successful drug development for patients with biliary tract cancer."
Ongoing Research
While this approval is a significant step forward, 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 developed in multiple clinical trials as a targeted treatment option for patients with other solid tumors that express HER2.
Biliary Tract Cancer: An Unmet Need
Biliary tract cancer, including gallbladder cancer and intrahepatic and extrahepatic cholangiocarcinoma, accounts for less than 1% of all adult cancers globally and is often associated with a poor prognosis. Approximately 12,000 people are diagnosed with HER2+ BTC annually across the US, Europe, and Japan, highlighting the critical need for effective therapies.
