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 biliary tract cancer (BTC). This approval marks a significant advancement in the treatment landscape for BTC, a disease with historically poor prognosis and limited treatment options. Ziihera, developed by Jazz Pharmaceuticals, is a bispecific HER2-directed antibody, offering a chemotherapy-free option for these patients.
The approval was based on data from the HERIZON-BTC-01 trial, a Phase 2b study evaluating zanidatamab as a single agent in patients with HER2-positive BTC. The trial included 62 patients with HER2-positive (IHC 3+) BTC who had received prior gemcitabine-containing therapy. The study demonstrated an objective response rate (ORR) of 52% (95% CI: 39, 65) and a Kaplan Meier estimated median duration of response (DOR) of 14.9 months (95% CI: 7.4-not estimable) as determined by independent central review (ICR) according to RECIST v1.1.
Clinical Efficacy and Safety
The HERIZON-BTC-01 trial's primary endpoint was confirmed ORR by ICR. Key secondary endpoints included other efficacy and safety outcomes. The trial excluded patients with prior HER2-targeted therapy use. Patients received zanidatamab (20 mg/kg IV every 2 weeks), and tumor assessments were conducted every 8 weeks per RECIST v1.1.
The safety profile of Ziihera was evaluated in 80 patients. Serious adverse reactions occurred in 53% of patients. The most common adverse reactions (≥20%) were diarrhea, infusion-related reaction, abdominal pain, and fatigue. Serious adverse reactions in >2% of patients included biliary obstruction (15%), biliary tract infection (8%), sepsis (8%), pneumonia (5%), diarrhea (3.8%), gastric obstruction (3.8%), and fatigue (2.5%). A fatal adverse reaction of hepatic failure occurred in one patient.
Ongoing Confirmatory Trial
Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. The confirmatory, global, randomized Phase 3 trial HERIZON-BTC-302 (NCT06282575) is ongoing. This trial is evaluating 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 Beyond Biliary Tract Cancer
Zanidatamab is also being investigated in other HER2-expressing solid tumors, including gastroesophageal adenocarcinomas (GEAs) and metastatic breast cancer (mBC). The HERIZON-GEA-01 trial is evaluating zanidatamab plus chemotherapy with or without tislelizumab as first-line treatment for advanced/metastatic HER2-positive GEAs. The EmpowHER-303 trial is evaluating zanidatamab in combination with physician's choice chemotherapy for HER2-positive mBC patients who have progressed on or are intolerant to previous trastuzumab deruxtecan treatment.
Warnings and Precautions
Ziihera carries a boxed warning for embryo-fetal toxicity, advising patients of the risk and need for effective contraception. Other warnings and precautions include potential for left ventricular dysfunction, infusion-related reactions, and diarrhea. LVEF should be assessed prior to initiation and at regular intervals during treatment. Premedications should be administered to prevent infusion-related reactions, and antidiarrheal treatment should be administered as clinically indicated.
Impact on Biliary Tract Cancer Treatment
"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," 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. Stacie Lindsey, CEO and founder of the Cholangiocarcinoma Foundation, added, "The approval of Ziihera offers a promising treatment option. It provides patients and their loved ones the possibility of more time together and an improved quality of life."
