Ziihera Approved for Biliary Tract Cancer

On Nov. 20, 2024, the US Food and Drug Administration (FDA) granted accelerated approval to Ziihera^® (zanidatamab-hrii – Jazz Pharmaceuticals), a bispecific human epidermal growth factor receptor 2 (HER2)-directed antibody for the treatment of adults with previously treated, unresectable or metastatic HER2-positive biliary tract cancer (BTC). This approval came ahead of the expected Nov. 29, 2024, approval date. The recommended dose is 20mg/kg every two weeks as an intravenous (IV) infusion and requires premedication with acetaminophen, an antihistamine, and a corticosteroid to avoid potential infusion-related reactions. Ziihera carries a boxed warning for embryo-fetal toxicity and requires effective contraception. Cost information is not known at this time and launch information is expected on Dec. 11, 2024. For full prescribing information, please click here.

At a Glance

• Brand Drug: Ziihera^® (zanidatamab-hrii)
• Manufacturer: Jazz Pharmaceuticals
• Date Approved: Nov. 20, 2024
• Indication:  For the treatment of adults with previously treated, unresectable or metastatic HER2-positive [immunohistochemistry (IHC) 3+] BTC, as detected by an FDA-approved test
• Dosage Forms Available: 300mg of lyophilized powder in single-dose vials for reconstitution, dilution, and IV infusion
• Launch Date: Jazz Pharmaceuticals plans to announce launch information on Dec. 11, 2024.
• Estimated Annual Cost: Cost information is not known at this time.
• Bile ducts are located in the liver, gallbladder, pancreas, and small intestines and move bile from the gallbladder and the liver to the small intestines, where it helps to digest food. BTC, also called bile duct cancer (BDC) and cholangiocarcinoma, tends to spread quickly, and its symptoms are like those of many other conditions. It can occur inside (intrahepatic) and outside (extrahepatic) the liver, the gallbladder, and the ducts.
• About 8,000 Americans – mostly adults in their 70s or older – are diagnosed as having BTC each year. Most patients (>65%) are diagnosed with tumors that cannot be removed surgically. Challenging not only to diagnose but also to treat, it has an overall five-year survival rate of less than 10%, falling to less than 5% for metastatic cases. Up to one-third of BTC cases are positive for HER2 mutations. IHC testing on tumor biopsies determines the amount of HER2 present in the tumor on a four-point scale. IHC readings of 0 to 1+ are negative for HER2, a 2+ score is indecisive and results of 3+ indicate HER2 is present.
• Ziihera was granted accelerated approval based on an open-label global trial of 87 patients divided into two cohorts based on tumor expression and given Ziihera 20mg/kg every two weeks. In the cohort with HER2 IHC 2+/3+ BTC (n=80), the objective response rate (ORR) was 52%, the median duration of response (DOR) was 14.9 months, and progression-free survival (PFS) was 5.5 months. In general, ORR to second-line, standard-of-care chemo in patients with BTC is reported to be 5% to 15%. The Phase III confirmatory trial is ongoing and Ziihera will require clinical benefit confirmation before receiving full approval.
• The most common adverse events in patients receiving Zither were diarrhea, infusion-related reactions, abdominal pain, and fatigue. Serious adverse events occurred in 53% of patients and 2.5% permanently discontinued the drug due to adverse events.
• For previously treated, inoperable BTC, treatment options are few. Enhertu^® (fam-trastuzumab deruxtecan-nxki – Daiichi Sankyo and AstraZeneca) is a HER2-directed antibody and topoisomerase inhibitor conjugate (ADC) that in April 2024 received an expanded indication to treat adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options. Keytruda^® (pembrolizumab – Merck) and Imfinzi^® (durvalumab – AstraZeneca) are also FDA-approved to treat BTC, though not HER2 specific. Both are programmed death-ligand 1 (PD-L1) blocking antibodies, and each is used in combination with the chemotherapy (chemo) drugs, cisplatin and gemcitabine.
• Ziihera is also being studied as a first-line treatment for HER2-positive BTC in combination with cisplatin-gemcitabine, advanced BTC for those with four rounds of previous drug therapy, and for treating HER2-positive gastroesophageal adenocarcinoma (GEA), and breast cancer previously treated with Enhertu.