The FDA has granted accelerated approval to zanidatamab-hrii (Ziihera; Jazz Pharmaceuticals) for the treatment of adult patients with previously treated unresectable or metastatic HER2-positive (IHC+) biliary tract cancer (BTC), as detected by an FDA-approved test. This approval marks a significant advancement in the treatment landscape for BTC, a disease with historically poor prognosis and limited therapeutic options. The decision was based on promising objective response rate (ORR) and duration of response (DOR) data observed in clinical trials.
Clinical Trial Data
The accelerated approval is supported by data from the open-label, global Phase 2b HERIZON-BTC-01 clinical trial (NCT04466891), which enrolled 87 patients with HER2-amplified, locally advanced unresectable or metastatic BTC who had previously received gemcitabine-containing therapy. Among these patients, 62 had HER2 IHC 3+ BTC. Patients received 20 mg/kg of intravenous zanidatamab monotherapy every 2 weeks.
The primary outcome measure of the trial was ORR, assessed up to 34 months. Secondary outcome measures included DOR, progression-free survival (PFS), overall survival (OS), and the incidence of adverse events (AEs), also assessed up to 34 months. Disease control rate was evaluated at 24 weeks and up to 34 months.
Efficacy and Safety
Results from the HERIZON-BTC-01 trial demonstrated a 52% ORR in patients treated with zanidatamab, with an estimated median DOR of approximately 14.9 months. These findings highlight the potential of zanidatamab as an effective treatment option for patients with HER2+ BTC.
Regarding safety, serious AEs occurred in approximately 53% of patients receiving zanidatamab, including biliary obstruction (15%), biliary tract infection (8%), sepsis (8%), pneumonia (5%), diarrhea (3.8%), gastric obstruction (3.8%), and fatigue (2.5%). The most common AEs were diarrhea, infusion-related reactions, abdominal pain, and fatigue. One fatal case of hepatic failure was reported.
Ongoing Confirmatory Trial
Continued approval for this indication is contingent upon the verification and description of clinical benefits in the confirmatory Phase 3 HERIZON-BTC-302 trial (NCT06282575). This ongoing, randomized 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+ BTC. The primary outcome measure is PFS, with secondary outcomes including OS, confirmed ORR, DOR, and the number of treatment-emergent AEs.
Expert Commentary
Rob Iannone, MD, MSCE, Executive Vice President, Global Head of Research and Development, and Chief Medical Officer of Jazz Pharmaceuticals, stated that the approval of zanidatamab, which previously received breakthrough therapy designation from the FDA, represents an important advance, offering the first and only dual HER2-targeted bispecific antibody and chemotherapy-free treatment for patients living with BTC.
Stacie Lindsey, CEO and founder of the Cholangiocarcinoma Foundation, emphasized the significant burden that metastatic BTC places on patients and their families. She noted that the approval of zanidatamab offers a promising treatment option that could provide patients and their loved ones with more time together and an improved quality of life.
