Zanidatamab BLA Submitted to FDA for HER2+ Biliary Tract Cancer


A biologics license application for zanidatamab is being reviewed by the FDA for treating previously treated, HER2-positive biliary tract cancer.

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  • Zanidatamab (ZW25) showed a 41.3% response rate and a manageable safety profile in a clinical trial for HER2–positive biliary tract cancer (BTC).
  • A larger confirmatory trial is now recruiting patients to evaluate zanidatamab in combination with standard therapy for the first-line treatment of HER2-positive BTC.
  • This could be the first HER2-targeted treatment specifically approved for this cancer in the US.

The rolling submission of a biologics license application (BLA) seeking FDA approval for zanidatamab as a treatment for previously treated, unresectable, locally advanced, or metastatic HER2-positive BTC has been completed, according to Jazz Pharmaceuticals.1

Zanidatamab is a HER2-targeted bispecific antibody being studied in the phase 2b HERIZON-BTC-01 trial (NCT04466891). This trial serves as the basis for the BLA. The primary end point of confirmed objective response rate (cORR) by independent central review (ICR) in cohort 1 (n = 80) as of the data cutoff date of October 10, 2022, was 41.3% (95% CI, 30.4-52.8).

The Kaplan Meier estimated median duration of response (DOR) in this cohort was 12.9 months (95% CI, 6.0-not estimable) by ICR, and the Kaplan-Meier estimated median progression-free survival (PFS) was 5.5 months (95% CI, 3.7-7.2; range, 0.3-18.5 months).1,2

A manageable and tolerable safety profile was also observed with zanidatamab in the trial as only 2 patients (2.3%) in the study discontinued treatment due to adverse events (AEs). No grade 4 AEs were seen, and no deaths were considered treatment-related. The most common AEs were diarrhea and infusion-related reactions. However, these generally were low-grade, reversible, and manageable.

If approved, this would mark the first HER2-targeted treatment specifically approved for BTC in the US.

Zanidatamab is also being evaluated in the confirmatory phase 3 HERIZON-BTC-302 trial (NCT06282575) for the frontline treatment of patients with advanced or metastatic HER2-positive BTC. The global, open-label, randomized trial is now enrolling patients.

3D rendering of gastrointestinal system

3D rendering of gastrointestinal system

Investigators are assessing the efficacy and safety of zanidatamab in combination with standard-of-care therapy compared with standard-of-care therapy alone.3

This trial is enrolling patients with confirmed BTC, including gallbladder cancer, intrahepatic cholangiocarcinoma, or extrahepatic cholangiocarcinoma. The cancer must be locally advanced and unresectable or metastatic, and not amenable to curative surgery, transplant, or ablation techniques. Patients can only have received a maximum of 2 cycles of prior systemic therapy with gemcitabine and a platinum agent, potentially combined with a PD-1/L1 inhibitor. The tumor must be HER2-positive, determined by specific tests on either new or archival biopsy tissue.

Further, measurable or non measurable disease according to RECIST 1.1 criteria is required. Eligible patients must be 18 years or older with an ECOG performance status of 0 or 1 and adequate organ function. Women of childbearing potential must have a negative pregnancy test and be willing to use birth control.

The primary end point of the trial is PFS. Secondary end points include overall survival, PFS, cORR, DOR, treatment-emergent AEs, maximum serum concentration of zanidatamab, number of participants who develop antidrug antibodies to zanidatamab, and time to definitive deterioration.

1. Jazz Pharmaceuticals completes zanidatamab biologics license application for previously treated HER2-positive metastatic biliary tract cancer. News release. April 2, 2024. Accessed April 2, 2024.
2. Harding JJ, Fan J, Oh D, et al. Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study. Lancet Oncol. 2023;24(7):772-782. doi: 10.1016/S1470-2045(23)00242-5
3. Efficacy and safety of zanidatamab with standard-of-care therapy against standard-of-care therapy for advanced HER2-positive biliary tract cancer. February 28, 2024. Accessed April 2, 2024.
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