FDA to Review Zanidatamab BLA for HER2+ Metastatic Biliary Tract Cancer


A rolling BLA for zanidatamab in previously treated, HER2-positive, advanced biliary tract cancer has been submitted to the FDA.



A rolling biologics license application (BLA) seeking the approval of zanidatamab (ZW25) for the treatment of patients with previously treated, HER2-positive, unresectable, locally advanced, or metastatic biliary tract cancer has been completed and submitted to the FDA.1

The submission is based on data from the phase 2b HERIZON-BTC-01 trial (NCT04466891), which demonstrated that patients with HER2-positive biliary tract cancer treated in cohort 1 (n = 80) experienced a confirmed objective response rate (ORR) of 41.3% (95% CI, 30.4%-52.8%) by independent review committee (IRC) assessment, which included a complete response (CR) rate of 1.3% and a partial response (PR) rate of 40%; 27.5% of patients achieved stable disease (SD), 30% had progressive disease (PD), and 1.3% were not evaluable for response.2

“This important milestone brings us one step closer to delivering zanidatamab, a targeted treatment option, to patients living with HER2-positive biliary tract cancer, a type of cancer that is associated with a 5-year overall survival [OS] rate of less than 5%,” Rob Iannone, MD, MSCE, executive vice president and global head of research and development at Jazz Pharmaceuticals, stated in a news release.1

HERIZON-BTC-01 enrolled patients with locally advanced or metastatic biliary tract cancer, and tissue was required to confirm HER2 status via central laboratory. Other key inclusion criteria included PD after treatment with a gemcitabine-based regimen, no prior treatment with HER2-targeted therapies, and an ECOG performance status of 0 or 1.2 Patients with HER2-positive biliary tract cancer, defined as immunohistochemistry (IHC) 2+ or 3+, were enrolled to cohort 1. Cohort 2 included patients with a HER2 status of IHC 0 or 1+.3

All patients received zanidatamab monotherapy at 20 mg/kg once every 2 weeks. Every 8 weeks, patients underwent assessment via CT or MRI.

Confirmed ORR by ICR assessment in cohort 1 served as the trial’s primary end point. Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), OS, and safety.

In cohort 1, the median age was 64 years (range, 58-70) and 56% of patients were female. More than half of patients were Asian (65%), from Asia (63%), and had an ECOG performance status of 1 (73%).3 Regarding disease subtypes, 51% had gallbladder cancer, 29% had intrahepatic cholangiocarcinoma, and 20% had extrahepatic cholangiocarcinoma. Eighty-nine percent of patients had American Joint Committee on Cancer stage IV disease at the time of study entry. Most patients had HER2 3+ disease status by IHC (78%) and the remainder had HER2 2+ status (23%).

Patients had received a median of 1 prior line of therapy for metastatic or locally advanced disease. Prior systemic treatment included a gemcitabine-based regimen (100%), gemcitabine plus cisplatin (76%), fluoropyrimidine-based treatment (34%), a PD-1/PD-L1 inhibitor (26%), or fluoropyrimidine (6%). Moreover, 16% of patients previously received radiotherapy and 31% previously underwent curative-intent surgery.

Additional efficacy data from cohort 1 showed that the median time to first response by ICR assessment was 1.8 months (95% CI, 1.7-2.0), and the median DOR was 12.9 months (95% CI, 6.0-not estimable). Notably, 81.8% of patients experienced a duration of response of at least 16 weeks. The ICR-assessed DCR was 68.8% (95% CI, 57.4%-78.7%). The median PFS was 5.5 months (95% CI, 2.7-7.2).2

Per investigator assessment, the ORR achieved with the agent was also 41.3% (95% CI, 30.4%-52.8%), with CR, PR, SD, and PD rates of 5%, 36.3%, 26.3%, and 31.3%, respectively. The median time to first response was also 1.8 months (95% CI, 1.6-3.7), and the median DOR was 11.1 months (95% CI, 5.6-14.1). The investigator-assessed DCR was 67.5% (95% CI, 56.1%-77.6%), and the median PFS by investigator assessment was 5.4 months (95% CI, 3.6-7.2).

Regarding safety, at least 1 treatment-emergent adverse effect (AE) was experienced by 97% of patients, with 72% of patients experiencing at least 1 effect determined by the investigator to be related to zanidatamab. The most common treatment-related AEs (TRAEs) included diarrhea (grade 1/2, 32%; grade 3, 5%), infusion-related reaction (32%; 1%), decreased ejection fraction (6%; 3%), nausea (8%; 1%), increased alanine aminotransferase (7%; 0%), increased aspartate aminotransferase (6%; 1%), vomiting (7%; 0%), fatigue (6%; 0%), anemia (2%; 2%), hypokalemia (1%; 1%), decreased platelet count (1%; 1%), increased blood bilirubin (0%; 1%), enteritis (0%; 1%), increased lipase (0%; 1%), oral candidiasis (0%; 1%), pneumonitis (0%; 1%), and stomatitis (0%; 1%).

“Zanidatamab is a biparatopic HER2-targeted bispecific antibody that simultaneously binds two non-overlapping epitopes of HER2 resulting in multiple mechanisms of action,” Iannone added.1 “Second-line biliary tract cancer represents the first of multiple indications we are evaluating and we are excited about zanidatamab's potential as a new option for multiple HER2-expressing cancers, with ongoing phase 3 trials in first-line biliary tract, first-line gastroesophageal adenocarcinoma, and previously treated breast cancer."


  1. Jazz Pharmaceuticals completes zanidatamab biologics license application for previously treated HER2-positive metastatic biliary tract cancer. News release. Jazz Pharmaceuticals. April 2, 2024. Accessed April 2, 2024. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-completes-zanidatamab-biologics-license
  2. Pant S, Fan J, Oh D-Y, et al. Results from the pivotal phase (Ph) 2b HERIZON-BTC-01 study: Zanidatamab in previously-treated HER2‑amplified biliary tract cancer (BTC). J Clin Oncol. 2023;41(suppl 16):4008. doi:10.1200/JCO.2023.41.16_suppl.4008
  3. Harding JJ, Fan J, Oh D-Y, 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
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