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Zanidatamab Demonstrates Efficacy in Refractory HER2-Amplified Biliary Tract Cancer

November 2023 Vol 16, No 6

Improving clinical outcomes in the second line of treatment in patients with advanced biliary tract cancer (BTC) remains an important goal, and researchers have been exploring various therapeutic targets, including HER2, an oncogene that creates a protein that encourages cell growth and accelerates the spread of cancers.1-3 HER2-targeted therapies have demonstrated clinical benefit in patients with breast, lung, and gastric cancers, but there is currently no approved HER2-targeted therapy for patients with BTC.2 Zanidatamab is a HER2-targeted bispecific antibody that has demonstrated promising activity in a phase 1 clinical trial, which included patients with BTC.4

At the 2023 American Society of Clinical Oncology Annual Meeting, Shubham Pant, MD, MBBS, Professor, Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, presented preliminary results from the phase 2b HERIZON-BTC-01 study, which is investigating the efficacy of zanidatamab in patients with treatment-refractory HER2-positive BTC, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer.2 The results were published simultaneously in The Lancet Oncology.5

Study Details

This ongoing open-label, single-arm study launched in September 2020 and has since completed recruitment.2 A total of 87 patients were placed in either cohort 1 or cohort 2, depending on their immunohistochemistry (IHC) test score: 80 patients were placed in cohort 1 (IHC 2+ or 3+) and 7 patients in cohort 2 (IHC 0 or 1+). In cohort 1, 41 patients had gallbladder cancer, 23 patients had intrahepatic cholangiocarcinoma, and 16 patients had extrahepatic cholangiocarcinoma. All patients had received 1 previous line of gemcitabine-containing therapy. The median patient age was 64 years and 65% of patients were Asian, 28.7% were White, and 5.7% were another race/ethnicity. Results from cohort 2 were not included as it contained a small sample size and did not reveal any unique responses.2

The primary end point of the trial was confirmed objective response rate (ORR), and select secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.

The confirmed ORR for patients in cohort 1 was 41.3%, confirmed by both independent central review and investigator assessment.2 In addition, in cohort 1, the DCR was 68.8%, and 68.4% of evaluable patients had a decrease in target lesions.2 The median PFS was 5.5 months in cohort 1, and OS data are not yet available.2 Median duration of treatment was 5.6 months, median DOR was 12.9 months, and median time to first response was 1.8 months.2

The most common treatment-related adverse events of any grade in both cohorts included diarrhea (n=36), infusion-related reactions (n=30), decrease in ejection fraction (n=11), nausea (n=9), and anemia (n=6).2 Only 2 patients had treatment-related adverse events leading to treatment discontinuation (grade 2 decrease in ejection fraction and grade 3 pneumonitis).2 No treatment-related deaths occurred.2

Zanidatamab demonstrated antitumor activity in patients with treatment-refractory HER2-positive BTC while exhibiting a manageable and tolerable safety profile. From these preliminary data, the investigators concluded that zanidatamab may provide clinical benefit and has the potential to become a treatment option in patients with HER2-positive BTC.2 Dr Pant and his team are still assessing PFS and OS in these patients. In addition, other studies are underway to further evaluate the therapeutic potential of zanidatamab as monotherapy and in combination with first-line chemotherapy for patients with HER2-positive BTC.


  1. Valle JW, Kelley RK, Nervi B, Oh D-Y, Zhu AX. Biliary tract cancer. Lancet. 2021;397:428-444.
  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.
  3. Connell CM, Doherty GJ. Activating HER2 mutations as emerging targets in multiple solid cancers. ESMO Open. 2017;2:e000279.
  4. Meric-Bernstam F, Beeram M, Hamilton E, et al. Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study. Lancet Oncol. 2022;23:1558-1570.
  5. Harding JJ, Fan J, Oh D-Y, et al; for the HERIZON-BTC-01 Study Group. Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study. Lancet Oncol. June 2, 2023. Epub ahead of print. doi:10.1016/S1470-2045(23)00242-5.

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