Sustained Responses Achieved With Zanidatamab in HER2+ Biliary Tract Cancer


The safety profile of zanidatamab in the HERIZON-BTC-01 trial appears to remain consistent after longer follow-up.

“In this long-term analysis, zanidatamab monotherapy demonstrated durable and sustained responses in patients with HER2-positive unresectable, locally advanced, or metastatic biliary tract cancer who had been previously treated,” according to lead study author Shubham Pant, MD, MBBS.

“In this long-term analysis, zanidatamab monotherapy demonstrated durable and sustained responses in patients with HER2-positive unresectable, locally advanced, or metastatic biliary tract cancer who had been previously treated,” according to lead study author Shubham Pant, MD, MBBS.

Patients with previously treated advanced, unresectable, or metastatic HER2-amplified biliary tract cancer continued to derive benefit from treatment with zanidatamab in the phase 2b HERIZON-BTC-01 trial (NCT04466891), according to long-term follow-up data presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.1

Results showed that the confirmed objective response rate (cORR) with zanidatamab was 41.3% and the disease control rate (DCR) was 68.8%, which was maintained from the study’s primary analysis. One additional patient achieved a complete response (CR), marking 2 CRs in the study thus far. Furthermore, the median duration of response (DOR) increased to 14.9 months (95% CI, 7.4-not reached).

The median overall survival (OS) in the cohort of patients with immunohistochemistry (IHC) 2+ or 3+ was 15.5 months (95% CI, 10.4-18.5) and the 6- and 12-month OS rates were 80.3% (95% CI, 69.4%-87.6%) and 56.2% (95% CI, 44.3%-66.5%), respectively.

“In this long-term analysis, zanidatamab monotherapy demonstrated durable and sustained responses in patients with HER2-positive unresectable, locally advanced, or metastatic biliary tract cancer who had been previously treated,” lead study author Shubham Pant, MD, MBBS, professor in the Department of Gastrointestinal Medical Oncology and in the Department of Investigational Cancer Therapeutics (Phase I Center) at The University of Texas MD Anderson Cancer Center, in Houston, Texas, said in a poster presentation during the meeting.

Biliary tract cancer, which is associated with poor prognosis, comprises less than 1% of all adult cancers. Furthermore, those who progress on frontline therapy and then go on to receive chemotherapy is linked with poor tolerability and a median OS of approximately 6 to 9 months.

Zanidatamab is a humanized, IgG1-like, HER2-targeted bispecific antibody binding to 2 HER2-distinct domains. Prior results of this agent in HERIZON-BTC-01 showed that at a median follow-up of 12.4 months, the cORR was 41.3% with a manageable safety profile in patients with previously treated HER2-positive biliary tract cancer.2

In May 2024, the FDA granted priority review to a biologics license application seeking the approval of zanidatamab as a treatment of patients with previously treated, unresectable, HER2-positive, locally advanced or metastatic biliary tract cancer, based on the initial findings from the trial.3 The regulatory agency will decide on the approval by November 29, 2024. The FDA’s target action date under the Prescription Drug User Fee Act is November 29, 2024.

In the phase 2 HERIZON-BTC-01 trial, patients with advanced, unresectable, or metastatic HER2-amplified biliary tract cancer were enrolled into 2 cohorts: immunohistochemistry (IHC) 2+ or 3+ (n = 80; cohort 1) and IHC 0 or 1+ (n = 7; cohort 2). Treatment with zanidatamab was given at 20 mg/kg intravenously every 2 weeks with mandatory infusion-related reaction (IRR) prophylaxis on days 1 and 15 of 28-day cycles. Patients underwent CT/MRI per RECIST 1.1 criteria every 8 weeks.

To be eligible for enrollment, patients had to be at least 18 years old, have received prior gemcitabine-containing therapy, had at least 1 measurable target lesion for RECIST 1.1 criteria, and an ECOG performance status of 0 to 1. They could not have previously received HER2-targeted therapies.

The primary end point was cORR per independent central review in cohort 1, and select secondary end points included DOR, DCR, progression-free survival, and OS, as well as safety and tolerability.

At the 2024 ASCO Annual Meeting, Pant presented on the efficacy and safety of zanidatamab in patients with HER2-positive biliary tract cancer with a longer median follow-up of 22 months (range, 16-34) and a data cutoff date of July 28, 2023.

More specific OS data within cohort 1 showed that in patients with IHC 2+, the median OS was 5.2 months (95% CI, 3.1-10.2); the 6-month OS rate was 41.7% (95% CI, 17.5%-64.4%) and the 12-month OS rate was 20.8% (95% CI, 5.1%-43.7%). In those with IHC 3+, the median OS was 18.1 months (95% CI, 12.2-23.2), and the 6- and 12-month OS rates were 90.1% (95% CI, 79.2%-95.4%) and 65.0% (95% CI, 51.6%-75.6%), respectively.

Regarding safety in cohorts 1 and 2, Pant noted that zanidatamab’s safety profile was generally unchanged with additional follow-up. Most patients experienced treatment-emergent adverse effects (TEAEs; 96.6%). Patients experienced grade 1 or 2 (51.7%) or grade 3 or 4 (20.7%) treatment-related adverse effects (TRAEs); serious TRAEs were reported in 9.2% of patients.

The most common all-grade and grade 3 to 4 TRAEs were diarrhea (36.8%; 4.6%), infusion-related reaction (IRR; 33.3%; 1.1%), decreased ejection fraction (10.3%; 3.4%), nausea (9.2%; 1.1%), increased alanine aminotransferase (ALT; 6.9%; 1.1%), increased aspartate aminotransferase (AST; 6.9%; 2.3%), vomiting (6.9%; 0%), fatigue (5.7%; 0%), and anemia (4.6%; 3.4%).

AEs of special interest consisted of IRRs (all-grade, 33.3%; grade 3-4, 1.1%), confirmed cardiac events (5.7%; 3.4%), and noninfectious pulmonary toxicities (1.1%; 1.1%).

TRAEs that led to dose reductions included grade 3 diarrhea (n = 1), grade 1 diarrhea and grade 1 nausea (n = 1), and grade 2 decreased weight (n = 1). Pant reported that 1 patient experienced serious TRAEs of increased ALT and increased AST since the prior analysis.

No patients discontinued treatment due to TRAEs since the prior analysis. Overall, this rate was 2.3%.

The ongoing, international, phase 3 HERIZON-BTC-02 trial (NCT06282575) is evaluating frontline zanidatamab in combination with standard cisplatin/gemcitabine with or without a PD-1/PD-L1 inhibitor in patients with advanced HER2-positive biliary tract cancer.

Disclosures: Pant cited consulting roles for Ask Gene, Boehringer Ingelheim, Ipssen, Janssen, Novartis, and Zymeworks; funding from 4D Pharma, Amal Therapeutics, Arcus Biosciences, Astellas Pharma, BioNtech, Boehringer Ingelheim, Bristol Myers Squibb, Elicio Therapeutics, Framewave, Immuneering, ImmunoMET, Ipsen, Janssen, Lilly, Mirati Therapeutics, NGM Biopharmaceuticals, Novartis, Pfizer, Rgenix, Xencor, and Zymeworks.


  1. Pant S, Fan J, Oh D-Y, et al. Zanidatamab in previously-treated HER2-positive (HER2+) biliary tract cancer (BTC): Overall survival (OS) and longer follow-up from the phase 2b HERIZON-BTC-01 study.J Clin Oncol. 2024;42(suppl 16; abstr 4091). doi:10.1200/JCO.2024.42.16_suppl.4091
  2. 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
  3. Zanidatamab granted priority review for HER2-positive metastatic biliary tract cancer. News release. Jazz Pharmaceuticals. May 29, 2024. Accessed May 29, 2024.
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