Zanidatamab Nets European Approval in Pretreated HER2+ Biliary Tract Cancer

Biliary Tract Cancer

| Image by Ashling Wahner & MJH Life Sciences Using AI

The HER2-directed bispecific antibody zanidatamab-hrii (Ziihera) has received conditional marketing authorization from the European Commission (EC) for the treatment of adult patients with unresectable locally advanced or metastatic HER2-positive (immunohistochemistry [IHC] 3+) biliary tract cancer (BTC) who received at least 1 previous line of systemic therapy.1 The approval makes zanidatamab the first HER2-targeted therapy to receive conditional approval for HER2-positive BTC in the European Union (EU).

The regulatory decision was supported by data from the phase 2b HERIZON-BTC-01 trial (NCT04466891). Data from HERIZON-BTC-01 demonstrated that the confirmed overall response rate (ORR) per independent central review (ICR) in cohort 1 (n = 80) was 41.3% (95% CI, 30.4%-52.8%), including 2 patients who achieved a complete response, meeting the primary end point of the study.1,2 At a median follow-up of 22 months (range, 16-34), the median overall survival (OS) was 15.5 months (95% CI, 10.4-18.5) and the median duration of response (DOR) was 14.9 months (95% CI, 7.4-not reached).2 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.

"[Patients] with HER2-positive BTC who progress after first-line therapy face a challenging prognosis, with limited treatment options, poor tolerability, and median OS of only six to nine months," Arndt Vogel, MD, managing senior consultant and professor in the Department of Gastroenterology, Hepatology, and Endocrinology, as well as the head of the GI-Cancer Center and of the Center for Personalized Medicine at Hannover Medical School in Germany, stated in a news release.1 "Zanidatamab provides a much-needed targeted monotherapy for this population, and in the HERIZON-BTC-01 trial, it demonstrated clinically meaningful and durable responses with a manageable safety profile. These data represent a welcome advance for patients with historically poor outcomes and highlight the importance of HER2 testing in BTC to ensure eligible patients are identified for biomarker-driven treatment."

HERIZON-BTC-01 was a global, multicenter, single-arm study that enrolled adult patients with HER2-positive unresectable, locally advanced, or metastatic BTC who experienced disease progression following prior treatment with gemcitabine-based therapy.3 Eligible patients were not permitted to have received prior HER2-targeted therapies and needed to have an ECOG performance status of 0 or 1, as well as at least 1 measurable targeted lesion per RECIST 1.1 criteria.2 Cohort 1 included patients with a HER2 IHC of 2+ or 3+ and cohort 2 (n = 7) included those with a HER2 IHC of 0 or 1+.

All patients received intravenous zanidatamab at 20 mg/kg every 2 weeks of a 28-day cycle. Patients also received mandatory infusion-related reaction prophylaxis with corticosteroids, antihistamines, and acetaminophen.

The primary end point, which was assessed in cohort 1, was confirmed ORR per ICR. Secondary end points included OS, DOR, progression-free survival, disease control rate, and safety and tolerability.

Additional findings from HERIZON-BTC-01 revealed that the confirmed ORR was 51.6% among patients with a HER2 expression of 3+ by IHC (n = 62) was 51.6%; the confirmed ORR was 5.6% in patients with a HER2 expression of 2+ by IHC (n = 18). The median OS in the respective subgroups was 18.1 months (95% CI, 12.2-23.2) and 5.2 months (95% CI, 3.1-10.2). 2 The 6- and 12-month OS rates were higher in the 3+ subgroup compared with the 2+ group, at 90.1% (95% CI, 79.2%-95.4%) vs 41.7% (95% CI, 17.5%-64.4%), respectively, and 65.0% (95% CI, 51.6%-75.6%) vs 20.8% (95% CI, 5.1%-43.7%), respectively.

In terms of safety, any-grade treatment-emergent adverse effects occurred at a rate of 96.6% in the overall population; any-grade treatment-related adverse effects (TRAEs) were reported at a rate of 72.4%. Common any-grade TRAEs included diarrhea (36.8%), infusion-related reactions (33.3%), and decreased ejection fraction (10.3%). No deaths related to treatment with zanidatamab were reported.

In November 2024, zanidatamab received accelerated approval from the FDA in patients with previously treated, unresectable or metastatic HER2-positive (IHC 3+) BTC, as detected by an FDA-approved test.4 This approval was also supported by data from HERIZON-BTC-01.

The continued approval of zanidatamab for this patient population in the EU is contingent upon findings from the phase 3 HERIZON-BTC-302 trial (NCT06282575).1 HERIZON-BTC-302 is evaluating zanidatamab in combination with standard-of-care (SOC) therapy vs SOC treatments alone for the first-line treatment of patients with HER2-positive BTC. The EC approval extends to all EU member states, as well as Iceland, Norway, and Liechtenstein.

"This conditional approval represents significant progress for the patients we serve who have been diagnosed with advanced HER2-positive BTC," Robert Iannone, MD, MSCE, executive vice president, global head of research and development, and chief medical officer of Jazz Pharmaceuticals, added in the news release.1 "[Zanidatamab] is the first HER2-targeted therapy authorized in the EU specifically for this population, and the EC’s decision reflects both the strength of the HERIZON-BTC-01 data and the urgency for innovation in rare gastrointestinal cancers. This milestone reinforces our commitment to advancing biomarker-driven therapies that address serious unmet needs and improve patient outcomes. We are actively recruiting for our global phase 3 trial in first-line HER2-positive BTC and continue to explore zanidatamab's potential in other HER2-expressing tumors."

References

1. Jazz Pharmaceuticals receives European Commission marketing authorization for Ziihera (zanidatamab) for the treatment of advanced HER2-positive biliary tract cancer. News release. Jazz Pharmaceuticals. July 1, 2025. Accessed July 1, 2025. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-receives-european-commission-marketing
2. Pant S, Fan J, Oh DY, 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):4091. doi:10.1200/JCO.2024.42.16_suppl.4091
3. Harding JJ, Fan J, Oh DY, 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
4. FDA grants accelerated approval to zanidatamab-hrii for previously treated unresectable or metastatic HER2-positive biliary tract cancer. FDA. November 21, 2024. Accessed July 1, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zanidatamab-hrii-previously-treated-unresectable-or-metastatic-her2