Zanidatamab Receives EU Conditional Marketing Authorization in HER2+ BTC

Zanidatamab-hrii (Ziihera) has received conditional marketing authorization from the European Commission (EC) as a monotherapy in adult patients with unresectable locally advanced or metastatic HER2-positive biliary tract cancer (BTC), according to a news release from the drug’s developer, Jazz Pharmaceuticals plc.¹

The EC decision is supported by results from the phase 2b HERIZON-BTC-01 trial (NCT04466891), which assessed the monotherapy in patients with previously treated, unresectable, locally advanced or metastatic HER2-positive BTC, the largest phase 2b trial conducted to date for this population. Zanidatamab showed a confirmed objective response rate (ORR) by independent committee review (ICR) of 41.3% (95% CI, 30.4%-52.8%), including 2 complete responses, among patients with centrally confirmed HER2-positive tumors in cohort 1 (n = 80) after a median follow-up of 21.9 months.

Additional efficacy data revealed that the median duration of response (DOR) was 14.9 months in cohort 1 (95% CI, 7.4-not reached [NR]), and the median overall survival (OS) was 15.5 months (95% CI, 10.4-18.5). Prespecified subgroup analysis data revealed that among patients with immunohistochemistry (IHC) 3+ tumors (n = 62), zanidatamab elicited a confirmed ORR of 51.6% (95% CI, 38.6%-64.5%), a median DOR of 14.9 months (95% CI, 7.4-24.0), and a median OS of 18.1 months (95% CI, 12.2-22.9).

Continued approval is contingent upon the verification and description of clinical benefit in the ongoing phase 3 HERIZON-BTC-302 trial (NCT06282575), which is evaluating the agent in combination with standard-of-care (SOC) therapy vs SOC therapy alone in patients with first-line HER2-positive BTC.

“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, said in the news release on the EC decision.¹ “[Zanidatamab] is the first HER2-targeted therapy authorized in the European Union specifically for this population, and the [EC] decision reflects both the strength of the HERIZON-BTC-01 data and the urgency for innovation in rare gastrointestinal cancers….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.”

Those with advanced, unresectable, or metastatic HER2-positive BTC (n = 87) were assigned into 2 cohorts: the first included those with IHC 2+ or 3+ disease (n = 80), and the second included those with IHC 0 or 1+ disease (n = 7).² Patients in both cohorts received 20 mg/kg of intravenous zanidatamab every 2 weeks with infusion-related reaction prophylaxis on days 1 and 15 of 28-day cycles.

Patients eligible for enrollment were 18 years and older, received prior gemcitabine, had at least 1 measurable lesion per RECIST v1.1 criteria, had an ECOG performance score of 0 to 1, and were naïve to HER2-targeted therapies.

The primary end point of the trial was confirmed ORR per ICR in cohort 1. Secondary end points encompassed DOR, disease control rate, progression-free survival, OS, and safety.

The most common any-grade adverse effects (AEs) included diarrhea (46%), infusion-related reactions (33.3%), abdominal pain (26.4%), anemia (25.3%), and fatigue (24.1%). Serious AEs occurred in 16.1% of patients, the most frequent of which included diarrhea (2.3%), fatigue (2.3%), and alanine aminotransferase increase (2.3%).

Zanidatamab received FDA approval as a treatment for patients with previously treated, unresectable, or metastatic HER2-positive BTC in November 2024.³ Additionally, the monotherapy was recommended for conditional marketing approval by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency in April 2025.⁴

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 plc. July 1, 2025. Accessed July 1, 2025. https://tinyurl.com/yfdw7ex5
2. 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):4091. doi:10.1200/JCO.2024.42.16_suppl.4091
3. Jazz Pharmaceuticals announces U.S. FDA approval of Ziihera® (zanidatamab-hrii) for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC). News release. Jazz Pharmaceuticals plc. November 20, 2024. Accessed July 1, 2025. https://shorturl.at/k6u8A
4. Jazz Pharmaceuticals receives CHMP positive opinion for zanidatamab for the treatment of advanced HER2-positive biliary tract cancer. News release. Jazz Pharmaceuticals plc. April 25, 2025. Accessed July 1, 2025. https://tinyurl.com/235t87us