CHMP Recommends EU Approval of Zanidatamab for HER2+ Advanced Biliary Tract Cancer

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The European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending the conditional approval of zanidatamab (Ziihera) for the treatment of adult patients with unresectable locally advanced or metastatic HER2-positive (immunohistochemistry [IHC] 3+) biliary tract cancer who have received at least 1 prior line of systemic therapy.1

The recommendation is supported by findings from the phase 2b HERIZON-BTC-01 trial (NCT04466891), which evaluated zanidatamab in previously treated patients with inoperable or advanced HER2-positive biliary tract cancer.

Among the 80 patients enrolled in cohort 1, findings at a median follow-up of 22 months (range, 16-34), zanidatamab produced a confirmed objective response rate (cORR) of 41.3%.2 The median duration of response was 14.9 months (95% CI, 7.4-not reached), and the median overall survival (OS) was 15.5 months (95% CI,10.4-18.5).

"This positive CHMP opinion is a welcome step for physicians and patients in Europe who face a critical unmet need in HER2-positive biliary tract cancers, a rare and aggressive group of cancers with poor prognosis and limited treatment options," Robert Iannone, MD, MSCE, executive vice president, global head of research and development, and chief medical officer of Jazz Pharmaceuticals, stated in a news release.1 "If approved, zanidatamab would be the first HER2-targeted therapy licensed for this difficult-to-treat cancer in the European Union, marking an important milestone in addressing this unmet need. We look forward to the European Commission's decision and the opportunity to provide a new treatment option for patients."

HERIZON-BTC-01 Trial Overview

The phase 2b trial is an ongoing, multicenter study evaluating the efficacy and safety of zanidatamab in patients with locally advanced, unresectable, or metastatic biliary tract cancer, including gallbladder cancer and intrahepatic or extrahepatic cholangiocarcinoma, who have previously received gemcitabine-containing therapy.2

Patients were stratified into two cohorts based on HER2 status by IHC: cohort 1 included patients with HER2-positive tumors (IHC 2+ or 3+), and cohort 2 included patients with HER2-low or HER2-negative tumors (IHC 0 or 1+). Zanidatamab was administered at a dose of 20 mg/kg intravenously every two weeks.

The primary end point of the trial was cORR in cohort 1. Key secondary end points included DoR, OS, and the frequency and severity of treatment-emergent adverse effects (TEAEs). Updated efficacy analyses focused exclusively on Cohort 1, while safety assessments incorporated data from both cohorts.

Across all 87 patients from cohorts 1 and 2, 18 patients (21%) experienced grade 3 or higher treatment-related AEs (TRAEs). The most frequently reported grade 3 TRAEs occurring in more than two patients included diarrhea (5%), anemia (3%), and decreased ejection fraction (3%). Only one patient experienced a grade 4 TRAE (increased aspartate aminotransferase level). No treatment-related deaths were reported.

Serious AEs occurred in 9% of patients, and treatment discontinuation due to AEs was infrequent, with two patients (2%) discontinuing therapy because of pneumonitis or decreased ejection fraction.

Zanidatamab has received multiple regulatory designations supporting its clinical development across HER2-expressing gastrointestinal malignancies.1 On November, 2020, the FDA granted breakthrough therapy designation for zanidatamab in patients with previously treated, HER2-amplified biliary tract cancer.

In November 2024, the FDA granted accelerated approval to zanidatamab-hrii for adult patients with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer, as detected by an FDA-approved test.3

Currently, the phase 3, multicenter, open-label, single-arm HERIZON-BTC-302 trial (NCT06282575) is underway to evaluate the efficacy of zanidatamab monotherapy as first-line treatment in patients with metastatic biliary tract cancer. The study is enrolling patients with HER2-amplified, inoperable, advanced, or metastatic disease, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer.

References

1. Jazz pharmaceuticals receives CHMP positive opinion for zanidatamab for the treatment of advanced HER2-positive biliary tract cancer. News Release. Jazz Pharmaceuticals. April 25, 2025. Accessed April 25, 2025. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-receives-chmp-positive-opinion-zanidatamab
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. doi10.1200/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. November 20, 2024. Accessed April 25, 2025. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-us-fda-approval-ziiherar