The FDA has granted accelerated approval to zanidatamab-hrii (Ziihera) for adult patients with previously treated, unresectable or metastatic HER2-positive (immunohistochemistry 3+) biliary tract cancer, as detected by an FDA-approved test. This regulatory decision marks a significant advancement in the treatment landscape for this aggressive cancer.
The approval was supported by data from the phase 2b HERIZON-BTC-01 trial (NCT04466891), which demonstrated promising results. In the trial, patients treated with the bispecific antibody (n = 62) experienced an overall response rate (ORR) of 52% (95% CI, 39%-65%) and an estimated median duration of response of 14.9 months (95% CI, 7.4-not estimable).
Clinical Efficacy and Safety
Updated data presented at the 2024 ASCO Annual Meeting further highlighted the efficacy of zanidatamab. In the overall evaluable population enrolled in cohort 1 (n = 80), which included patients with HER2-positive IHC 3+ disease (n = 62) and IHC 2+ disease (n = 18), the confirmed ORR was 41.3%; the disease control rate was 68.8%. The confirmed ORRs were 51.6% and 5.6% in the IHC 3+ and IHC 2+ subgroups, respectively. At a median follow-up of 22 months (range, 16-34), the median DOR increased to 14.9 months (95% CI, 7.4-not reached).
The safety profile of zanidatamab was also evaluated. Among patients treated in cohorts 1 and 2 (n = 87), 96.6% experienced any-grade treatment-emergent adverse effects (TEAEs). Any-grade treatment-related AEs (TRAEs) occurred in 72.4% of patients at grades 1 or 2 (51.7%) or grade 3 or 4 (20.7%). No grade 5 TRAEs were reported. Serious TRAEs were observed in 9.2% of patients, and TRAEs led to treatment discontinuation in 2.3% of patients. The most common TRAEs included diarrhea (any-grade, 36.8%; grade 3/4, 4.6%) and infusion-related reaction (33.3%; 1.1%).
Addressing Unmet Needs in Biliary Tract Cancer
Biliary tract cancer is a devastating disease with a poor prognosis, characterized by 5-year survival rates under 5% in the metastatic setting. According to Rob Iannone, MD, MSCE, executive vice president, global head of research and development, and chief medical officer of Jazz Pharmaceuticals, "Patients with unresectable or metastatic HER2-positive biliary tract cancer have had a high unmet need with limited treatment options and few approved therapies. The approval of [zanidatamab] is an important advance and offers the first and only dual HER2-targeted bispecific antibody and chemotherapy-free treatment for patients living with biliary tract cancer."
Trial Design and Patient Population
HERIZON-BTC-01 enrolled patients at least 18 years of age with advanced or metastatic HER2-positive biliary tract cancer. Prior treatment with a gemcitabine-containing regimen was required; however, prior HER2-targeted therapies were not permitted. Other key inclusion criteria consisted of at least 1 measurable lesion per RECIST 1.1 criteria and an ECOG performance status of 0 or 1. Patients with HER2-positive IHC 3+ or 2+ disease were enrolled in cohort 1, and those with IHC 0 or 1+ disease were included in cohort 2 (n = 7). All patients received zanidatamab at 20 mg/kg once every 2 weeks in 28-day cycles. Infusion-related reaction prophylaxis was required.
Confirmed ORR per independent central review served as the trial's primary end point. Secondary end points included DOR, DCR, progression-free survival, overall survival (OS), and safety.
Future Directions
Under the accelerated approval pathway, the FDA may require verification and description of clinical benefit for zanidatamab in a confirmatory trial for continued approval in this indication. Jazz Pharmaceuticals plans to continue advancing research of zanidatamab in biliary tract cancer and other HER2-expressing solid tumors.
