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 brings a new treatment option to patients facing this challenging disease.
The approval was primarily supported by data from the phase 2b HERIZON-BTC-01 trial (NCT04466891). The study evaluated the efficacy and safety of zanidatamab in patients with HER2-positive biliary tract cancer who had received prior gemcitabine-based chemotherapy. 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 Outcomes
Updated data presented at the 2024 ASCO Annual Meeting further highlighted the clinical benefits 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).
Additional updated data showed that the median OS was 15.5 months (95% CI, 10.4-18.5) in the overall population in cohort 1, 18.1 months (95% CI, 12.2-23.2) in patients with HER2-positive IHC 3+ disease, and 5.2 months (95% CI, 3.1-10.2) in those with IHC 2+ disease. The 12-month OS rates were 56.2% (95% CI, 44.3%-66.5%), 65.0% (95% CI, 51.6%-75.6%), and 20.8% (95% CI, 5.1%-43.7%), respectively.
Study 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.
Safety Profile
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%), infusion-related reaction (33.3%; 1 .1%), decreased ejection fraction (10.3%; 3.4%), nausea (9.2%; 1.1%), increased alanine aminotransferase levels (6.9%; 1.1%), increased aspartate aminotransferase levels (6.9%; 2.3%), vomiting (6.9%; 0%), fatigue (5.7%; 0%), and anemia (4.6%; 3.4%).
Addressing Unmet Needs
"Biliary tract cancer is a devastating disease with a poor prognosis and 5-year survival rates under 5% in the metastatic setting. Patients with unresectable or metastatic HER2-positive biliary tract cancer have had a high unmet need with limited treatment options and few approved therapies," said Rob Iannone, MD, MSCE, executive vice president, global head of research and development, and chief medical officer of Jazz Pharmaceuticals. "The approval of [zanidatamab], which previously received breakthrough therapy designation from the FDA for this indication, 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."
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.
