FDA approves Ziihera for advanced HER2-positive biliary tract cancer
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The FDA granted accelerated approval to zanidatamab-hrii for treatment of adults with previously treated unresectable or metastatic HER2-positive biliary tract cancer.
Zanidatamab-hrii (Ziihera, Jazz Pharmaceuticals) is a HER2-targeted bispecific antibody administered via IV.
Biliary tract cancer is a heterogenous group of malignancies that includes gallbladder cancer, extrahepatic cholangiocarcinoma and intrahepatic cholangiocarcinoma.
Patients with locally advanced or metastatic biliary tract cancer who experience disease progression after first-line treatment typically derive limited clinical benefit from subsequent therapies. Five-year survival for people with metastatic disease is less than 5%.
HER2 overexpression or gene amplification rates range from 4% to 5% for intrahepatic cholangiocarcinoma, 17% to 19% for extrahepatic cholangiocarcinoma, and 19% to 31% for gallbladder cancer.
The FDA based approval on results of the phase 2B HERIZON-BCT-01 trial, which assessed zanidatamab monotherapy — dosed at 20 mg/kg via IV every 2 weeks — for patients with HER2-amplified, locally advanced unresectable or metastatic biliary tract cancer.
The study included 87 participants (median age, 64 years; 54% women; 66% Asian). Half (51.7%) had gallbladder cancer, 29.9% had intrahepatic cholangiocarcinoma and 18.4% had extrahepatic cholangiocarcinoma.
All patients had received gemcitabine-containing therapy, and they had received a median one (interquartile range, 1-2) prior line of therapy for locally advanced or metastatic disease. Protocol excluded patients who received prior HER2-targeted therapies.
Researchers assigned patients to one of two cohorts based on immunohistochemistry (IHC) status.
Cohort 1 included 80 patients with HER2-positive disease, defined as IHC2+/3+ status. Cohort 2 included seven patients with IHC0/1+ status.
Objective response rate per independent central review in cohort 1 served as the primary endpoint. Secondary outcomes included duration of response, PFS, disease control rate, OS and safety/tolerability.
Among 62 patients with IHC3+ status per central assessment, results showed an ORR of 52% (95% CI, 39-65) and an estimated median response duration of 14.9 months (95% CI, 7.4 to not estimable).
"As a clinical investigator and medical oncologist focused on advancing the care of patients with biliary tract and liver cancers, I have experienced firsthand the significant unmet need for effective therapies for patients with these diseases," James J. Harding, MD, associate attending physician at Memorial Sloan Kettering Cancer Center, said in a Jazz Pharmaceuticals press release. "Zanidatamab has demonstrated antitumor activity and is now a new option for patients with HER2-positive biliary tract cancer. I look forward to continued and successful drug development for patients with biliary tract cancer."
Safety analyses that included both cohorts showed 96.6% experienced any treatment-emergent adverse event and 72.4% experienced treatment-related adverse events, the most common of which were diarrhea (36.8%), infusion-related reaction (33.3%), ejection fraction decrease (10.3%) and nausea (9.2%).
Eighteen patients (20.7%) experienced grade 3/grade 4 treatment-related adverse events, the most common of which were diarrhea (4.6%), ejection fraction decrease (3.4%), anemia (3.4%), anemia (3.4%) and increased aspartate aminotransferase (2.3%).
Five patients (5.7%) experienced confirmed cardiac events; three were grade 3/grade 4. One patient (1.1%) developed a grade 3/grade 4 non-infectious pulmonary toxicity.
No treatment-related deaths occurred. Two patients (2.3%) discontinued therapy due to treatment-related adverse events.
The prescribing information includes a boxed warning for embryo-fetal toxicity.
Continued approval of zanidatamab may be contingent on verification of the therapy in this setting through a confirmatory trial.
A randomized phase 3 trial — HERIZON-BTC-302 — is underway to evaluate zanidatamab in combination with standard therapy for first-line treatment of HER2-positive biliary tract cancer.
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