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)
JAZZ 11.21.2024
Ziihera is the first and only dual HER2-targeted bispecific antibody approved for HER2+ BTC in the
Ziihera received accelerated approval based on results including a 52% objective response rate and median duration of response of 14.9 months as determined by independent central review (ICR) from the HERIZON-BTC-01 clinical trial
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"BTC is a devastating disease with a poor prognosis and five-year survival rates under five percent in the metastatic setting. Patients with unresectable or metastatic HER2-positive BTC have had a high unmet need with limited treatment options and few approved therapies," said
The FDA approval ofZiiherais based on compelling data from the HERIZON-BTC-01 trial, which included the evaluation of zanidatamab as a single agent in previously treated HER2-positive (as determined by Roche Diagnostic's PATHWAY®anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody companion diagnostic) BTC and is the largest Phase 2b clinical trial to date specifically for this patient population. The trial achieved its primary endpoint of confirmed objective response rate (cORR) by independent central review (ICR) and results were presented at the
"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," said Dr. James Harding, associate attending, Gastrointestinal Oncology and Early Drug Development Services, at
"Metastatic biliary tract cancer, BTC, places a significant burden on patients, affecting their quality of life and their emotional and mental well-being, as well as that of their families," said
The efficacy ofZiiherawas evaluated in 62 patients with HER2-positive (IHC 3+ by central assessment) BTC in Cohort 1 of HERIZON-BTC-01, with major efficacy outcome measures of ORR and DOR as determined by ICR according to RECIST (Response Evaluation Criteria in Solid Tumors) v1.1.1The study demonstrated an ORR of 52% [95% confidence interval (CI): 39, 65)] with a
Boxed Warning for Embryo-fetal toxicity: Exposure toZiiheraduring pregnancy can cause embryo-fetal harm. Advise patients of the risk and need for effective contraception.1
The safety profile forZiiherahas been demonstrated in 80 patients in the HERIZON-BTC-01 trial. Serious adverse reactions occurred in 53% of patients who receivedZiihera. The most common adverse reactions in patients who receivedZiihera(≥ 20%) were diarrhea, infusion-related reaction, abdominal pain, and fatigue. Serious adverse reactions in > 2% of patients included biliary obstruction (15%), biliary tract infection (8%), sepsis (8%), pneumonia (5%), diarrhea (3.8%), gastric obstruction (3.8%), and fatigue (2.5%). A fatal adverse reaction of hepatic failure occurred in one patient who receivedZiihera. Permanent discontinuation due to an adverse reaction occurred in 2.5% of patients who receivedZiihera.1See additional safety information below and full prescribing informationhttps://pp.jazzpharma.com/pi/ziihera.en.USPI.pdf.
The confirmatory, global, randomized Phase 3 trial HERIZON-BTC-302 (NCT06282575) is ongoing and is evaluating zanidatamab in combination with standard-of-care therapy versus standard-of-care therapy alone in the first-line setting for patients with HER2-positive BTC. Continued approval forZiiheramay be contingent upon verification and description of clinical benefit in this confirmatory trial.
Zanidatamab is also being investigated in a number of additional tumor types, including Phase 3 trials in gastroesophageal adenocarcinomas (GEAs) and metastatic breast cancer (mBC). The HERIZON-GEA-01 trial evaluating the potential of zanidatamab plus chemotherapy with or without tislelizumab as first-line treatment for patients with advanced/metastatic HER2-positive GEAs. The EmpowHER-303 trial is evaluating the potential of zanidatamab in combination with physician's choice chemotherapy for the treatment of HER2-positive mBC for patients who have progressed on, or are intolerant to, previous trastuzumab deruxtecan treatment.
About the Phase 2b HERIZON-BTC-01 TrialThe Phase 2b HERIZON-BTC-01 trial of zanidatamab was an open-label, global Phase 2b study, which enrolled 87 patients with HER2-amplified, locally advanced unresectable or metastatic BTC (gallbladder cancer, intra-/extra-hepatic cholangiocarcinoma) into 2 cohorts and included 62 patients with HER2 IHC 3+ BTC. The trial evaluated zanidatamab (20 mg/kg IV every 2 weeks) in patients who had received prior gemcitabine-containing therapy. Patients with prior HER2-targeted therapy use were excluded from the trial. All patients were required to have HER2 status confirmed with tissue samples by a central lab. Patients (n=87) were assigned into two cohorts based on tumor IHC status: Cohort 1 (n=80) included patients who were IHC 2+/3+ (HER2-amplified) and Cohort 2 (n=7) included patients who were IHC 0/1+. Tumors were assessed every 8 weeks per RECIST v1.1. The primary endpoint was ORR by independent central review (ICR) in Cohort 1, with secondary endpoints including other efficacy and safety outcomes.
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More information aboutZiihera, the Full Prescribing Information, including Boxed Warning and Patient Information, is availablehere.
AboutZiihera®(zanidatamab-hrii)Ziihera(zanidatamab-hrii) is a bispecific HER2-directed antibody that binds to two extracellular sites on HER2. Binding of zanidatamab-hrii with HER2 results in internalization leading to a reduction of the receptor on the tumor cell surface. Zanidatamab-hrii induces complement-dependent cytotoxicity (
Zanidatamab is not approved anywhere else in the world.
Zanidatamab is being developed in multiple clinical trials as a targeted treatment option for patients with solid tumors that express HER2. Zanidatamab is being developed by Jazz and BeiGene, Ltd. (BeiGene) under license agreements from Zymeworks, which first developed the molecule.
The FDA granted Breakthrough Therapy designation for zanidatamab development in patients with previously treated HER2 gene-amplified BTC, and two Fast Track designations for zanidatamab: one as a single agent for refractory BTC and one in combination with standard-of-care chemotherapy for 1L gastroesophageal adenocarcinoma (GEA). Additionally, zanidatamab has received Orphan Drug designations from FDA for the treatment of BTC and GEA, as well as Orphan Drug designation from the European Medicines Agency for the treatment of BTC and gastric cancer.
Important Safety Information |
WARNING: EMBRYO-FETAL TOXICITYExposure to ZIIHERA during pregnancy can cause embryo-fetal harm. Advise patientsof the risk and need for effective contraception. |
WARNINGS AND PRECAUTIONS
Embryo-Fetal ToxicityZIIHERA can cause fetal harm when administered to a pregnant woman. In literature reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death.
Verify the pregnancy status of females of reproductive potential prior to the initiation of ZIIHERA. Advise pregnant women and females of reproductive potential that exposure to ZIIHERA during pregnancy or within 4 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment with ZIIHERA and for 4 months following the last dose of ZIIHERA.
Left Ventricular Dysfunction
ZIIHERA can cause decreases in left ventricular ejection fraction (LVEF). LVEF declined by >10% and decreased to <50% in 4.3% of 233 patients. Left ventricular dysfunction (LVD) leading to permanent discontinuation of ZIIHERA was reported in 0.9% of patients. The median time to first occurrence of LVD was 5.6 months (range: 1.6 to 18.7). LVD resolved in 70% of patients.
Assess LVEF prior to initiation of ZIIHERA and at regular intervals during treatment. Withhold dose or permanently discontinue ZIIHERA based on severity of adverse reactions.
The safety of ZIIHERA has not been established in patients with a baseline ejection fraction that is below 50%.
Infusion-Related ReactionsZIIHERA can cause infusion-related reactions (IRRs). An IRR was reported in 31% of 233 patients treated with ZIIHERA as a single agent in clinical studies, including Grade 3 (0.4%), and Grade 2 (25%). IRRs leading to permanent discontinuation of ZIIHERA were reported in 0.4% of patients. IRRs occurred on the first day of dosing in 28% of patients; 97% of IRRs resolved within one day.
Prior to each dose of ZIIHERA, administer premedications to prevent potential IRRs. Monitor patients for signs and symptoms of IRR during ZIIHERA administration and as clinically indicated after completion of infusion. Have medications and emergency equipment to treat IRRs available for immediate use.
If an IRR occurs, slow, or stop the infusion, and administer appropriate medical management. Monitor patients until complete resolution of signs and symptoms before resuming. Permanently discontinue ZIIHERA in patients with recurrent severe or life-threatening IRRs.
Diarrhea
ZIIHERA can cause severe diarrhea.
Diarrhea was reported in 48% of 233 patients treated in clinical studies, including Grade 3 (6%) and Grade 2 (17%). If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Withhold or permanently discontinue ZIIHERA based on severity.
ADVERSE REACTIONS
Serious adverse reactions occurred in 53% of 80 patients with unresectable or metastatic HER2-positive BTC who received ZIIHERA. Serious adverse reactions in >2% of patients included biliary obstruction (15%), biliary tract infection (8%), sepsis (8%), pneumonia (5%), diarrhea (3.8%), gastric obstruction (3.8%), and fatigue (2.5%). A fatal adverse reaction of hepatic failure occurred in one patient who received ZIIHERA.
The most common adverse reactions in 80 patients with unresectable or metastatic HER2-positive BTC who received ZIIHERA (≥20%) were diarrhea (50%), infusion-related reaction (35%), abdominal pain (29%), and fatigue (24%).
USE IN SPECIFIC POPULATIONS
Pediatric Use
Safety and efficacy of ZIIHERA have not been established in pediatric patients.
Geriatric Use
Of the 80 patients who received ZIIHERA for unresectable or metastatic HER2-positive BTC, there were 39 (49%) patients 65 years of age and older. Thirty-seven (46%) were aged 65-74 years old and 2 (3%) were aged 75 years or older.
No overall differences in safety or efficacy were observed between these patients and younger adult patients.
About Biliary Tract CancerBTC, including gallbladder cancer and intrahepatic and extrahepatic cholangiocarcinoma, account for <1% of all adult cancers globally and are often associated with a poor prognosis.2,3The human epidermal growth factor receptor 2 (HER2) is a well-validated target for antitumor therapy in other cancers. Across the
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Jazz Pharmaceuticals plc Caution Concerning Forward-Looking Statements
This press release contains forward-looking statements, including, but not limited to, statements related to the potential to transform the current treatment paradigm for BTC, our goal of delivering a potential chemotherapy-free option to more patients living with other HER2-expressing solid tumors, the planned date for commercial availability in the
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1ZIIHERA (zanidatamab-hrii) Prescribing Information.
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