Ziihera

Ziihera (zanidatamab-hrii) is a targeted treatment used for HER2-positive gastroesophageal adenocarcinoma (GEA) and biliary tract cancer (BTC) in certain adults. Ziihera is a bispecific HER2-directed antibody, which means it binds to two different places on the HER2 protein found on some cancer cells.

Ziihera is a targeted antibody treatment rather than chemotherapy, although it is often given together with chemotherapy.

Ziihera (zanidatamab-hrii) is given as an intravenous infusion every 2 to 3 weeks.

Ziihera is approved to treat two types of cancer in adults.

Gastroesophageal adenocarcinoma (GEA)

Ziihera is used to treat GEA, which includes stomach cancer (gastric cancer), cancer of the food pipe (esophageal cancer) and cancer where the two meet (gastroesophageal junction, or GEJ, cancer). Ziihera is used as the first treatment when the cancer cannot be removed by surgery (unresectable) or has spread to other parts of the body (metastatic), in one of two ways:

• with fluoropyrimidine-containing and platinum-containing chemotherapy plus tislelizumab-jsgr, when the tumor is HER2-positive at IHC 3+ or IHC 2+/ISH+
• with fluoropyrimidine-containing and platinum-containing chemotherapy alone, when the tumor is HER2-positive at IHC 3+

Biliary tract cancer (BTC)

Ziihera is used to treat biliary tract cancer, which includes cancer of the bile duct (cholangiocarcinoma) and cancer of the gallbladder. Ziihera is used on its own when the cancer cannot be removed by surgery or has spread, has already been treated with another therapy, and is HER2-positive at IHC 3+.

The biliary tract cancer use was approved under accelerated approval based on how many people responded to treatment (overall response rate) and how long those responses lasted (duration of response). Continued approval for this use may depend on further trials confirming the benefit.

HER2 status must be confirmed with an FDA-authorized test for both uses.

Ziihera's mechanism of action is binding to two extracellular sites on HER2. This binding leads to a reduction of the receptor on the tumor cell surface and induces complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis. In laboratory and animal studies, these mechanisms resulted in tumor growth inhibition and tumor cell death.

Ziihera has a Boxed Warning for severe diarrhea and for harm to an unborn baby. A boxed warning is the most serious warning by the FDA.

Severe diarrhea

When Ziihera is given with fluoropyrimidine-containing and platinum-containing chemotherapy, with or without tislelizumab-jsgr, it can cause diarrhea that is severe, life-threatening, or fatal. Diarrhea can also cause you to lose fluids and body salts (electrolytes).

To lower this risk, your healthcare provider will start you on preventive antidiarrheal medicine (loperamide) during the first cycle of treatment and will tell you to drink more fluids. Tell your healthcare provider right away if you get new or worsening diarrhea, and take your antidiarrheal medicine as prescribed. Your provider may pause your treatment, lower your dose or stop Ziihera permanently depending on how severe the diarrhea is.

Harm to an unborn baby

Receiving Ziihera during pregnancy, or within 4 months before becoming pregnant, can harm an unborn baby (embryo-fetal toxicity). If you can become pregnant, your healthcare provider will do a pregnancy test before you start treatment, and you should use effective birth control during treatment and for 4 months after your last dose. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment.

The prescribing information lists no contraindications for Ziihera. Before you start treatment, tell your healthcare provider about all of your medical conditions, including if you:

• have or have had any heart problems
• are pregnant, think you may be pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.

The serious side effects of Ziihera are severe diarrhea, harm to an unborn baby, heart problems (left ventricular dysfunction) and infusion-related reactions. Severe diarrhea and harm to an unborn baby are the subject of Ziihera's Boxed Warning, the most serious warning the FDA requires.

Ziihera can cause four serious side effects:

• Severe diarrhea, which can be life threatening or fatal when Ziihera is given with chemotherapy
• Harm to an unborn baby during pregnancy or within 4 months before conceiving
• Heart problems, seen as a drop in how well the heart pumps blood
• Infusion-related reactions during or after an infusion

Tell your healthcare provider right away if you get new or worsening diarrhea, or if you become pregnant or think you may be pregnant during treatment with Ziihera.

How does Ziihera affect the heart?

Ziihera can weaken how well the heart pumps blood, measured as a drop in left ventricular ejection fraction (LVEF). A drop in ejection fraction was reported in 9% of people who received Ziihera with chemotherapy and tislelizumab-jsgr, 5% of people who received Ziihera with chemotherapy, and 4.3% of people who received Ziihera on its own. It resolved in 70% to 78% of those affected, depending on the regimen.

Your healthcare provider will check your heart function before you start Ziihera and at regular intervals during treatment, and may pause or permanently stop treatment depending on the results. Ziihera has not been studied in people whose ejection fraction is below 50% before treatment.

Tell your healthcare provider right away if you have:

• new or worsening shortness of breath
• feeling more tired than usual
• swelling of your ankles or feet
• irregular heartbeat
• sudden weight gain
• dizziness or feeling light-headed
• loss of consciousness

What are the symptoms of an infusion reaction with Ziihera?

Infusion-related reactions were reported in 22% to 31% of people receiving Ziihera, despite the use of preventive medicines. Most reactions were mild or moderate, and the majority resolved within the first day. Reactions can happen during or after an infusion.

Your care team will watch you during the infusion and may slow it down, pause it or stop it depending on how severe the reaction is. Tell your healthcare provider right away if you have:

• shortness of breath or trouble breathing
• fever or chills
• rash
• flushing
• nausea or vomiting
• dizziness or feeling light-headed
• chest discomfort

The most common side effects of Ziihera are diarrhea, nausea, vomiting, decreased appetite, fatigue, low potassium, rash, numbness or tingling in the hands or feet, and infusion-related reactions. Diarrhea is the most common, affecting 79% to 83% of people when Ziihera is given with chemotherapy and 50% of people when Ziihera is given on its own.

The side effects below were reported in 20% or more of people in clinical trials.

Side effects of Ziihera with chemotherapy and tislelizumab-jsgr

* Grade 3 or 4 rates are not reported separately for this side effect in the prescribing information.

Side effects of Ziihera with chemotherapy

* Grade 3 or 4 rates are not reported separately for this side effect in the prescribing information.

Side effects of Ziihera used on its own for biliary tract cancer

Common changes in blood test results included lower hemoglobin, lower potassium, lower calcium, lower magnesium, lower sodium, and increases in liver enzymes and creatinine.

These are not all of the possible side effects of Ziihera. Tell your healthcare provider about any side effect that bothers you or does not go away. You may report side effects to the FDA at 1-800-FDA-1088.

Ziihera is given by a healthcare provider as an infusion into a vein, every 2 or 3 weeks depending on your cancer type and dose schedule.

• Your first infusion is given over 120 minutes.
• If the first infusion goes well, your second is given over 90 minutes.
• Later infusions may be given over 60 minutes if earlier ones were well tolerated.

You will be given medicines 30 to 60 minutes before each dose to help prevent infusion-related reactions or make them less severe. These premedications are acetaminophen, an antihistamine such as diphenhydramine, and a corticosteroid such as hydrocortisone.

If you are being treated for gastroesophageal adenocarcinoma, you will also be given loperamide 4 mg twice daily starting on Day 1 and continuing for at least 7 days during the first cycle, to help prevent diarrhea. If you have any diarrhea during that first cycle, this preventive treatment continues for at least the first 7 days of each later cycle.

When Ziihera is part of a combination regimen for gastroesophageal adenocarcinoma, it is given first, followed by tislelizumab-jsgr if it is part of your regimen, then chemotherapy. If your regimen includes fluorouracil, it is given as an infusion and not as a rapid injection (bolus), because a bolus may increase diarrhea.

The dose depends on which cancer is being treated. For gastroesophageal adenocarcinoma, the dose is based on body weight bands, and for biliary tract cancer it is calculated per kilogram of body weight.

Treatment continues until the cancer progresses or the side effects become unacceptable. If side effects occur, your healthcare provider may reduce your dose. Ziihera is stopped permanently in people who cannot tolerate the first dose reduction.

Call your healthcare provider as soon as possible to reschedule your appointment. Your provider will decide when to give the missed dose.

If you are receiving Ziihera with chemotherapy, with or without tislelizumab-jsgr, a missed dose is given as soon as possible when 7 days or fewer have passed since it was scheduled. If more than 7 days have passed, the dose is skipped and treatment restarts on day 1 of the next cycle. If you are receiving Ziihera on its own, the dose is given as soon as possible rather than waiting for the next planned dose, and the schedule is adjusted to keep a 2-week gap between doses.

Ziihera is not recommended during pregnancy. Based on how it works, Ziihera can harm an unborn baby. There are no human or animal studies of Ziihera in pregnancy, but reports of another HER2-directed antibody used during pregnancy describe low amniotic fluid (oligohydramnios), which led to underdeveloped lungs, bone problems and newborn death in some cases.

If you can become pregnant, your healthcare provider will confirm you are not pregnant before your first dose. Use effective birth control during treatment and for 4 months after your last dose. If you receive Ziihera during pregnancy or within 4 months before conceiving, your provider will monitor you for low amniotic fluid.

It is not known whether zanidatamab-hrii passes into breast milk or how it might affect a breastfed child or milk supply. Talk with your healthcare provider about the best way to feed your baby. This discussion should take into account that Ziihera stays in the body for some time, with a half-life of about 24 days and a washout period of 4 months.

It is not known if Ziihera is safe and effective in children. Safety and effectiveness have not been established in patients under 18 years of age.

Yes, in one regimen. When Ziihera was given with chemotherapy and tislelizumab-jsgr, people aged 65 and older had more severe side effects overall (87%) than younger adults (80%), and more severe diarrhea (32% compared with 20%). Fatal side effects were also more common in this age group (4.4% compared with 0.6%).

When Ziihera was given with chemotherapy without tislelizumab-jsgr, or on its own for biliary tract cancer, no overall differences in safety were seen between older and younger adults.

Gastroesophageal adenocarcinoma

Ziihera was studied in HERIZON-GEA-01, an open-label trial in 914 adults with previously untreated, unresectable or metastatic HER2-positive gastroesophageal adenocarcinoma. Participants were randomly assigned to Ziihera with chemotherapy and tislelizumab-jsgr, Ziihera with chemotherapy, or trastuzumab with chemotherapy.

Compared with trastuzumab plus chemotherapy, Ziihera plus chemotherapy and tislelizumab-jsgr extended how long people lived and how long they lived without their cancer growing.

In people whose tumors were HER2 IHC 3+, Ziihera with chemotherapy alone also improved progression-free survival, with a median of 14.2 months compared with 7.6 months for trastuzumab with chemotherapy. Overall survival data for this comparison were not yet mature at the time of analysis. The benefit seen with Ziihera plus chemotherapy alone was driven mainly by the IHC 3+ group, and this combination is approved only for that group.

Biliary tract cancer

Ziihera was studied in Cohort 1 of HERIZON-BTC-01, a single-arm trial in 62 adults with unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer who had already received at least one gemcitabine-based chemotherapy regimen.

Ziihera vials are stored by your healthcare provider in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton until they are prepared for use. The vials must not be frozen.

Ziihera is distributed by Jazz Pharmaceuticals, Inc., Palo Alto, CA 94306, and manufactured by Jazz Pharmaceuticals Ireland Limited, Dublin, Ireland. For more information, visit www.ZIIHERA.com or call 1-800-520-5568.

Active ingredient: zanidatamab-hrii

Inactive ingredients: polysorbate 20, sodium succinate, succinic acid and sucrose

Ziihera is supplied as a sterile, preservative-free, white powder in a single-dose vial containing 300 mg of zanidatamab-hrii. Each carton contains 2 single-dose vials.