Zanidatamab

ZIIHERA is a bispecific HER2-directed antibody indicated for: Gastroesophageal Adenocarcinoma (GEA) • in combination with fluoropyrimidine- and platinum-containing chemotherapy, and tislelizumab-jsgr, as first-line treatment of adult patients with HER2-positive (IHC 3+ or IHC 2+/ISH+) unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma, as detected by an FDA-authorized test. • in combination with fluoropyrimidine- and platinum-containing chemotherapy, as first-line treatment of adult patients with HER2-positive (IHC 3+) unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma, as detected by an FDA-authorized test.

Zanidatamab-hrii is a bispecific HER2-directed antibody that binds to extracellular domains 2 (ECD2) and 4 (ECD4) on HER2. Similar to other HER2-directed antibodies, in vitro binding of zanidatamab-hrii with HER2 causes clustering and results in internalization leading to a reduction of the receptor on the tumor cell surface. Zanidatamab-hrii induces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). These mechanisms result in tumor growth inhibition and cell death in vitro and in vivo.

• Premedicate all patients to reduce the risk of infusion-related reactions (IRRs). • Administer loperamide during the first cycle to patients receiving ZIIHERA in combination with fluoropyrimidine- and platinum-containing chemotherapy for diarrhea prophylaxis. Gastroesophageal Adenocarcinoma (GEA): • Patients weighing less than 70 kg: ZIIHERA 1,800 mg intravenously every 3 weeks or 1,200 mg every 2 weeks infusion in combination with fluoropyrimidine- and platinum-containing chemotherapy, with or without tislelizumab-jsgr. • Patients weighing 70 kg or greater: ZIIHERA 2,400 mg intravenously every 3 weeks or 1,600 mg every 2 weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy, with or without tislelizumab-jsgr. Biliary Tract Cancer: ZIIHERA 20 mg/kg intravenously every 2 weeks.

None. • None.

Boxed warning (diarrhea and embryo-fetal toxicity ziihera): in combination with fluoropyrimidine- and platinum-containing chemotherapy, with or without tislelizumab-jsgr, can cause severe diarrhea, including life threatening and fatal cases. Use antidiarrheal prophylaxis during the first cycle when ZIIHERA is given in combination with these drugs. Manage with antidiarrheals and supportive measures as clinically indicated. • Left Ventricular Dysfunction: Assess left ventricular ejection fraction (LVEF) prior to initiation of ZIIHERA and at regular intervals during treatment. Withhold or permanently discontinue ZIIHERA based on severity. • Infusion-Related Reactions (IRRs): Premedicate before each infusion of ZIIHERA. Interrupt the infusion, decrease the infusion rate, and/or permanently discontinue ZIIHERA based on severity.

The following clinically significant adverse reactions are described in greater detail in other sections of the labeling: • Diarrhea • Embryo-Fetal Toxicity • Left Ventricular Dysfunction • Infusion-Related Reactions • Most common adverse reactions (≥ 20%) with ZIIHERA in combination with chemotherapy and tislelizumab-jsgr were diarrhea, nausea, decreased appetite, vomiting, hypokalemia, fatigue, rash, peripheral neuropathy, and IRR. • Most common adverse reactions (≥ 20%) with ZIIHERA in combination with chemotherapy were diarrhea, nausea, vomiting, decreased appetite, fatigue, hypokalemia, peripheral neuropathy, IRR, and rash. • Most common adverse reactions (≥ 20%) with ZIIHERA as a single agent were diarrhea, IRR, abdominal pain, and fatigue.

Do not freeze. Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton until time of reconstitution.