2.1 Patient Selection

Select patients for treatment of unresectable or metastatic biliary tract cancer based on HER2-positive (IHC 3+) tumor specimens, as detected by an FDA-approved test [see Clinical Studies (14)].

Information on FDA-approved tests for HER2 protein expression in biliary tract cancers is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 Premedications

Premedicate all patients 30 to 60 minutes prior to each dose of ZIIHERA to reduce the risk of infusion-related reactions [see Warnings and Precautions (5.3)]:

•

Administer acetaminophen, an antihistamine (such as diphenhydramine) and a corticosteroid (such as hydrocortisone).

2.3 Recommended Dosage

Recommended Dosage and Administration

The recommended dosage of ZIIHERA is 20 mg/kg, administered as an intravenous infusion once every 2 weeks until disease progression or unacceptable toxicity.

Missed dose

If a planned dose of ZIIHERA is delayed or missed, administer the dose as soon as possible; do not wait until the next planned dose. Adjust the administration schedule to maintain a 2-week interval between doses.

2.4 Dosage Modifications for Adverse Reactions

•

The recommended dosage reduction of ZIIHERA for adverse reactions is 15 mg/kg as described in Table 1.

•

Permanently discontinue ZIIHERA in patients who cannot tolerate 15 mg/kg.

2.5 Preparation and Administration Instructions

Administer only as an intravenous infusion after ZIIHERA is reconstituted and diluted.

Reconstitution

•

Calculate the recommended dose based on the patient’s weight to determine the number of vials needed.

•

Remove the vial(s) from the refrigerator and allow the vial(s) to reach room temperature.

•

Reconstitute each 300 mg vial of ZIIHERA with 5.7 mL of Sterile Water for Injection by slowly directing the stream toward the inside of the wall of the vial, to obtain a final concentration of 50 mg/mL in an extractable volume of 6 mL.

•

Swirl the vial gently until completely dissolved. Do not shake or vigorously swirl.

•

Allow the reconstituted vial to settle to allow bubbles to dissipate.

•

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted product should be a colorless to light yellow, clear to slightly opalescent solution with no visible particles. Discard the reconstituted vial if any discoloration or particulate matter is observed.

•

The product does not contain a preservative. Use the reconstituted ZIIHERA solution immediately or store the reconstituted ZIIHERA solution for up to 4 hours, either at room temperature (18°C to 24°C [64°F to 75°F]) or in a refrigerator (2°C to 8ºC [36°F to 46ºF]).

Dilution

•

Withdraw the necessary volume for the calculated dose from each vial [see Dosage and Administration (2.3)].

•

Slowly add the necessary dose volume to an infusion bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection to prepare an infusion solution with a final concentration of the diluted solution between 0.4 mg/mL and 6 mg/mL.

•

Gently invert the infusion bag to mix. Do not shake.

•

The infusion solution must be a clear, colorless solution with no visible particles. Do not use if visible particles are observed or if the solution is discolored.

•

Discard any unused portion left in the vial(s).

•

Use the infusion solution immediately upon dilution or store the infusion solution at room temperature (18°C to 24°C [64°F to 75°F]) for up to 12 hours or in the refrigerator (2ºC to 8ºC [36ºF to 46ºF]) for up to 24 hours.

o

These time limits include the beginning of reconstitution through the duration of infusion.

o

If these specified times are exceeded, discontinue the current infusion bag and prepare a new bag which contains the remaining dosage of ZIIHERA to be infused.

•

Compatibility with intravenous administration materials and the infusion solution has been demonstrated in the following materials:

o

Intravenous (IV) Bag: Polyvinyl chloride (PVC), polyolefin (PO), ethyl vinyl acetate (EVA), polypropylene (PP) and ethylene-propylene copolymer.

o

Infusion sets: Polyvinyl chloride/ bis (2-ethylhexyl) phthalate (PVC/DEHP). Polyurethane (PUR), polyethylene-lined (PE-lined) acrylonitrile-butadiene-styrene (ABS).

o

Inline filters: Polyethersulfone solution filter (PES), polyvinylidene fluoride air filter (PVDF).

o

Closed System Transfer devices: acrylonitrile-butadiene-styrene (ABS), acrylic c-polymer, polycarbonate (PC), polyisoprene (PI), polyester, polypropylene (PP) polytetrafluoroethylene (PTFE), silicone and stainless steel (SS).

Administration

•

Administer ZIIHERA as an intravenous infusion with a 0.2 or 0.22 micron filter.

•

Do not administer as an intravenous push or bolus.

•

Do not co-administer ZIIHERA and other intravenous drugs through the same intravenous line.

5.1 Embryo-Fetal Toxicity

Based on the mechanism of action, ZIIHERA can cause fetal harm when administered to a pregnant woman. There are no human or animal data on the use of ZIIHERA in pregnancy. 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 while receiving ZIIHERA and for 4 months following the last dose of ZIIHERA.

5.2 Left Ventricular Dysfunction

ZIIHERA can cause decreases in left ventricular ejection fraction (LVEF). LVEF declined by greater than 10% and decreased to less than 50% in 4.3% of 233 patients. LVD leading to permanent discontinuation of ZIIHERA was reported in 0.9% of patients. The median time to first occurrence of left ventricular dysfunction was 5.6 months (range: 1.6 to 18.7 months). Left ventricular dysfunction 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 [see Dosage and Administration (2.4)].

The safety of ZIIHERA has not been established in patients with a baseline ejection fraction that is below 50% [see Dosage and Administration (2.4)].

5.3 Infusion-Related Reactions

ZIIHERA 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 [see Dosage and Administration (2.2)]. 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 infusion-related reactions [see Dosage and Administration (2.4)].

5.4 Diarrhea

ZIIHERA can cause severe diarrhea [see Adverse Reactions (6.1)].

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 [see Dosage and Administration (2.4)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population of ZIIHERA described in WARNINGS AND PRECAUTIONS reflect exposure in 233 patients administered ZIIHERA 20 mg/kg intravenously as a single agent in two single-arm, open-label studies (ZWI‑ZW25‑101 and HERIZON‑BTC‑01), which enrolled 109 patients with biliary tract cancer, and 124 patients with other cancers. Among 233 patients who received ZIIHERA, 39% were exposed for 6 months or longer, and 17% were exposed for greater than one year.

Biliary Tract Cancer

The safety of ZIIHERA was evaluated in 80 patients with previously treated, unresectable or metastatic HER2-positive biliary tract cancer who received at least one prior gemcitabine-containing chemotherapy regimen in HERIZON‑BTC‑01 [See Clinical Studies (14)]. Patients received ZIIHERA 20 mg/kg by IV infusion once every 2 weeks until disease progression or unacceptable toxicity. The median duration of exposure to ZIIHERA was 5.6 months (range: 0.5 to 27.2 months).

Serious adverse reactions occurred in 53% of patients 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.

Permanent discontinuation due to an adverse reaction occurred in 2.5% of patients who received ZIIHERA. Adverse reactions which resulted in permanent discontinuation in ≥ 1% of patients who received ZIIHERA included decreased ejection fraction and pneumonitis.

Dosage interruptions due to an adverse reaction, excluding temporary interruptions of ZIIHERA infusions due to infusion-related reactions, occurred in 41% of patients who received ZIIHERA. The most frequent adverse reactions (> 2% of patients) that required dosage interruption were diarrhea, increased alanine aminotransferase, increased aspartate aminotransferase, decreased ejection fraction, pneumonia, cholangitis, fatigue, biliary obstruction, abdominal pain, increased blood creatinine, and decreased potassium.

Dosage reductions due to an adverse reaction occurred in 4% of patients who received ZIIHERA. Adverse reactions requiring dosage reductions in > 1% of patients were diarrhea, nausea, and decreased weight.

The most common adverse reactions in patients receiving ZIIHERA (≥ 20%) were diarrhea, infusion-related reaction, abdominal pain, and fatigue.

Table 3 summarizes the adverse reactions that occurred in HERIZON‑BTC‑01.

* Graded per CTCAE version 5.

a Diarrhea includes diarrhea and enteritis

b Abdominal pain includes abdominal pain and abdominal pain upper

c Fatigue includes asthenia and fatigue

d Rash includes dermatitis, dermatitis acneiform, palmar-plantar erythrodysaesthesia syndrome, rash, rash maculo-papular, and rash pustular

Table 4 summarizes the laboratory abnormalities in HERIZON‑BTC‑01.

*The denominator used to calculate the rate varied from 78 to 80 based on the number of patients with a baseline value and at least one post-treatment value.

8.1 Pregnancy

Risk Summary

Based on mechanism of action, ZIIHERA can cause fetal harm when administered to a pregnant woman. There are no human or animal data on the use of ZIIHERA in pregnancy. 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. Use of ZIIHERA is not recommended during pregnancy (see CLINICAL CONSIDERATIONS). Advise patients of potential risks to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Monitor women who received ZIIHERA during pregnancy or within 4 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with local standard of care.

8.2 Lactation

Risk Summary

There are no data on the presence of zanidatamab‑hrii in human milk, the effects on the breastfed child, or the effects on milk production. Published data suggest human IgG is present in human milk but does not enter neonatal or infant circulation in substantial amounts. Consider developmental and health benefits of breastfeeding along with the mother’s clinical need for ZIIHERA treatment and any potential adverse effects on the breastfed child from ZIIHERA or from the underlying maternal condition. This consideration should also take into account the ZIIHERA half-life of approximately 21 days and a washout period of 4 months [see Clinical Pharmacology (12.3)].

8.3 Females and Males of Reproductive Potential

ZIIHERA can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.1), Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to the initiation of ZIIHERA [see Use in Specific Populations (8.1)].

Contraception

Females

ZIIHERA can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with ZIIHERA and for 4 months following the last dose of ZIIHERA.

8.4 Pediatric Use

Safety and efficacy of ZIIHERA have not been established in pediatric patients.

8.5 Geriatric Use

Of the 80 patients who received ZIIHERA for unresectable or metastatic biliary tract cancer in HERIZON‑BTC‑01, 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 [see Clinical Studies (14)].

No overall differences in safety or effectiveness were observed between these patients and younger adult patients.

12.1 Mechanism of Action

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 (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.

12.2 Pharmacodynamics

Zanidatamab‑hrii exposure-response relationships and the time course of the pharmacodynamic response are unknown.

Cardiac Electrophysiology

A mean increase in the QTc interval > 20 ms was not observed at the recommended approved dosage.

12.3 Pharmacokinetics

Zanidatamab‑hrii PK parameters are presented as means (percent coefficient of variation) following administration of ZIIHERA 20 mg/kg every 2 weeks after the 7th or later dose unless otherwise indicated.

Zanidatamab‑hrii maximum concentration (Cmax) is 600 (22.2) µg/mL, the lowest measured concentration (Ctrough) is 178 (29.6) µg/mL, and total systemic exposure (AUC0-336h) is 3,976 (22.5) days*µg/mL following administration of ZIIHERA. The Cmax of zanidatamab‑hrii is dose proportional and the total systemic exposure (AUC0-inf) of zanidatamab‑hrii is greater than dose proportional with increasing doses. The mean Ctrough accumulation ratio of zanidatamab‑hrii is approximately 2.4.

Distribution

The volume of distribution of zanidatamab‑hrii is approximately 7.5 (33) L based on the population pharmacokinetic analysis.

Elimination

The estimated half-life (t1/2) of zanidatamab‑hrii is approximately 21 days with an associated clearance (CL) of 0.012 L/h (27.9) based on the population pharmacokinetic analysis.

Metabolism

Zanidatamab‑hrii is expected to be metabolized into small peptides by catabolic pathways.

Specific Populations

No clinically significant differences in the pharmacokinetics of zanidatamab-hrii were observed based on age (24 to 88 years), sex, race (White and Asian), mild and moderate renal impairment (eGFR 30 to 89 mL/min estimated using the CKD‑EPI), mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and AST > ULN or total bilirubin between 1 and 1.5 times ULN and any AST), or body weight (35 kg to 128 kg).

The effect of severe renal impairment (eGFR 15 to 29 mL/min), end-stage renal disease (eGFR < 15 mL/min) with or without hemodialysis, and moderate (total bilirubin > 1.5 to ≤ 3 ULN and any AST) or severe (total bilirubin > 3 ULN and any AST) hepatic impairment on the pharmacokinetics of zanidatamab‑hrii is unknown.

12.6 Immunogenicity

There is insufficient information to characterize the anti-drug antibody response to zanidatamab‑hrii and the effects of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of zanidatamab‑hrii.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies have not been conducted to evaluate the carcinogenic or mutagenic potential of zanidatamab‑hrii.

Fertility studies with zanidatamab‑hrii have not been conducted.