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. ( 1.1 )
• 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. ( 1.1 ) Biliary Tract Cancer (BTC)
• for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) BTC, as detected by an FDA-authorized test.* ( 1.2 ) *This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1 )

1.1 Gastroesophageal Adenocarcinoma (GEA)

• ZIIHERA, in combination with fluoropyrimidine- and platinum-containing chemotherapy and tislelizumab-jsgr, is indicated for the 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 [see Dosage and Administration ( 2.1 )] .
• ZIIHERA, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the 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 [see Dosage and Administration ( 2.1 )] .

1.2 Biliary Tract Cancer (BTC) ZIIHERA, as a single agent, is indicated for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC), as detected by an FDA-authorized test [see Dosage and Administration ( 2.1 )] . This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies ( 14.2 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

For injection: 300 mg white lyophilized powder in a single-dose vial. For injection: 300 mg lyophilized powder in a single-dose vial. ( 3 )

None.

• None. ( 4 )

• 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. ( 2.4 , 5.3 )
• 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. ( 2.2 , 2.4 , 5.4 )

5.1 Diarrhea ZIIHERA can cause severe diarrhea. When ZIIHERA is used in combination with fluoropyrimidine- and platinum-containing chemotherapy with or without tislelizumab-jsgr, severe, life threatening, and fatal cases of diarrhea can occur despite loperamide prophylaxis [see Adverse Reactions ( 6.1 ), Use in Specific Populations ( 8.5 )] . The risk of severe and life threatening diarrhea is higher when ZIIHERA is administered with chemotherapy and tislelizumab-jsgr, with a higher risk in patients aged 65 years or older compared to younger patients [see Geriatric Use ( 8.5 )] . Advise patients to increase oral fluids, begin antidiarrheals, and notify their healthcare provider immediately if diarrhea occurs [see Patient Counseling Information ( 17 )] . Administer antidiarrheal prophylaxis with loperamide in cycle 1 for all patients receiving ZIIHERA in combination with fluoropyrimidine- and platinum-containing chemotherapy with or without tislelizumab-jsgr. Begin loperamide at the first loose stool when ZIIHERA is administered in combination with chemotherapy or as a single agent. Administer fluids, electrolytes, and additional antidiarrheal agents as necessary. When ZIIHERA was used in combination with chemotherapy with or without tislelizumab-jsgr, 9% of patients had a dose reduction of ZIIHERA due to diarrhea and concomitant agents were dose reduced in 22% of patients. Before modifying the dose of ZIIHERA, evaluate, modify or discontinue drug(s) contributing to diarrhea in accordance with their respective prescribing information. Withhold, reduce the dose, or permanently discontinue ZIIHERA based on severity [see Dosage and Administration ( 2.2 , 2.4 )] . In a Phase 2 study evaluating ZIIHERA in combination with FOLFOX in patients with GEA, 57% of patients who received a fluorouracil bolus without loperamide prophylaxis (N=14), experienced Grade 3 diarrhea, while 30% of patients who did not receive a fluorouracil bolus but received loperamide prophylaxis (N=10) experienced Grade 3 diarrhea. If treating patients with ZIIHERA in combination with FOLFOX, do not administer the fluorouracil bolus. Gastroesophageal Adenocarcinoma (GEA) In Combination with fluoropyrimidine- and platinum-containing chemotherapy and tislelizumab: When ZIIHERA was used in combination with fluoropyrimidine- and platinum-containing chemotherapy and tislelizumab-jsgr, diarrhea was reported in 85% of 330 patients treated in clinical studies, including Grade 4 (2.1%), Grade 3 (24%), and Grade 2 (31%) events. Fatal outcomes resulting from diarrhea occurred in 1.5% of patients. Diarrhea leading to dose reduction of ZIIHERA occurred in 10% of patients, and permanent discontinuation of ZIIHERA occurred in 3.9% of patients. In cycle 1, diarrhea at Grade 4 severity occurred in 1.5% and Grade 3 severity occurred in 15% of patients despite use of loperamide prophylaxis. The median time to onset for cycle 1 diarrhea was 6 days and median time to resolution was 18 days. In Combination with fluoropyrimidine- and platinum-containing chemotherapy: When ZIIHERA was used in combination with fluoropyrimidine- and platinum-containing chemotherapy , diarrhea was reported in 81% of 395 patients treated in clinical studies, including Grade 4 (1.3%), Grade 3 (20%) and Grade 2 (33%). Diarrhea leading to dose reduction of ZIIHERA occurred in 10% of patients, and permanent discontinuation of ZIIHERA occurred in 1.8% of patients. In cycle 1, diarrhea at Grade 4 severity occurred in 0.8% and Grade 3 severity occurred in 14% of patients despite use of loperamide prophylaxis. The median time to onset for cycle 1 diarrhea was 6 days and median time to resolution was 18 days. Biliary Tract Cancer (BTC) When ZIIHERA was used as a single agent, diarrhea was reported in 49% of 233 patients treated in clinical studies, including Grade 3 (6%) and Grade 2 (17%). Grade 3 diarrhea occurred in 2.6% of patients during cycle 1 of treatment. Of all diarrhea events occurring during the first cycle of treatment, median time to onset was 4 days and median time to resolution was 21 days.

5.2 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.

5.3 Left Ventricular Dysfunction (LVD) ZIIHERA can cause decreases in left ventricular ejection fraction (LVEF). 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 )] . Gastroesophageal Adenocarcinoma (GEA) In patients who received ZIIHERA in combination with chemotherapy and tislelizumab-jsgr, LVEF decrease (an absolute decline in LVEF of more than 10%, resulting in a final value below 50%) was observed in 9% of 330 patients. LVD leading to permanent discontinuation of ZIIHERA was reported in 3% of patients. Fatal outcomes due to LVD occurred in one patient (0.3%). The median time to first occurrence of LVD was 6.9 months (range: 1.2 to 29.1 months). Left ventricular dysfunction resolved in 78% of patients. In patients who received ZIIHERA in combination with chemotherapy, LVEF decrease was observed in 5% of 395 patients. LVD leading to permanent discontinuation of ZIIHERA was reported in 1.0% of patients. The median time to first occurrence of left ventricular dysfunction was 6.0 months (range: 1.4 to 15.0 months). Left ventricular dysfunction resolved in 70% of patients. Biliary Tract Cancer (BTC) In patients who received ZIIHERA as a single agent, LVEF decrease was observed 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). LVD resolved in 70% of patients.

5.4 Infusion-Related Reactions ZIIHERA can cause infusion-related reactions (IRRs). Prior to each dose of ZIIHERA, administer premedication 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 IRRs [see Dosage and Administration ( 2.4 )] . […]

The following clinically significant adverse reactions are described in greater detail in other sections of the labeling:

• Diarrhea [see Warnings and Precautions ( 5.1 )]
• Embryo-Fetal Toxicity [see Warnings and Precautions ( 5.2) ]
• Left Ventricular Dysfunction [see Warnings and Precautions (5.3 )]
• Infusion-Related Reactions [see Warnings and Precautions ( 5.4 )]
• 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. ( 6.1 )
• Most common adverse reactions (≥ 20%) with ZIIHERA in combination with chemotherapy were diarrhea, nausea, vomiting, decreased appetite, fatigue, hypokalemia, peripheral neuropathy, IRR, and rash. ( 6.1 )
• Most common adverse reactions (≥ 20%) with ZIIHERA as a single agent were diarrhea, IRR, abdominal pain, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals, Inc. at 1‑800‑520‑5568 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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. Gastroesophageal Adenocarcinoma (GEA) The pooled safety population of ZIIHERA described in WARNINGS AND PRECAUTIONS, reflects exposure to ZIIHERA in combination with chemotherapy, with or without tislelizumab-jsgr, in 725 patients with GEA from four open-label studies, including HERIZON-GEA-01 (N=605), ZWI-ZW25-201 (N=46), ZWI-ZW25-101 (N=41), and BGB-A317-ZW25-101 (N=33) at doses of 1,800 mg every 3 weeks (< 70 kg), 2,400 mg every 3 weeks (≥ 70 kg), 1,200 mg every 2 weeks (< 70 kg), 1,600 mg every 2 weeks (≥ 70 kg), or other doses. Among the 330 patients who received ZIIHERA in combination with chemotherapy and tislelizumab-jsgr for GEA, 64% were exposed for 6 months or longer, and 41% were exposed for 1 year or more. Among the 395 patients who received ZIIHERA in combination with chemotherapy for GEA, 57% were exposed for 6 months or longer, and 34% were exposed for 1 year or more. Biliary Tract Cancer (BTC) The pooled safety population of ZIIHERA administered 20 mg/kg intravenously as a single agent, described in WARNINGS AND PRECAUTIONS reflects exposure in 233 patients in two single-arm, open-label studies (ZWI-ZW25-101 and HERIZON-BTC-01): 109 patients with biliary tract cancer, and 124 patients with other cancers. Among 233 patients who received ZIIHERA as a single agent, 39% were exposed for 6 months or longer, and 17% were exposed for greater than one year. Gastroesophageal Adenocarcinoma (GEA) (HERIZON-GEA-01) The safety of ZIIHERA administered in combination with chemotherapy, with or without tislelizumab-jsgr for the treatment of GEA was evaluated in 901 patients [see Clinical Studies ( 14.1 )] . Patients received ZIIHERA by IV infusion every 3 weeks at 1,800 mg (< 70 kg body weight) or 2,400 mg (≥ 70 kg), with or without tislelizumab-jsgr and an investigator choice of a fluoropyrimidine- and platinum-based chemotherapy (CAPOX or FP) or trastuzumab with CAPOX or FP [see Clinical Studies ( 14.1 )] . Treatment in each arm continued until disease progression or unacceptable toxicity. ZIIHERA in combination with tislelizumab-jsgr and chemotherapy Sixty-three percent (63%) of patients were exposed to ZIIHERA for 6 months or longer and 39% 1 year or longer). Serious adverse reactions occurred in 59% of patients who received ZIIHERA. Serious adverse reactions in > 2% of patients included diarrhea (17%), infusion-related reactions (5%), vomiting (4.8%), hypokalemia (4.4%), acute kidney injury (3.7%), pneumonia (3.7%), nausea (2.4%), decreased appetite (2.4%), and anemia (2.4%). Fatal adverse reactions occurred in 2.4% of patients who received ZIIHERA in combination with tislelizumab-jsgr and chemotherapy include acute kidney injury (N=2), cardiac failure, diarrhea, dehydration, hypovolemic shock and intestinal obstruction (all N=1). Permanent discontinuation of ZIIHERA occurred in 13% of patients. Adverse reactions that resulted in permanent discontinuation of ZIIHERA in ≥ 1% of patients included diarrhea (4.4%) and ejection fraction decreased (2.7%). Dosage interruptions of ZIIHERA, excluding temporary interruptions of ZIIHERA infusions due to infusion-related reactions, occurred in 65% of patients. Adverse reactions requiring a dose interruption of ZIIHERA in > 3% of patients, excluding infusion-related reactions, were diarrhea (14%), neutropenia (11%), platelet count decreased (9%), fatigue (7%), ejection fraction decreased (7%), anemia (6%), hypokalemia (4.8%), decreased appetite (4.4%), vomiting (3.4%), and rash (3.1%). Dosage reductions of ZIIHERA occurred in 14% of patients. The adverse reactions requiring dosage reduction of ZIIHERA in ≥ 1% of patients were diarrhea (10%) and hypokalemia (1.0%). The most common adverse reactions (≥ 20%) were diarrhea (83%), nausea (56%), decreased appetite (46%), vomiting (44%), hypokalemia (39%), fatigue (37%), rash (36%), peripheral neuropathy (27%), and infusion-related reaction (25%). ZIIHERA in combination with chemotherapy Fifty-seven percent (57%) of patients were exposed to ZIIHERA for 6 months or longer and 32% for 1 year or longer. Serious adverse reactions occurred in 49% of patients who received ZIIHERA. Serious adverse reactions in > 2% of patients included diarrhea (11%), vomiting (3.3%), decreased appetite (2.6%), pneumonia (2.6%), sepsis (2.6%), hypokalemia (2.3%), and nausea (2.3%). Permanent discontinuation of ZIIHERA occurred in 10% of patients. Adverse reactions that resulted in permanent discontinuation of ZIIHERA in ≥ 1% of patients included ejection fraction decreased (2.0%), infusion-related reaction (1.6%), and diarrhea (1.6%). Dosage interruptions of ZIIHERA, excluding temporary interruptions of ZIIHERA infusions due to infusion-related reactions, occurred in 56% of patients. Adverse reactions requiring a dose interruption of ZIIHERA, excluding infusion-related reactions, occurring in > 3% of patients were diarrhea (14%), neutropenia (10%), platelet count decreased (10%), anemia (6%), ejection fraction decreased (6%), fatigue (6%), and hypokalemia (3.9%). Dosage reductions of ZIIHERA occurred in 15% of patients who received ZIIHERA in combination with chemotherapy. Adverse reactions requiring dosage reductions of ZIIHERA in ≥ 1% of patients were diarrhea (11%), decreased appetite (1.0%), and ejection fraction decreased (1.0%). The most common adverse reactions in patients receiving ZIIHERA in combination with chemotherapy (≥ 20%) were diarrhea (79%), nausea (54%), vomiting (44%), decreased appetite (40%), fatigue (36%), hypokalemia (33%), peripheral neuropathy (32%), infusion-related reaction (25%), and rash (22%). Table 5 summarizes the adverse reactions in HERIZON-GEA-01. Table 5: Adverse Reactions (≥ 10%) With an Increased Incidence (≥ 5% Increase in All Grades) in a ZIIHERA-containing arm in HERIZON-GEA-01 Adverse Reaction* ZIIHERA with chemotherapy and tislelizumab-jsgr N = 294 ZIIHERA with chemotherapy N = 305 Trastuzumab with chemotherapy N = 302 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Gastrointestinal disorders Diarrhea a 83 26 79 21 53 14 Nausea 56 8 54 4.3 48

3.0 Vomiting b 44 6 44 3.6 34

4.3 Metabolism and nutrition disorders Decreased appetite 46 8 40 7 36 6 General disorders and administration site conditions Fatigue c 37 7 36 7 30 6 Skin and subcutaneous tissue disorders Rash d 36 5 22 2.6 25 5 Pruritus 17 0.7 8 0.3 3.6 0 Injury, poisoning, and procedural complications Infusion-related reaction 25 1.7 25 2.3 13

0.7 Investigations Ejection fraction decreased e 12 3.1 9 2.3 7 1.3 * Graded per CTCAE version 5. […]

• Females and Males of Reproductive Potential: Verify the pregnancy status of females prior to initiation of ZIIHERA. ( 8.3 )

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 24 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 ( 5.2 ) and 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 Gastroesophageal Adenocarcinoma (GEA) ZIIHERA in combination with tislelizumab-jsgr and chemotherapy Of 302 patients randomized to ZIIHERA in combination with chemotherapy and tislelizumab-jsgr in HERIZON-GEA-01, there were 139 (46%) patients 65 years of age and older. One hundred and six (35%) were aged 65-74 years old and 33 (11%) were aged 75 years or older [see Clinical Studies ( 14.1 )] . There was a higher incidence of Grade ≥ 3 adverse reactions observed in patients 65 years of age and older (87%) as compared to younger patients (80%). The incidence of Grade 3 or 4 diarrhea was higher in patients 65 years and older (32%) compared to patients younger than 65 years (20%). There was an increased incidence of fatal adverse reactions in patients 65 years and older (4.4%); including acute kidney injury (N=2), cardiac failure, dehydration, hypovolemic shock and intestinal obstruction (all N=1), compared to younger patients (0.6%), including diarrhea (N=1). ZIIHERA in combination with chemotherapy Of 304 patients randomized to ZIIHERA in combination with chemotherapy in HERIZON-GEA-01, there were 130 (43%) patients 65 years of age and older. One hundred (33%) were aged 65-74 years old and 30 (10%) were aged 75 years or older [see Clinical Studies ( 14.1 )] . No overall differences in safety were observed between patients 65 years of age and older and younger adult patients. Biliary Tract Cancer Of the 80 patients who received ZIIHERA for unresectable or metastatic biliary tract cancer in HERIZON-BTC-01 as a single agent, 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 ( 14.2 )] . No overall differences in safety or effectiveness were observed between patients 65 years of age and older compared to younger adult patients.

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.