Bizengri Drug Information

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 described in the WARNINGS AND PRECAUTIONS reflects exposure to BIZENGRI as a single agent at 750 mg administered intravenously every 2 weeks until disease progression or unacceptable toxicity in 175 patients with NRG1 gene fusion positive tumors in the eNRGy study. Of these, there were 99 patients with NSCLC, 39 patients with pancreatic adenocarcinoma and 37 patients with other solid tumors . Among the 175 patients who received BIZENGRI, the median duration of exposure to BIZENGRI was 5.3 months (range: 0.1 to 36), including 45% of patients exposed for at least 6 months and 15% of patients exposed for at least 1 year.

In this pooled safety population, the most common (≥ 10%) adverse reactions were diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions (IRR), dyspnea, rash, constipation, vomiting, abdominal pain, and edema. The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were increased GGT, decreased hemoglobin, decreased sodium, decreased platelets, increased AST, increased ALT, increased alkaline phosphatase, decreased magnesium, decreased phosphate, increased aPTT, and increased bilirubin. NRG1 Gene Fusion Positive Unresectable or Metastatic NSCLC eNRGy Study The safety of BIZENGRI was evaluated in the eNRGy study in 99 patients with unresectable or metastatic NSCLC with NRG1 gene fusions.

Patients received BIZENGRI as a single agent at 750 mg intravenously every 2 weeks until disease progression or unacceptable toxicity. Among patients who received BIZENGRI, 47% were exposed for 6 months or longer and 17% were exposed for greater than one year. The median age was 66 years (range: 27 to 88), 54% were 65 years or older; 62% were female; 37% were White, 53% were Asian, 2% were Black or African American; and 1% were Hispanic or Latino.

Serious adverse reactions occurred in 25% of patients who received BIZENGRI. Serious adverse reactions in ≥ 2% of patients included pneumonia (n=4) dyspnea and fatigue (n=2 each). Serious adverse reactions occurring in one patient each were: abdominal pain, acute kidney injury, ascites, bradycardia, carotid artery stenosis, cellulitis, acute cholecystitis, COVID-19, decreased appetite, dehydration, dizziness, dysphagia, hyponatremia, ileus, lymphadenitis, nausea, gastric obstruction, pericardial effusion, pneumonitis, pulmonary hypertension, sepsis, staphylococcal infection, tumor pain, urinary tract infection, viral infection and vomiting. Fatal adverse reactions occurred in 3 (3%) patients and included respiratory failure (n=2) and cardiac failure (n=1). Permanent discontinuation of BIZENGRI due to an adverse reaction occurred in 3% of patients. Adverse reactions resulting in permanent discontinuation of BIZENGRI included dyspnea, pneumonitis and sepsis (n=1 each). Dosage interruptions of BIZENGRI due to an adverse reaction, excluding temporary interruptions of BIZENGRI due to infusion-related reactions, occurred in 29% of patients.

Adverse reactions leading to dosage interruptions in ≥2% of patients included dyspnea, COVID-19, arrhythmia, increased ALT, increased AST, and pneumonia. Table 3 summarizes the adverse reactions in the eNRGy study in patients with NRG1 gene fusion positive unresectable or metastatic NSCLC. Table 3: Adverse Reactions (≥10%) in Patients with NRG1 Gene Fusion Positive NSCLC Who Received BIZENGRI in the eNRGy Study Adverse Reaction Based on NCI CTCAE v4.03 and MedDRA v26.0 BIZENGRI (N=99) All Grades % Grade 3 or 4 % Gastrointestinal disorders Diarrhea Includes post-procedural diarrhea 25 2 Nausea 10 1 Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes back pain, pain in extremity, musculoskeletal chest pain, myalgia, arthralgia, non-cardiac chest pain, bone pain, musculoskeletal stiffness, neck pain, spinal pain. 23 1 Respiratory, thoracic and mediastinal disorders Dyspnea Includes dyspnea exertional 18 5 Cough Includes productive cough 15 1 General disorders and administration site conditions Fatigue Includes asthenia 17 2 Edema Includes breast edema, peripheral edema, face edema 11 0 Skin and subcutaneous tissue disorders Rash Includes eczema, erythema, dermatitis, dermatitis contact, rash maculopapular, rash erythematous. 14 0 Injury, poisoning and procedural complications Infusion-related reactions Includes chills, IRR, nausea, cough, diarrhea, back pain, body temperature increased, dyspnea, face edema, fatigue, non-cardiac chest pain, oropharyngeal discomfort, paresthesia, pyrexia, and vomiting. AEs that were considered IRRs were counted under the composite term 'IRR', irrespective of the reported PT. 12 0 Metabolism and nutrition disorders Decreased appetite 11 1 Clinically relevant adverse reactions in <10% of patients receiving BIZENGRI were stomatitis (7%), vomiting (8%), cardiac failure and pneumonitis (2% each). Table 4 summarizes the laboratory abnormalities in the eNRGy study in patients with NRG1 gene fusion positive unresectable or metastatic NSCLC. Table 4: Select Laboratory Abnormalities ≥ 20% that Worsened from Baseline in Patients with NRG1 Gene Fusion Positive NSCLC Who Received BIZENGRI in the eNRGy Study Laboratory Abnormality BIZENGRI The denominator used to calculate the rate varied from 93 to 96 based on the number of patients with a baseline value and at least one post-treatment value.

All Grades % Grade 3 or 4 % Hematology Decreased hemoglobin 35

Chemistry Increased alanine aminotransferase 30 3.1 Decreased magnesium 28 4.3 Increased alkaline

phosphatase 27 0 Decreased phosphate 26

Increased gamma-glutamyl transferase 23 5 Increased aspartate aminotransferase 22 3.1 Decreased potassium

21

NRG1 Gene Fusion Positive Unresectable or Metastatic Pancreatic Adenocarcinoma eNRGy Study

The safety of BIZENGRI was evaluated in the eNRGy study in 39 patients with unresectable or metastatic pancreatic adenocarcinoma with NRG1 gene fusions. Patients received BIZENGRI as a single agent at 750 mg intravenously every 2 weeks until disease progression or unacceptable toxicity. Among patients who received BIZENGRI, 50% were exposed for 6 months or longer and 13% were exposed for greater than one year.

The median age was 51 years (range: 21 to 74), 23% were 65 years or older; 49% were female; 82% were White, 13% were Asian, 2.6% were Black or African American; and 5% were Hispanic or Latino. Serious adverse reactions occurred in 23% of patients who received BIZENGRI. Serious adverse reactions occurring in one patient each were: anemia, thrombocytopenia, tachycardia, abdominal pain, hemorrhoidal hemorrhage, nausea, cholestatic jaundice, COVID-19, liver abscess, traumatic fracture, blood creatinine increased, back pain, myelodysplastic syndrome, and respiratory disorder. There were 2 fatal adverse reactions, one due to COVID-19 and one due to respiratory failure.

Dosage interruptions of BIZENGRI due to an adverse reaction, excluding temporary interruptions of BIZENGRI due to infusion-related reactions, occurred in 33% of patients. Adverse reactions leading to dosage interruptions in ≥2% of patients included COVID-19, pneumonia, increased AST, neutropenia, abdominal pain, agitation, increased blood alkaline phosphatase, increased blood bilirubin, constipation, increased creatinine, hemorrhage, hyperbilirubinemia, cholestatic jaundice, tachycardia, traumatic fracture, and upper respiratory infection. Table 5 summarizes the adverse reactions in the eNRGy study in patients with NRG1 gene fusion positive pancreatic adenocarcinoma.

Table 5: Adverse Reactions (≥10%) in Patients with NRG1 Gene Fusion Positive Pancreatic Adenocarcinoma Who Received BIZENGRI in the eNRGy Study Adverse Reaction Based on NCI CTCAE v4.03 and MedDRA v26.0 BIZENGRI (N=39) All Grades (%) Grade 3 or 4 (%) Gastrointestinal disorders Diarrhea 36 5 Nausea 23 5 Vomiting 23

Abdominal pain 18 5 Constipation 15 0 Abdominal distension 13 0 Stomatitis

10 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes back pain, pain in extremity, musculoskeletal chest pain, myalgia, arthralgia, non-cardiac chest pain, bone pain, musculoskeletal stiffness, neck pain, spinal pain 28

General disorders and administration site conditions Fatigue Includes asthenia 21 5 Edema

Includes peripheral edema, face edema, localized edema, peripheral swelling 13 0 Pyrexia 10 0 Infections and infestations COVID-19 18 0 Injury, poisoning and procedural complications Infusion-related reactions Includes chills, IRR, nausea, cough, diarrhea, back pain, body temperature increased, dyspnea, face edema, fatigue, non-cardiac chest pain, oropharyngeal discomfort, paresthesia, pyrexia, and vomiting 15 0 Vascular disorders Hemorrhage Includes epistaxis, hematochezia, hematuria, hemorrhoidal hemorrhage 13 5 Psychiatric disorders Anxiety 10 0 Skin and subcutaneous tissue disorders Dry skin 10 0 Clinically relevant adverse reactions in <10% of patients receiving BIZENGRI were decreased appetite (5%), and rash (8%). Table 6 summarizes the laboratory abnormalities in the eNRGy study in patients with NRG1 gene fusion positive pancreatic adenocarcinoma. Table 6: Select Laboratory Abnormalities ≥ 20% That Worsened from Baseline in Patients with NRG1 Gene Fusion Positive Pancreatic Adenocarcinoma Who Received BIZENGRI in the eNRGy Study Laboratory Abnormality BIZENGRI The denominator used to calculate the rate varied from 35 to 39, based on the number of patients with a baseline value and at least one post-treatment value. (N=39) All Grades (%) Grade 3 or 4 (%) Chemistry Increased alanine aminotransferase 51 5 Increased aspartate aminotransferase 31 5 Increased bilirubin 31 5 Decreased phosphate 31

Increased alkaline phosphatase 28 8 Decreased sodium 28 10 Decreased albumin 26

0 Decreased potassium 26

Decreased magnesium 24 2.6 Increased gamma-glutamyl transferase 23 15 Hematology Decreased platelets

26 10 Decreased hemoglobin 23 10 Decreased leukocytes 21

NRG1 Gene Fusion Positive Advanced, Unresectable or Metastatic Cholangiocarcinoma eNRGy Study

The safety of BIZENGRI was evaluated in the eNRGy study in 22 patients with unresectable or metastatic cholangiocarcinoma with NRG1 gene fusions. Patients received BIZENGRI as a single agent at 750 mg intravenously every 2 weeks until disease progression or unacceptable toxicity. Among patients who received BIZENGRI, 64% were exposed for 6 months or longer and 36% were exposed for greater than one year.

Serious adverse reactions occurred in 23% of patients who received BIZENGRI. Dosage interruptions of BIZENGRI due to an adverse reaction, excluding temporary interruptions of BIZENGRI due to infusion-related reactions, occurred in 32% of patients. Adverse reactions leading to dosing interruptions or delays in at least 2 patients were increased ALT and increased AST. Table 7 summarizes the adverse reactions in the eNRGy study in patients with NRG1 gene fusion positive advanced, unresectable or metastatic cholangiocarcinoma. Table 7 Adverse Reactions (≥10%) in Patients with NRG1 Gene Fusion Positive Cholangiocarcinoma Who Received BIZENGRI in the eNRGy Study Adverse Reaction Based on NCI CTCAE v4.03 and MedDRA v26.0 BIZENGRI (N=22) All Grades % Grade 3 or 4 % Gastrointestinal disorders Diarrhea 41 0 Abdominal pain Includes abdominal pain, abdominal pain upper and abdominal discomfort 36 9 Nausea 27 0 Vomiting 14 0 Ascites 14 0 General disorders and administration site conditions Fatigue Includes fatigue and asthenia 46 5 Injury, poisoning and procedural complications Infusion related reaction Includes IRR, nausea, diarrhea.

AEs that were considered IRRs were counted under the composite term "IRR" irrespective of the reported Preferred Term 14 0 Respiratory, thoracic and mediastinal disorders Dyspnea Includes dyspnea, dyspnea exertional 23 5 Cough 27 0 Metabolism and nutrition disorders Decreased appetite 23 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes arthralgia, back pain, muscle spasms, myalgia, pain in extremity, muscular weakness. 36 0 Skin and subcutaneous disorders Dry skin 14 0 Table 8 summarizes the laboratory abnormalities in the eNRGy study in patients with NRG1 gene fusion positive advanced, unresectable or metastatic cholangiocarcinoma. Table 8 Select Laboratory Abnormalities ≥ 20% that Worsened from Baseline in Patients with NRG1 Gene Fusion Positive Cholangiocarcinoma Who Received BIZENGRI in the eNRGy Study Laboratory Abnormality BIZENGRI (N=22) All Grades % Grade 3 or 4 % Hematology Decreased platelets 46 0 Decreased hemoglobin 41 14 Chemistry Decreased magnesium 59 5 Increased alanine aminotransferase 50 9 Increased aspartate aminotransferase 41 14 Increased alkaline phosphatase 41 14 Decreased phosphate 41 14 Increased gamma-glutamyl transferase 36 23 Increased bilirubin 32 5 Decreased potassium 32 0 Decreased sodium 32 0 Decreased albumin 23 0 Coagulation Increased activated partial thromboplastin time (aPTT) 27 5

Pregnancy Risk Summary Based on its mechanism of action, BIZENGRI can cause fetal harm when administered to a pregnant woman . There are no available data on the use of BIZENGRI in pregnant women to inform a drug-associated risk. Animal studies have demonstrated that HER2 and/or HER3 deficiency results in embryo-fetal malformation, including effects on cardiac, vascular and neuronal development, and embryolethality (see Data ). Human IgG1 is known to cross the placenta; therefore, BIZENGRI has the potential to be transmitted from the mother to the developing fetus. Advise patients of the potential risk to a fetus.

There are clinical considerations if BIZENGRI is used in pregnant women, or if a patient becomes pregnant within 2 months after the last dose of BIZENGRI ( see Clinical Considerations ). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Monitor women who received BIZENGRI during pregnancy or within 2 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.

Data Human Data There are no available data on the use of BIZENGRI in pregnant women. In literature reports in pregnant women receiving a HER2-directed antibody, cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported. These case reports described oligohydramnios in pregnant women who received HER2-directed antibody alone or in combination with chemotherapy.

In some case reports, amniotic fluid index increased after use of a HER2-directed antibody was stopped. Animal Data There were no animal reproductive or developmental toxicity studies conducted with zenocutuzumab-zbco. A literature-based assessment of the effects on reproduction demonstrated that HER2 and HER3 are critically important in embryo-fetal development.

HER2 knockout mice or mice expressing catalytically inactive HER2 die at mid-gestation due to cardiac dysfunction. HER2 knockout mice have also shown abnormal sympathetic nervous system development. In HER3-deficient mice, embryolethality occurred on embryonic day 13.5 due to cardiac and vascular defects, as well as abnormalities in other organs (neural crest, pancreas, stomach, and adrenal). In addition, HER3 is shown to be involved in mammary gland ductal morphogenesis in mice.

Zenocutuzumab-zbco can cause embryo-fetal toxicity based on its mechanism of action.

Pediatric Use The safety and effectiveness of BIZENGRI have not been established in pediatric patients.