BIZENGRI

1 INDICATIONS AND USAGE BIZENGRI® is a bispecific HER2- and HER3-directed antibody indicated for the treatment of: Adults with advanced, unresectable or metastatic non-small cell lung cancer (NSCLC) harboring a neuregulin 1 ( NRG1 ) gene fusion with disease progression on or after prior systemic therapy.* ( 1.1 ) Adults with advanced, unresectable or metastatic pancreatic adenocarcinoma harboring a neuregulin 1 ( NRG1 ) gene fusion with disease progression on or after prior systemic therapy.* ( 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 Advanced Unresectable or Metastatic NRG1 Fusion-Positive Non-Small Cell Lung Cancer BIZENGRI is indicated for the treatment of adults with advanced unresectable or metastatic non-small cell lung cancer (NSCLC) harboring a neuregulin 1 ( NRG1 ) gene fusion with disease progression on or after prior systemic therapy. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies ( 14.1 )]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). 1.2 Advanced Unresectable or Metastatic NRG1 Fusion-Positive Pancreatic Adenocarcinoma BIZENGRI is indicated for the treatment of adults with advanced unresectable or metastatic pancreatic adenocarcinoma harboring a neuregulin 1 ( NRG1 ) gene fusion with disease progression on or after prior systemic therapy. 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).

2 DOSAGE AND ADMINISTRATION Select patients for treatment with BIZENGRI based on the presence of an NRG1 gene fusion. ( 2.1 ) Evaluate left ventricular ejection fraction (LVEF) before initiating BIZENGRI. ( 2.2 ) The recommended dosage of BIZENGRI is 750 mg every 2 weeks until disease progression or unacceptable toxicity. ( 2.3 ) Administer premedications before each infusion to reduce the risk of infusion-related reactions. ( 2.4 ) Administer as an intravenous infusion, after dilution, over 4 hours. ( 2.7 ) 2.1 Patient Selection Select patients for treatment with BIZENGRI based on the presence of an NRG1 gene fusion in tumor specimens [see Clinical Studies ( 14.1 , 14.2 )] . An FDA-approved test for the detection of NRG1 gene fusions is not currently available. 2.2 Recommended Evaluation Before Initiating BIZENGRI Before initiating BIZENGRI, evaluate left ventricular ejection fraction (LVEF) [see Warnings and Precautions ( 5.3 )]. 2.3 Recommended Dosage The recommended dosage of BIZENGRI is 750 mg as an intravenous (IV) infusion every 2 weeks until disease progression or unacceptable toxicity [see Dosage and Administration ( 2.7 )]. Administer premedications before each BIZENGRI infusion as recommended to reduce the risk of infusion-related reactions [see Dosage and Administration ( 2.4 )] . 2.4 Recommended Premedications Prior to each infusion of BIZENGRI, administer premedications to reduce the risk of infusion-related reactions (IRRs) [see Warnings and Precautions ( 5.1 )] (see Table 1 ) . Table 1: Premedications Prior to BIZENGRI Infusions 1 Optional after initial BIZENGRI infusion Medication Dose Route of Administration Corticosteroid 1 Dexamethasone (10 mg) Oral or intravenous Antipyretic Acetaminophen (1,000 mg) Oral or intravenous H1 Antihistamine Dexchlorpheniramine (5 mg) or other anti-H1 equivalent Intravenous or oral 2.5 Dosage Modifications for Adverse Reactions No dose reduction is recommended for BIZENGRI. The recommended dosage modifications of BIZENGRI for adverse reactions are provided in Table 2 . Table 2: Recommended BIZENGRI Dosage Modifications and Management for Adverse Reactions Adverse Reaction Severity Dose Modifications and Management Infusion-related reactions (IRRs)/Hypersensitivity/Anaphylactic Reactions [see Warnings and Precautions ( 5.1 )] ≤ Grade 3 IRR Interrupt BIZENGRI infusion if IRR is suspected and monitor patient until reaction symptoms resolve. Provide symptomatic treatment as needed. Resume the infusion at 50% of the infusion rate at which the reaction occurred. The infusion rate may be escalated if there are no additional symptoms. Corticosteroid premedication can be used as necessary for subsequent BIZENGRI infusions [see Recommended Premedications ( 2.4 )] . Grade 4 IRR or any grade hypersensitivity/ anaphylactic reaction Permanently discontinue BIZENGRI. Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions ( 5.2 )] Grade 1 Interrupt BIZENGRI until recovery. Consider prompt initiation of corticosteroids when the diagnosis is suspected. Resume treatment after resolution. ≥ Grade 2 Permanently discontinue BIZENGRI. Promptly treat with corticosteroids. Left Ventricular Dysfunction [see Warnings and Precautions ( 5.3 )] LVEF is 45-49% and absolute decrease from baseline ≥10% or LVEF less than 45% Interrupt BIZENGRI. Repeat LVEF assessment within 3 weeks. If LVEF is less than 45% or LVEF has not recovered to within 10% from baseline, permanently discontinue BIZENGRI. If LVEF is 50% or greater or LVEF is 45-49% and recovered to within 10% of baseline, resume BIZENGRI and monitor LVEF every 12 weeks while on treatment and as clinically indicated. Symptomatic congestive heart failure (CHF) Permanently discontinue BIZENGRI. Other Clinically Relevant Adverse Reactions [see Adverse Reactions ( 6.1 )] Grade 3 or 4 Withhold BIZENGRI until recovery to ≤ Grade 1 or baseline. Provide symptomatic treatment as needed. Resume treatment after resolution of symptoms. 2.6 Preparatio…

5 WARNINGS AND PRECAUTIONS Infusion-Related Reactions (IRR)/Hypersensitivity/Anaphylactic Reactions : Administer BIZENGRI in a setting with emergency resuscitation equipment and staff who are trained to monitor for IRRs and to administer emergency medications. Monitor for signs and symptoms of IRR. Interrupt infusion in patients with ≤ Grade 3 IRRs and administer symptomatic treatment as needed. Resume infusion at a reduced rate after resolution of symptoms. Immediately stop the infusion and permanently discontinue BIZENGRI for Grade 4 or life-threatening IRR or hypersensitivity/anaphylaxis. ( 5.1 ) Interstitial Lung Disease (ILD)/Pneumonitis : Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Permanently discontinue BIZENGRI in patients with ≥ Grade 2 ILD/pneumonitis. ( 5.2 ) Left Ventricular Dysfunction : Assess LVEF before initiating BIZENGRI and at regular intervals during treatment as clinically indicated. Manage through treatment interruption or discontinuation. Permanently discontinue BIZENGRI in patients with symptomatic congestive heart failure (CHF). ( 5.3 ) 5.1 Infusion-Related Reactions/Hypersensitivity/Anaphylactic Reactions BIZENGRI can cause serious and life-threatening infusion-related reactions (IRRs), hypersensitivity and anaphylactic reactions. Signs and symptoms of IRR may include chills, nausea, fever, and cough. In the eNRGy study, 13% of patients experienced IRRs, all were Grade 1 or 2; 91% occurred during the first infusion. The median time to onset was 63 minutes (range: 13 minutes to 240 minutes) from the start of infusion. Administer BIZENGRI in a setting with emergency resuscitation equipment and staff who are trained to monitor for IRRs and to administer emergency medications. Monitor patients closely for signs and symptoms of infusion reactions during infusion and for at least 1 hour following completion of first BIZENGRI infusion and as clinically indicated. Prior to the first BIZENGRI infusion, premedicate with a corticosteroid, an H1 antihistamine and acetaminophen to reduce the risk of IRRs [see Dosage and Administration ( 2.4 )]. Corticosteroid premedication can be used as necessary for subsequent BIZENGRI infusions. Interrupt BIZENGRI infusion in patients with ≤ Grade 3 IRRs and administer symptomatic treatment as needed. Resume infusion at a reduced rate after resolution of symptoms [see Dosage and Administration ( 2.5 )]. Immediately stop the infusion and permanently discontinue BIZENGRI for Grade 4 or life-threatening IRR or hypersensitivity/anaphylaxis reactions. 5.2 Interstitial Lung Disease/Pneumonitis BIZENGRI can cause serious and life-threatening interstitial lung disease (ILD)/pneumonitis. In the eNRGy study [see Adverse Reactions ( 6.1 )], ILD/pneumonitis occurred in 2 (1.1%) patients treated with BIZENGRI. Grade 2 ILD/pneumonitis (Grade 2) resulting in permanent discontinuation of BIZENGRI occurred in 1 (0.6%) patient. Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold BIZENGRI in patients with suspected ILD/pneumonitis and administer corticosteroids as clinically indicated. Permanently discontinue BIZENGRI if ILD/pneumonitis ≥ Grade 2 is confirmed [see Dosage and Administration ( 2.5 )]. 5.3 Left Ventricular Dysfunction BIZENGRI can cause left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease occurred with anti-HER2 therapies, including BIZENGRI. Treatment with BIZENGRI has not been studied in patients with a history of clinically significant cardiac disease or LVEF less than 50% prior to initiation of treatment. In the eNRGy study [see Adverse Reactions ( 6.1 )], Grade 2 LVEF decrease [Grade 2 LVEF decrease (40%-50%; 10 - 19% drop from baseline)] occurred in 2% of evaluable patients. Cardiac failure without LVEF decrease occurred in 1.7% of patients including 1 (0.6%) fatal event. Before initiating BIZENGRI, evaluate LVEF and monitor at regular i…

4 CONTRAINDICATIONS None. None. ( 4 )

8.1 Pregnancy Risk Summary Based on its mechanism of action, BIZENGRI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Infusion-Related Reactions/Hypersensitivity/Anaphylaxis [ see Warnings and Precautions ( 5.1 )] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions ( 5.2 )] Left Ventricular Dysfunction [ see Warnings and Precautions ( 5.3 ) ] Embryo-Fetal Toxicity [ see Warnings and Precautions ( 5.4 ) ] The most common adverse reactions (≥ 10%) in patients were diarrhea musculoskeletal pain, fatigue, nausea, infusion-related reactions (IRR), dyspnea, rash, constipation, vomiting, abdominal pain, and edema. ( 6.1 ) 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merus N.V. at 1-844-637-8787 (MERUSUS) 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. 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 [see Clinical Studies ( 14.1 , 14.2 )] . 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 [see Clinical Studies ( 14.1 )]. 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) …