Zenocutuzumab

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 Preparation Dilute and prepare BIZENGRI for intravenous infusion before administration. For the initial infusion, prepare BIZENGRI as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction. Check that the BIZENGRI solution is clear to slightly opalescent, colorless to slightly yellow. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if discoloration or visible particles are present. Withdraw and then discard 37.5 mL 0.9% Sodium Chloride Injection from the 250 mL infusion bag. Only use infusion bags made of polyvinylchloride (PVC), polyolefin or polyolefin/polyamide coextruded plastic. Withdraw a total of 37.5 mL of BIZENGRI from 2 vials and add it to the infusion bag. The final volume in the infusion bag should be 250 mL. Discard any unused portion left in the vial. Gently invert the bag to mix the solution. Do not shake. If not used immediately, store the diluted solution refrigerated at 2°C to 8°C (36°F to 46°F) and protect from light after preparation unless the infusion is initiated within 2 hours of preparation. 2.7 Administration If the infusion time exceeds the recommended storage time, the infusion bag must be discarded and a new infusion bag prepared to continue the infusion. Diluted BIZENGRI solution must by administered within: 6 hours from end of preparation of infusion solution stored at room temperature [15°C to 25°C (59°F to 77°F)] 28 hours from end of preparation of infusion solution stored refrigerated [2°C to 8°C (36°F to 46°F)] If the diluted BIZENGRI solution has been refrigerated, allow it to reach room temperature (approximately 30 minutes) prior to administration. Administer diluted BIZENGRI solution [see Dosage and Administration ( 2.6 )] by intravenous infusion using an infusion set made of either PVC, polyethylene (PE), polyurethane (PUR) or polybutadiene (PB) with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.2 micrometer). Do not infuse BIZENGRI concomitantly in the same IV line with other agents. Administer BIZENGRI infusion via a peripheral or central line. Monitor patients closely for signs and symptoms of infusion-related reactions during BIZENGRI infusion and monitor patients for at least 1 hour following completion of the first BIZENGRI infusion and as clinically indicated [see Warnings and Precautions ( 5.1 )]. Administer intravenous infusion over 4 hours.

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 Partner Therapeutics, Inc. at 1-888-479-5385 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) 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 1 Based on NCI CTCAE v4.03 and MedDRA v26.0 2 Includes post-procedural diarrhea 3 Includes back pain, pain in extremity, musculoskeletal chest pain, myalgia, arthralgia, non-cardiac chest pain, bone pain, musculoskeletal stiffness, neck pain, spinal pain. 4 Includes dyspnea exertional 5 Includes productive cough 6 Includes asthenia 7 Includes breast edema, peripheral edema, face edema 8 Includes eczema, erythema, dermatitis, dermatitis contact, rash maculopapular, rash erythematous. 9 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. Adverse Reaction 1 BIZENGRI (N=99) All Grades % Grade 3 or 4 % Gastrointestinal disorders Diarrhea 2 25 2 Nausea 10 1 Musculoskeletal and connective tissue disorders Musculoskeletal pain 3 23 1 Respiratory, thoracic and mediastinal disorders Dyspnea 4 18 5 Cough 5 15 1 General disorders and administration site conditions Fatigue 6 17 2 Edema 7 11 0 Skin and subcutaneous tissue disorders Rash 8 14 0 Injury, poisoning and procedural complications Infusion-related reactions 9 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 1 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. Laboratory Abnormality BIZENGRI 1 All Grades % Grade 3 or 4 % Hematology Decreased hemoglobin 35 4.2 Chemistry Increased alanine aminotransferase 30 3.1 Decreased magnesium 28 4.3 Increased alkaline phosphatase 27 0 Decreased phosphate 26 1.1 Increased gamma-glutamyl transpeptidase 23 5 Increased aspartate aminotransferase 22 3.1 Decreased potassium 21 2.1 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 [see Clinical Studies ( 14.2 )]. 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 1 Based on NCI CTCAE v4.03 and MedDRA v26.0 2 Includes back pain, pain in extremity, musculoskeletal chest pain, myalgia, arthralgia, non-cardiac chest pain, bone pain, musculoskeletal stiffness, neck pain, spinal pain 3 Includes asthenia 4 Includes peripheral edema, face edema, localized edema, peripheral swelling 5 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 6 Includes epistaxis, hematochezia, hematuria, hemorrhoidal hemorrhage Adverse Reaction 1 BIZENGRI (N=39) All Grades (%) Grade 3 or 4 (%) Gastrointestinal disorders Diarrhea 36 5 Nausea 23 5 Vomiting 23 2.6 Abdominal pain 18 5 Constipation 15 0 Abdominal distension 13 0 Stomatitis 10 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain 2 28 2.6 General disorders and administration site conditions Fatigue 3 21 5 Edema 4 13 0 Pyrexia 10 0 Infections and infestations COVID-19 18 0 Injury, poisoning and procedural complications Infusion-related reactions 5 15 0 Vascular disorders Hemorrhage 6 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%) [including dermatitis acneiform, erythema, dermatitis, dermatitis contact, rash maculopapular, rash erythematous]. 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 1 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. Laboratory Abnormality BIZENGRI 1 (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 2.9 Increased alkaline phosphatase 28 8 Decreased sodium 28 10 Decreased albumin 26 0 Decreased potassium 26 2.6 Decreased magnesium 24 2.6 Increased gamma-glutamyl transpeptidase 23 15 Hematology Decreased platelets 26 10 Decreased hemoglobin 23 10 Decreased leukocytes 21 2.6

12.3 Pharmacokinetics Zenocutuzumab-zbco pharmacokinetic parameters are expressed as mean unless otherwise specified. Zenocutuzumab-zbco exposure increases proportionally over a dose range from 480 mg (0.6 times the approved recommended dosage) to 900 mg (1.2 times the approved recommended dosage). The median time to steady state of zenocutuzumab-zbco concentrations is 8 weeks and the median accumulation ratio is 1.6-fold at the approved recommended dosage. Distribution Zenocutuzumab-zbco volume of distribution is 6 L (CV 18%). Elimination The steady state zenocutuzumab-zbco half-life is 8 days (SD ±1.3 days) with a clearance of 22 mL/h (CV 37%). Metabolism Zenocutuzumab-zbco is expected to be metabolized into small peptides by catabolic pathways. Specific Populations No clinically significant differences in the pharmacokinetics of zenocutuzumab-zbco were observed based on age (22 to 88 years), sex, race [White or Asian], body weight (38 to 126 kg), albumin level (20 to 49 g/L), mild or moderate renal impairment (creatinine clearance (CLcr) 30 to 89 mL/min), and mild hepatic impairment (total bilirubin >1 to 1.5 times ULN or AST > ULN). The pharmacokinetics of zenocutuzumab-zbco in patients with moderate to severe hepatic impairment (total bilirubin > 1.5 to 3 times ULN with any AST) or severe renal impairment (CLcr < 30 mL/min) is unknown.