EMRELIS

Telisotuzumab vedotin-tllv is a c-Met directed antibody-drug conjugate (ADC) comprised of a humanized immunoglobulin G1 kappa (IgG1κ) monoclonal antibody conjugated to the small molecule microtubule-disrupting agent, monomethyl auristatin E (MMAE), via a protease-cleavable valine-citrulline (vc) linker. The antibody is produced in a mammalian cell line (Chinese hamster ovary) and the drug-linker is produced by chemical synthesis. Each monoclonal antibody molecule carries an average of 3 MMAE molecules. Telisotuzumab vedotin-tllv has an approximate molecular weight of 152 kDa. EMRELIS (telisotuzumab vedotin-tllv) for injection is a sterile, white to off-white, preservative-free, lyophilized powder in a single-dose vial for reconstitution and dilution prior to intravenous infusion. EMRELIS is supplied as 20 mg per vial or 100 mg per vial and requires reconstitution with Sterile Water for Injection, USP (1.1 mL and 5.2 mL, respectively) to obtain a concentration of 20 mg/mL [see Dosage and Administration ( 2.4 )] . Following reconstitution, each mL delivers 20 mg of telisotuzumab vedotin-tllv, and histidine (2.33 mg), polysorbate 80 (0.10 mg), sucrose (70.0 mg), and Water for Injection. Hydrochloric acid was added to adjust the pH to 6.0. Telisotuzumab vedotin-tllv is a c-Met directed antibody-drug conjugate (ADC) comprised of a humanized immunoglobulin G1 kappa (IgG1κ) monoclonal antibody conjugated to the small molecule microtubule-disrupting agent, monomethyl auristatin E (MMAE), via a protease-cleavable valine-citrulline (vc) linker. The antibody is produced in a mammalian cell line (Chinese hamster ovary) and the drug-linker is produced by chemical synthesis. Each monoclonal antibody molecule carries an average of 3 MMAE molecules. Telisotuzumab vedotin-tllv has an approximate molecular weight of 152 kDa.

EMRELIS is indicated for the treatment of adult patients with locally advanced or metastatic, non-squamous non-small cell lung cancer (NSCLC) with high c-Met protein overexpression [≥50% of tumor cells with strong (3+) staining], as determined by an FDA-approved test [see Dosage and Administration ( 2.1 )] , who have received a prior systemic therapy . This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR) [see Clinical Studies ( 14 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). EMRELIS is a c-Met-directed antibody and microtubule inhibitor conjugate indicated for the treatment of adult patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) with high c-Met protein overexpression [≥50% of tumor cells with strong (3+) staining], as determined by an FDA-approved test, who have received a prior systemic therapy. ( 1 ) This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1 )

For intravenous infusion only. ( 2.5 ) The recommended dosage of EMRELIS is 1.9 mg/kg administered intravenously every 2 weeks until disease progression or unacceptable toxicity. ( 2.2 ) Reconstitute and further dilute EMRELIS prior to intravenous infusion. ( 2.5 ) 2.1 Patient Selection Select patients for treatment with EMRELIS based on the presence of high c-Met protein overexpression [≥50% of tumor cells with strong (3+) staining] in patients with non-squamous NSCLC [see Indications and Usage ( 1 ) and Clinical Studies ( 14 )] . Information on FDA-approved tests for the detection of high c-Met protein overexpression is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage The recommended dosage of EMRELIS is 1.9 mg/kg (up to a maximum of 190 mg for patients greater than or equal to 100 kg) administered as an intravenous infusion over 30 minutes every 2 weeks until disease progression or unacceptable toxicity. 2.3 Dosage Modifications for Adverse Reactions The recommended dose reductions for adverse reactions are provided in Table 1. Table 1. Recommended Dose Reductions Dose Reduction Recommended Dosage First 1.6 mg/kg every 2 weeks Second 1.3 mg/kg every 2 weeks Third 1 mg/kg every 2 weeks Permanently discontinue EMRELIS in patients who are unable to tolerate 1 mg/kg. The recommended dosage modifications of EMRELIS for adverse reactions are provided in Table 2. Table 2. EMRELIS Dosage Modifications and Management for Adverse Reactions Adverse Reaction Severity a Dosage Modification Peripheral Neuropathy [see Warnings and Precautions ( 5.1 )] Grade 2 or 3 Withhold EMRELIS until recovery to Grade ≤1. Resume EMRELIS at the next lower dose level. Grade 4 Permanently discontinue EMRELIS. Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions ( 5.2 )] Grade 1 Withhold EMRELIS and consider corticosteroids as soon as ILD/pneumonitis is suspected. Resume EMRELIS upon radiographic resolution. Grade ≥2 Permanently discontinue EMRELIS. Keratitis [see Warnings and Precautions ( 5.3 )] Grade 2 Withhold EMRELIS. Refer patients to an eye care professional for an ophthalmic examination and treatment (e.g., lubricating and/or steroidal eye drops). Resume EMRELIS at the same dose at the discretion of the healthcare provider. Grade 3 or 4 Refer patients to an eye care professional for an ophthalmic examination and treatment (e.g., lubricating and/or steroidal eye drops). Permanently discontinue EMRELIS. Infusion-Related Reactions (IRR) [see Warnings and Precautions ( 5.4 )] Grade 1-3 Interrupt EMRELIS infusion and administer supportive treatment. Resume the infusion at a 50% rate reduction. Increase infusion rate as tolerated for subsequent doses. For patients who experience an IRR, administer premedications prior to all future doses (see Table 3 ). Grade 4 Permanently discontinue EMRELIS. Administer supportive treatment. Peripheral Edema [see Adverse Reactions ( 6.1 )] Grade ≥2 First occurrence Withhold EMRELIS until recovery to Grade ≤1. Resume EMRELIS at the same dose level. Subsequent occurrence Withhold EMRELIS until recovery to Grade ≤1. Resume EMRELIS at the next lower dose level. Other Adverse Reactions [see Adverse Reactions ( 6.1 )] Grade 3 First occurrence Withhold EMRELIS until recovery to Grade ≤1. Resume EMRELIS at the same dose. Subsequent occurrence Withhold EMRELIS until recovery to Grade ≤1. Resume EMRELIS at the next lower dose level. Grade 4 Permanently discontinue EMRELIS. a Adverse reactions were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 2. 4 Recommended Premedications for Patients Who Experience Infusion-Related Reactions Table 3 contains the recommended premedications for patients who experience infusion-related reactions to EMRELIS, for subsequent infusions. Table 3: Recommended Premedications for Patients Who Experience Infusion-Related Reactions Medication Class E xamples or equivalent Dose Route of Administration Dosing Window Prior to EMRELIS Administration H1 Antihistamine Diphenhydramine 25 to 50 mg Intravenously or orally Administer 30-60 minutes prior to each infusion H2 Antihistamine Famotidine 20 mg Intravenously or orally Administer 30-60 minutes prior to each infusion Antipyretic Acetaminophen 650 to 1,000 mg Intravenously or orally Administer 30-60 minutes prior to each infusion Glucocorticoid Methylprednisolone 125 mg or equivalent Intravenously Administer 30-60 minutes prior to each infusion 2. 5 Preparation and Administration EMRELIS contains a hazardous component. Follow applicable special handling and disposal procedures in accordance with local requirements. 1 Reconstitute and further dilute EMRELIS prior to intravenous infusion. Reconstitution of Lyophilized EMRELIS Before reconstitution, allow the vial to reach room temperature after removal of the vial from storage condition. Calculate the recommended dose based on the patient’s weight to determine the number of vials needed. For patients weighing greater than or equal to 100 kg, use 190 mg dose [see Dosage and Administration ( 2.2 )] . More than one vial may be needed to achieve the calculated dose. Using a sterile syringe, slowly inject Sterile Water for Injection, using the volume provided in Table 4, into the EMRELIS vial containing the lyophilized powder, which has a whole or fragmented cake-like appearance. The reconstituted solution has a concentration of 20 mg/mL EMRELIS. Table 4. Reconstitution Volumes Dose Vial Volume of Sterile Water for Injection required for reconstitution 20 mg vial 1.1 mL 100 mg vial 5.2 mL Swirl the vial gently until completely dissolved. Do not shake. Inspect the reconstituted solution for particulate matter and discoloration. The solution should appear clear to slightly opalescent and colorless to slightly yellow. Discard the vial if the reconstituted solution is discolored, is cloudy, or contains visible particulates. Use reconstituted EMRELIS immediately. If not used immediately, store the reconstituted EMRELIS vials in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours from the time of reconstitution. Do not freeze. Each vial of EMRELIS is intended for one-time use only. Discard any unused drug remaining in the vial. Dilution in Infusion Bag Calculate the required dose volume (mL) of reconstituted EMRELIS solution based on the prescribed dose. Withdraw the calculated dose volume (mL) of reconstituted solution from the EMRELIS vial using a sterile syringe. Discard any unused portion remaining in the vial(s). Inject the calculated amount of reconstituted solution into 0.9% Sodium Chloride Injection infusion bag so that the final EMRELIS concentration is between 1 mg/mL and 10 mg/mL. Use only 0.9% Sodium Chloride Injection. Gently invert the infusion bag to thoroughly mix the solution. Do not shake. After preparing the dose for infusion, visually inspect the bag content for particulates and discard if present. If not used immediately, the diluted solution can be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours and an additional 4 hours at room temperature at 9°C to 30°C (48°F to 86°F) until the end of administration. Do not freeze. Method of Administration If the prepared infusion solution was stored refrigerated at 2°C to 8°C (36°F to 46°F), allow the solution to reach room temperature prior to administration. Administer by intravenous infusion over 30 minutes using a dedicated infusion line with a 0.20 or 0.22 micron in-line filter made of polyether sulfone (PES), polyvinylidene fluoride (PVDF), or Polyamide (PA). Do not mix EMRELIS with other drugs or administer other drugs through the same intravenous line.

None. None. ( 4 )

The following clinically significant adverse reactions are described elsewhere in the labeling: Peripheral Neuropathy [see Warnings and Precautions ( 5.1 )] Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions ( 5.2 )] Ocular Surface Disorders [see Warnings and Precautions ( 5.3 )] Infusion-Related Reactions (IRR) [see Warnings and Precautions ( 5.4 )] The most common adverse reactions (≥20%) were peripheral neuropathy, fatigue, decreased appetite, and peripheral edema. ( 6.1 ) The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased lymphocytes, increased glucose, increased alanine aminotransferase, increased gamma glutamyl transferase, decreased phosphorus, decreased sodium, decreased hemoglobin and decreased calcium. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. LUMINOSITY The safety population described in WARNINGS AND PRECAUTIONS and below reflects exposure to EMRELIS in 168 patients with locally advanced or metastatic EGFR wild-type non-squamous NSCLC with c-Met protein overexpression who received EMRELIS as a single agent administered at 1.9 mg/kg intravenously every 2 weeks in the LUMINOSITY study [see Clinical Studies ( 14 )]. Among patients who received EMRELIS, 42% were exposed for 6 months or longer and 11% were exposed for greater than one year. The median age of patients who received EMRELIS was 64.5 years (range: 33 to 83 years); 70% were male; 65% were White; 1.8% were Black or African American, 33% were Asian; and 0.6% were of Hispanic or Latino ethnicity. Serious adverse reactions occurred in 35% of patients. Serious adverse reactions occurring in ≥2% of patients included ILD/pneumonitis (5%), pneumonia (5%), peripheral neuropathy (3.6%), and pleural effusion (2.4%). Fatal adverse reactions occurred in 5% of patients who received EMRELIS, including ILD/pneumonitis (1.8%), pneumonia (1.2%), sudden death (1.2%), noninfectious endocarditis (0.6%) and myocardial infarction (0.6%). Permanent discontinuations of EMRELIS due to adverse reactions occurred in 30% of patients. Adverse reactions which resulted in permanent discontinuation of EMRELIS in ≥2% included peripheral neuropathy and ILD/pneumonitis. Dosage interruptions due to adverse reactions occurred in 44% of patients. Adverse reactions which required dosage interruption in ≥2% of patients included peripheral neuropathy, fatigue, pneumonia, increased ALT, blurred vision, COVID-19, ILD/pneumonitis, and keratitis. Dose reductions due to adverse reactions occurred in 28% of patients. Adverse reactions which required dose reductions in ≥2% of patients included peripheral neuropathy, fatigue, and keratitis. The most common adverse reactions (≥20%) were peripheral neuropathy, fatigue, decreased appetite, and peripheral edema. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased lymphocytes, increased glucose, increased ALT, increased gamma glutamyl transferase, decreased phosphorus, decreased sodium, decreased hemoglobin and decreased calcium. Table 5 summarizes the adverse reactions in LUMINOSITY. Table 5. Adverse Reactions (≥10%) in Patients with EGFR Wild-Type Non-squamous NSCLC with c-Met Protein Overexpression in LUMINOSITY Adverse Reaction EMRELIS (N=168) All Grades 1 % Grade 3 or 4 1 % Nervous system disorders Peripheral neuropathy 2 51 11 General disorders and administration site conditions Fatigue 2 29 3.6 Peripheral edema 2 22 1.8 Metabolism and nutrition disorders Decreased appetite 22 0.6 Gastrointestinal disorders Nausea 15 0 Constipation 14 0.6 Vomiting 10 0.6 Eye disorders Blurred vision 3 15 1.2 Keratitis 4 11 0.6 Infections and infestations Pneumonia 2 13 6 Respiratory, thoracic and mediastinal disorders ILD/pneumonitis 2 10 3.6 1 Events were graded using NCI CTCAE version 4.03. 2 Grouped term. 3 Includes vision blurred, visual acuity reduced, visual impairment. 4 Includes corneal cyst, corneal disorder, corneal erosion, corneal edema, corneal opacity, keratitis, keratitis interstitial, punctate keratitis. Other clinically relevant adverse reactions in <10% of patients who received EMRELIS included arthralgia, dizziness, dry eye, infusion-related reaction and photophobia. Table 6 presents laboratory abnormalities in LUMINOSITY. Table 6. Select Laboratory Abnormalities (≥10%) that Worsened from Baseline in Patients with EGFR Wild-Type Non-squamous NSCLC with c-Met Protein Overexpression in LUMINOSITY Laboratory Abnormality EMRELIS (N=168) All Grades % Grade 3 or 4 % Chemistry Albumin decreased 61 0.6 Glucose increased 58 4.8 Calcium decreased 47 2.4 Alanine transaminase increased 41 4.8 Gamma glutamyl transferase increased 36 4.3 Aspartate aminotransferase increased 34 0.6 Phosphorus decreased 33 4.2 Sodium decreased 30 3.6 Alkaline phosphatase increased 30 0.6 Creatinine increased 16 1.2 Potassium decreased 14 1.2 Magnesium decreased 14 0.6 Glucose decreased 11 0 Magnesium increased 10 0 Hematology Lymphocytes decreased 37 10 Hemoglobin decreased 35 3.6 White blood cells decreased 16 1.2 Platelets decreased 14 0.6 Neutrophils decreased 10 1.2 Percentages were calculated using patients with worsening laboratory values from baseline and the number of patients with both baseline and post-treatment measurements as the denominator.

S trong CYP3A I nhibitors : concomitant use with EMRELIS may increase the AUC of MMAE. Monitor for increased risk of adverse reactions to EMRELIS. ( 7.1 ) 7.1 Effect of Other Drugs on EMRELIS Strong CYP3A Inhibitors Concomitant use with strong CYP3A inhibitors may increase unconjugated MMAE AUC [see Clinical Pharmacology ( 12.3 ) ] , which may increase the risk of EMRELIS adverse reactions. Monitor patients for adverse reactions when EMRELIS is given concomitantly with strong CYP3A inhibitors.