Telisotuzumab Vedotin

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 injection: 20 mg or 100 mg of telisotuzumab vedotin-tllv as a white to off-white, lyophilized powder in a single-dose vial for reconstitution and further dilution. For injection: 20 mg or 100 mg of telisotuzumab vedotin-tllv as a lyophilized powder in a single-dose vial. ( 3 )

None. None. ( 4 )

Peripheral Neuropathy : Monitor patients for new or worsening peripheral neuropathy. Withhold, reduce the dose, or permanently discontinue EMRELIS based on the severity. ( 5.1 ) I nterstitial Lung Disease (ILD)/ Pneumonitis : Severe, life-threatening or fatal ILD/pneumonitis may occur. Withhold or permanently discontinue EMRELIS based on the severity. ( 5.2 ) Ocular Surface Disorders : Monitor patients for signs or symptoms of ocular surface disorders, including vision changes. Withhold or permanently discontinue EMRELIS based on the severity. ( 5.3 ) Infusion – Related Reactions (IRR) : Monitor patients for IRR. Withhold, reduce the rate of infusion, or permanently discontinue EMRELIS based on the severity. For patients who experience IRR, administer premedications prior to subsequent infusions. ( 5.4 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients about the potential risk to a fetus and to use effective contraception. ( 5.5 )

5.1 Peripheral Neuropathy EMRELIS can cause peripheral neuropathy, including peripheral sensory neuropathy and peripheral motor neuropathy. In the safety population [see Adverse Reactions ( 6.1 )], peripheral neuropathy occurred in 51% of patients treated with EMRELIS, including Grade 3 in 11%. These adverse reactions included peripheral sensory neuropathy in 45% of patients and peripheral motor neuropathy in 9%. The median time to onset of peripheral neuropathy was 105 days (range: 1 to 472 days). Peripheral neuropathy led to permanent discontinuation of EMRELIS in 13% of patients. The median time to onset of peripheral neuropathy leading to treatment discontinuation was 249 days (range: 57 to 519 days). Of the 7 patients with motor neuropathy ongoing as of their last dose of EMRELIS, 6 had persistent Grade 1 or 2 symptoms 30 days after their last dose. Monitor patients for signs and symptoms of new or worsening peripheral neuropathy such as hypoesthesia, hyperesthesia, paresthesia, a burning sensation, neuropathic pain, or muscle weakness. Withhold, reduce the dose or permanently discontinue EMRELIS based on severity [see Dosage and Administration ( 2.3 )].

5.2 Interstitial Lung Disease /Pneumonitis EMRELIS can cause severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis. In the safety population [see Adverse Reactions ( 6.1 )], ILD/pneumonitis occurred in 10% of patients treated with EMRELIS, including Grade 3 in 3% and Grade 4 in 0.6%. There were 3 fatal cases of ILD/pneumonitis in patients who received EMRELIS. The median time to onset of ILD/pneumonitis was 48 days (range: 23 to 85 days). ILD/pneumonitis led to permanent discontinuation of EMRELIS in 7% of patients. The median time to onset of ILD/pneumonitis leading to treatment discontinuation was 46 days (range: 23 to 85 days). Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD/pneumonitis. Withhold or permanently discontinue EMRELIS based on severity [see Dosage and Administration ( 2.3 )].

5.3 Ocular Surface Disorders EMRELIS can cause ocular surface disorders including blurred vision, visual impairment, keratitis, and dry eye. In the safety population [see Adverse Reactions ( 6.1 )], ocular surface disorders occurred in 25% of patients treated with EMRELIS. The most common ocular surface disorders were blurred vision (15%), keratitis (11%), and dry eye (5%). Grade 3 ocular surface disorders occurred in 1.2% of patients [blurred vision (1.2%), and keratitis (0.6%)]. The median time to onset of ocular surface disorders was 47 days (range: 1 to 319 days). Monitor patients for ocular surface disorders during treatment with EMRELIS. Withhold EMRELIS and refer patients to an eye care professional for an ophthalmic examination and treatment for patients who develop Grade ≥2 ocular toxicity. Withhold or permanently discontinue EMRELIS based on severity [see Dosage and Administration ( 2.3 )].

5.4 Infusion – Related Reactions EMRELIS can cause infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, chills, nausea, chest discomfort, and hypotension. The median time to onset of IRR was 28 days (range: 1 to 43 days). In the safety population, [see Adverse Reactions ( 6.1 )] , IRR occurred in 3% of patients treated with EMRELIS including Grade 3 in 1.2% and Grade 4 in 0.6%. IRR led to permanent discontinuation of EMRELIS in 0.6% of patients. Monitor patients for signs and symptoms of infusion reactions during EMRELIS infusion. Withhold, reduce the rate of infusion, or permanently discontinue EMRELIS based on severity [see Dosage and Administration ( 2.3 )]. For patients who experience IRR, administer premedications prior to subsequent infusions. 5. 5 Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, EMRELIS can cause fetal harm when administered to a pregnant woman. The small molecule component of EMRELIS, MMAE, administered to rats caused adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities, at exposures similar to those occurring clinically at the recommended dose. Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with EMRELIS and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with EMRELIS and for 4 months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 )].

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.

Severe or Moderate Hepatic I mpairment : Avoid use of EMRELIS. ( 8.6 ) Lactation : Advise not to breastfeed. ( 8.2 ) Infertility : May impair fertility. ( 8.3 )

8.1 Pregnancy Risk Summary Based on the mechanism of action and findings in animals, EMRELIS can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available human data on EMRELIS use in pregnant women to inform a drug-associated risk. In an animal reproduction study, administration of the small molecule component of EMRELIS, MMAE, to pregnant rats during organogenesis resulted in embryo-fetal mortality and structural abnormalities at exposures similar to the clinical exposure at the recommended dose [see Data ] . Advise patients of the potential risks to a fetus. 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. Data Animal Data No embryo-fetal development studies in animals have been performed with telisotuzumab vedotin-tllv. In an embryo-fetal development study in pregnant rats, administration of two intravenous doses of MMAE, the small molecule component of EMRELIS, on gestational days 6 and 13 caused embryo-fetal mortality and structural abnormalities, including protruding tongue, agnathia, malrotated limbs, and gastroschisis compared to controls at a dose of 0.2 mg/kg (approximately 2 times the human area under the curve [AUC] at the recommended dose).

8.2 Lactation Risk Summary There are no data on the presence of telisotuzumab vedotin-tllv or MMAE in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with EMRELIS and for 1 month after the last dose.

8.3 Females and Males of Reproductive Potential EMRELIS can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 ) ] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating EMRELIS treatment. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with EMRELIS and for 2 months after the last dose. Males Based on genotoxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment with EMRELIS and for 4 months after the last dose. Infertility Females Based on findings in animal studies with MMAE-containing antibody-drug conjugates (ADCs), EMRELIS may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology ( 13.1 )] . Males Based on findings from animal studies, EMRELIS may impair male fertility. The reversibility of this effect is unknown [see Nonclinical Toxicology ( 13.1 )] .

8.4 Pediatric Use Safety and effectiveness of EMRELIS have not been established in pediatric patients.

8.5 Geriatric Use Of the 168 patients with previously treated EGFR wild-type non-squamous NSCLC with c-Met protein overexpression treated with EMRELIS in LUMINOSITY, 50% were ≥65 years of age and 12% were ≥75 years of age. No overall differences in safety or effectiveness were observed between older and younger patients.

8.6 Hepatic Impairment Avoid use of EMRELIS in patients with moderate or severe hepatic impairment (total bilirubin >1.5 x ULN and any AST). Patients with moderate or severe hepatic impairment are likely to have increased exposure to MMAE, which may increase the risk of adverse reactions. EMRELIS has not been studied in patients with moderate or severe hepatic impairment. No dosage adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >ULN and ≤1.5 x ULN and any AST) [see Clinical Pharmacology ( 12.3 ) ] .

Telisotuzumab vedotin-tllv is a c-Met-directed antibody drug conjugate (ADC). The antibody is a humanized IgG1κ directed against c-Met, the cell surface receptor for hepatocyte growth factor. The small molecule, MMAE, is a microtubule-disrupting agent, attached to the antibody via a protease cleavable linker. Following binding to c-Met-expressing cells, telisotuzumab vedotin-tllv undergoes internalization and intracellular cleavage of MMAE. MMAE disrupts the microtubule network of actively dividing cells, subsequently inducing cell cycle arrest and apoptotic cell death. Telisotuzumab vedotin-tllv exhibited antitumor activity in xenograft models of NSCLC.