Epcoritamab

EPKINLY is a bispecific CD20-directed CD3 T-cell engager indicated: For the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after two or more lines of systemic therapy. ( 1.1 ) This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). In combination with lenalidomide and rituximab for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL). ( 1.2 ) As monotherapy for the treatment of adult patients with relapsed or refractory FL after two or more lines of systemic therapy. ( 1.2 ) 1.1 DLBCL and High-grade B-cell Lymphoma EPKINLY is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate and durability 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 Follicular Lymphoma EPKINLY is indicated in combination with lenalidomide and rituximab for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL). EPKINLY is indicated as monotherapy for the treatment of adult patients with relapsed or refractory FL after two or more lines of systemic therapy.

EPKINLY is a clear to slightly opalescent, colorless to slightly yellow solution for subcutaneous injection: Injection: 4 mg/0.8 mL in a single-dose vial Injection: 48 mg/0.8 mL in a single-dose vial Injection: 4 mg/0.8 mL in a single-dose vial. ( 3 ) Injection: 48 mg/0.8 mL in a single-dose vial. ( 3 )

None. None. ( 4 )

Infections: Can cause fatal or serious infections. Monitor patients for signs or symptoms of infection, including opportunistic infections, and treat appropriately. ( 5.3 ) Cytopenias: Monitor complete blood cell counts during treatment. ( 5.4 ) Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 )

5.1 Cytokine Release Syndrome EPKINLY can cause CRS, including serious or fatal reactions [see Adverse Reactions (6.1) ] . Relapsed or Refractory Large B-cell Lymphoma CRS occurred in 51% (80/157) of patients with LBCL receiving EPKINLY at the recommended dosage schedule in EPCORE NHL-1, with Grade 1 CRS occurring in 37%, Grade 2 in 17%, and Grade 3 in 2.5% of patients. Recurrent CRS occurred in 31% of these patients. Most CRS events (92%) occurred during Cycle 1. In Cycle 1, CRS events occurred in 6% of patients after the 0.16 mg dose, 12% after the 0.8 mg dose, 43% after the first 48 mg dose, and 5% after the next 48 mg dose. The median time to onset of CRS from the most recent EPKINLY dose was 24 hours (range: 0 to 10 days). The median time to onset after the first 48 mg dose was 21 hours (range: 0 to 7 days). For patients with LBCL, assess whether hospitalization or outpatient monitoring for the first 48 mg dose (Cycle 1 Day 15) is appropriate based on comorbidities or other situational factors [see Dosage and Administration (2.1) ]. During outpatient monitoring after the first 48 mg dose, patients should remain in proximity to a healthcare facility that can assess and manage CRS. Relapsed or Refractory Follicular Lymphoma CRS occurred in 49% (42/86) of patients with FL receiving EPKINLY monotherapy at the recommended dosage schedule in EPCORE NHL-1, with Grade 1 CRS occurring in 45% and Grade 2 in 9% of patients. Recurrent CRS occurred in 48% of patients. Most CRS events (88%) occurred during Cycle 1. In Cycle 1, CRS events occurred in 12% of patients after the 0.16 mg dose, 6% after the 0.8 mg dose, 15% after the 3 mg dose, and 37% after the first 48 mg dose. The median time to onset of CRS from the most recent EPKINLY dose was 59 hours (range: 0.1 to 7 days). The median time to onset after the first 48 mg dose was 61 hours (range: 0.1 to 7 days). CRS occurred in 24% (32/131) of patients with FL receiving EPKINLY at the recommended dosage schedule in combination with lenalidomide and rituximab in EPCORE FL-1, with Grade 1 CRS occurring in 19%, Grade 2 in 5% of patients, and serious adverse reactions due to CRS in 12%. Recurrent CRS occurred in 41% of patients. Most CRS events (88%) occurred during Cycle 1. In Cycle 1, CRS occurred in 5% of patients after the 0.16 mg dose, 3.8% after the 0.8 mg dose, 2.3% after the 3 mg dose, and 18% after the first 48 mg dose. The median time to onset of CRS from the most recent EPKINLY dose was 78 hours (range: 0.2 to 12 days). The median time to onset after the first 48 mg dose was 41 hours (range: 0.3 to 12 days). For patients with FL, assess whether hospitalization or outpatient monitoring for the first 48 mg dose (Cycle 1 Day 22) is appropriate based on comorbidities or other situational factors [see Dosage and Administration (2.1) ] . During outpatient monitoring after the first 48 mg dose, patients should remain in proximity to a healthcare facility that can assess and manage CRS. Among patients with LBCL or FL who experienced CRS, signs and symptoms included pyrexia, hypotension, hypoxia, dyspnea, chills, and tachycardia. CRS resolved in 98% of patients, after a median duration of 2 days (range: < 1 to 27 days). Concurrent neurological adverse reactions associated with CRS occurred in 2.5% of patients with LBCL, 4.7% of patients with FL receiving EPKINLY monotherapy, and 1.5% of patients receiving EPKINLY in combination with lenalidomide and rituximab. Concurrent neurological adverse reactions included headache, confusional state, tremors, dizziness, and ataxia. Initiate EPKINLY according to the recommended step-up dosage schedule. Administer pretreatment medications to reduce the risk of CRS and monitor patients for potential CRS accordingly [see Dosage and Administration (2.2 , 2.3 , 2.4) ] . At the first signs or symptoms of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines, and administer supportive care as appropriate. Withhold or discontinue EPKINLY based on the severity of CRS [see Dosage and Administration (2.6) ] . Patients who experience CRS (or other adverse reactions that impair consciousness) should be evaluated and advised not to drive and to refrain from operating heavy or potentially dangerous machinery until resolution.

5.2 Immune Effector Cell-Associated Neurotoxicity Syndrome EPKINLY can cause life-threatening and fatal immune effector cell-associated neurotoxicity syndrome (ICANS) [see Adverse Reactions (6.1) ] . Relapsed or Refractory Large B-cell Lymphoma ICANS occurred in 6% (10/157) of patients with LBCL receiving EPKINLY at the recommended dosage schedule in EPCORE NHL-1, with Grade 1 ICANS in 4.5% and Grade 2 ICANS in 1.3% of patients. There was one (0.6%) fatal ICANS occurrence. Of the 10 ICANS events, 9 occurred within Cycle 1 of EPKINLY treatment, with a median time to onset of ICANS of 16.5 days (range: 8 to 141 days) from the start of treatment. Relative to the most recent administration of EPKINLY, the median time to onset of ICANS was 3 days (range: 1 to 13 days). The median duration of ICANS was 4 days (range: 0 to 8 days) with ICANS resolving in 90% of patients with supportive care. Relapsed or Refractory Follicular Lymphoma ICANS occurred in 6% (8/127) of patients with FL receiving EPKINLY monotherapy following the 2-step up dosage schedule in EPCORE NHL-1, with Grade 1 ICANS in 3.9% and Grade 2 ICANS in 2.4% of patients. The median time to onset of ICANS was 22 days (range: 14 to 66 days) from the start of treatment. Relative to the most recent administration of EPKINLY, the median time to onset of ICANS was 3 days (range: 0.4 to 7 days). The median duration of ICANS was 2 days (range: 1 to 7 days) with ICANS resolving in 100% of patients. Among patients with FL who received EPKINLY at the recommended dosage schedule in combination with lenalidomide and rituximab in EPCORE FL-1, ICANS occurred in 0.8% (1/131, Grade 1). For patients with LBCL or FL, clinical manifestations of ICANS included, but were not limited to confusional state, lethargy, tremor, dysgraphia, aphasia, and non-convulsive status epilepticus. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Monitor patients for potential ICANS following EPKINLY. At the first signs or symptoms of ICANS, immediately evaluate patient and provide supportive therapy based on severity. Withhold or discontinue EPKINLY per recommendations and consider further management per current practice guidelines [see Dosage and Administration (2.6) ] . Patients who experience signs or symptoms of ICANS or any other adverse reactions that impair cognition or consciousness should be evaluated, including potential neurology evaluation, and patients at increased risk should be advised not to drive and to refrain from operating heavy or potentially dangerous machinery until resolution.

5.3 Infections EPKINLY can cause fatal and serious infections [see Adverse Reactions (6.1) ] . Serious infections, including opportunistic infections, were reported in 15% of patients with LBCL receiving EPKINLY at the recommended dosage schedule in EPCORE NHL-1 and were most commonly due to sepsis (4.5%) and pneumonia (3.2%). Fatal infections occurred in 1.3% of patients and were due to COVID-19. […]

The following clinically significant adverse reactions are described elsewhere in the labeling: Cytokine Release Syndrome [see Warnings and Precautions (5.1) ]. Immune Effector Cell-Associated Neurotoxicity Syndrome [see Warnings and Precautions (5.2) ]. Infections [see Warnings and Precautions (5.3) ]. Cytopenias [see Warnings and Precautions (5.4) ]. EPKINLY as monotherapy for LBCL or FL: The most common (≥ 20%) adverse reactions are CRS, injection site reactions, fatigue, musculoskeletal pain, fever, diarrhea, COVID-19, rash and abdominal pain. The most common Grade 3 to 4 laboratory abnormalities (≥ 10%) are decreases in lymphocyte count, neutrophil count, hemoglobin, and platelets. ( 6.1 ) EPKINLY in combination with lenalidomide and rituximab for FL: The most common (≥ 20%) adverse reactions are rash, upper respiratory tract infections, fatigue, injection site reactions, constipation, diarrhea, CRS, pneumonia, COVID-19, and fever. The most common Grade 3 to 4 laboratory abnormalities (≥ 10%) are decreased neutrophil count, lymphocyte count, and platelets. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Genmab US, Inc. at 1-855-4GENMAB (1-855-443-6622) 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. Relapsed or Refractory Large B-cell Lymphoma (LBCL) EPCORE NHL-1 The safety of EPKINLY was evaluated in EPCORE NHL-1, a single-arm study of patients with relapsed or refractory LBCL after two or more lines of systemic therapy, including DLBCL not otherwise specified, DLBCL arising from indolent lymphoma, high grade B-cell lymphoma, and other B-cell lymphomas [see Clinical Studies (14.1) ] . A total of 157 patients with LBCL received EPKINLY via subcutaneous injection until disease progression or unacceptable toxicities according to the following 28-day cycle schedule: Cycle 1: EPKINLY 0.16 mg on Day 1, 0.8 mg on Day 8, 48 mg on Days 15 and 22 Cycles 2-3: EPKINLY 48 mg on Days 1, 8, 15, and 22 Cycles 4-9: EPKINLY 48 mg on Days 1 and 15 Cycles 10 and beyond: EPKINLY 48 mg on Day 1 Of the 157 patients treated, the median age was 64 years (range: 20 to 83), 60% were male, and 97% had an ECOG performance status of 0 or 1. Race was reported in 133 (85%) patients; of these patients, 61% were White, 19% were Asian, and 0.6% were Native Hawaiian or Other Pacific Islander. There were no Black or African American or Hispanic or Latino patients treated in the clinical trial as reported. The median number of prior therapies was 3 (range: 2 to 11). The study excluded patients with CNS involvement of lymphoma, allogeneic HSCT or solid organ transplant, an ongoing active infection, and any patients with known impaired T-cell immunity. The median duration of exposure for patients receiving EPKINLY was 5 cycles (range: 1 to 20 cycles). Serious adverse reactions occurred in 54% of patients who received EPKINLY. Serious adverse reactions in ≥ 2% of patients included CRS, infections (including sepsis, COVID-19, pneumonia, and upper respiratory tract infections), pleural effusion, febrile neutropenia, fever, and ICANS. Fatal adverse reactions occurred in 3.8% of patients who received EPKINLY, including COVID-19 (1.3%), hepatotoxicity (0.6%), ICANS (0.6%), myocardial infarction (0.6%), and pulmonary embolism (0.6%). Permanent discontinuation of EPKINLY due to an adverse reaction occurred in 3.8% of patients. Adverse reactions which resulted in permanent discontinuation of EPKINLY included COVID-19, CRS, ICANS, pleural effusion, and fatigue. Dosage interruptions of EPKINLY due to an adverse reaction occurred in 34% of patients who received EPKINLY. Adverse reactions which required dosage interruption in ≥ 3% of patients included CRS, neutropenia, sepsis, and thrombocytopenia. The most common (≥ 20%) adverse reactions were CRS, fatigue, musculoskeletal pain, injection site reactions, pyrexia, abdominal pain, nausea, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥ 10%) were decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, decreased hemoglobin, and decreased platelets. Table 11 summarizes the adverse reactions in EPCORE NHL-1. Table 11: Adverse Reactions (≥ 10%) in Patients with Relapsed or Refractory LBCL Who Received EPKINLY in EPCORE NHL-1 EPKINLY (N=157) Adverse Reaction Adverse reactions were graded based on CTCAE Version

5.0 All Grades (%) Grade 3 or 4 (%) Immune system disorders Cytokine release syndrome CRS was graded using ASTCT consensus criteria (Lee et al., 2019). 51

2.5 Only grade 3 adverse reactions occurred. General disorders and administration site conditions Fatigue Fatigue includes asthenia, fatigue, lethargy. 29

2.5 Injection site reactions Injection site reaction includes injection site erythema, injection site hypertrophy, injection site inflammation, injection site mass, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling, injection site urticaria. 27 0 Pyrexia 24 0 Edema Edema includes edema, edema peripheral, face edema, generalized edema, peripheral swelling. 14

1.9 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes back pain, bone pain, flank pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain, pain in extremity, spinal pain. 28

1.3 Gastrointestinal disorders Abdominal pain Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness. 23

1.9 Diarrhea 20 0 Nausea 20

1.3 Vomiting 12

0.6 Skin and subcutaneous disorders Rash Rash includes dermatitis bullous, erythema, palmar erythema, penile erythema, rash, rash erythematous, rash maculo-papular, rash pustular, recall phenomenon, seborrheic dermatitis, skin exfoliation. 15

0.6 Nervous system disorder Headache 13

0.6 Metabolism and nutrition disorders Decreased appetite 12

0.6 Cardiac disorders Cardiac arrhythmias Cardiac arrhythmias includes bradycardia, sinus bradycardia, sinus tachycardia, supraventricular extrasystoles, supraventricular tachycardia, tachycardia. 10

0.6 Clinically relevant adverse reactions in < 10% of patients who received EPKINLY included ICANS, sepsis, pleural effusion, COVID-19, pneumonia (including pneumonia and COVID-19 pneumonia), tumor flare, febrile neutropenia, upper respiratory tract infections, and tumor lysis syndrome. Table 12 summarizes laboratory abnormalities in EPCORE NHL-1. Table 12: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with Relapsed or Refractory LBCL Who Received EPKINLY in EPCORE NHL-1 Laboratory Abnormality Laboratory abnormalities were graded based on CTCAE Version 5.0 EPKINLY The denominator used to calculate the rate varied from 146 to 153 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Grade 3 or 4 (%) Hematology Lymphocyte count decreased 87 77 Hemoglobin decreased 62 12 White blood cells decreased 53 22 Neutrophils decreased 50 32 Platelets decreased 48 12 Chemistry Sodium decreased 56

2.6 Phosphate decreased CTCAE Version 5.0 does not include numeric thresholds for grading of hypophosphatemia; all grades represent patients with lab value < Lower Limit of Normal (LLN). […]

For certain CYP substrates, minimal changes in the concentration may lead to serious adverse reactions. Monitor for toxicity or drug concentrations of such CYP substrates when co-administered with EPKINLY. Epcoritamab-bysp causes release of cytokines [see Clinical Pharmacology (12.2) ] that may suppress activity of CYP enzymes, resulting in increased exposure of CYP substrates. Increased exposure of CYP substrates is more likely to occur after the first dose of EPKINLY and up to 14 days after the first 48 mg dose, and during and after CRS [see Warnings and Precautions (5.1) ] .

Lactation : Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on the mechanism of action, EPKINLY may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on the use of EPKINLY in pregnant women to evaluate for a drug-associated risk. No animal reproductive or developmental toxicity studies have been conducted with epcoritamab-bysp. Epcoritamab-bysp causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. In addition, based on expression of CD20 on B-cells and the finding of B-cell depletion in non-pregnant animals, epcoritamab-bysp can cause B-cell lymphocytopenia in infants exposed to epcoritamab-bysp in-utero. Human immunoglobulin G (IgG) is known to cross the placenta; therefore, EPKINLY has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the 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.

8.2 Lactation Risk Summary There is no information regarding the presence of epcoritamab-bysp in human milk, the effect on the breastfed child, or milk production. Because maternal IgG is present in human milk, and there is potential for epcoritamab-bysp absorption leading to serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with EPKINLY and for 4 months after the last dose.

8.3 Females and Males of Reproductive Potential EPKINLY may 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 EPKINLY. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with EPKINLY and for 4 months after the last dose.

8.4 Pediatric Use The safety and efficacy of EPKINLY in pediatric patients have not been established.

8.5 Geriatric Use LBCL In patients with relapsed or refractory LBCL who received EPKINLY in EPCORE NHL-1, 77 (49%) were 65 years of age and older, and 29 (19%) were 75 years of age or older. No clinically meaningful differences in safety or efficacy were observed between patients with relapsed or refractory LBCL who were 65 years of age and older compared with younger adult patients. FL In patients with relapsed or refractory FL who received EPKINLY in combination with lenalidomide and rituximab in EPCORE FL-1, 88 (36%) were 65 years of age or older and 20 (8%) were 75 years of age or older. No clinically meaningful differences in safety or efficacy were observed between patients who were 65 years of age and older compared with younger patients. In patients with relapsed or refractory FL who received EPKINLY in EPCORE NHL-1, 66 (52%) were 65 years of age or older, and 16 (13%) were 75 years of age and older. In patients with relapsed or refractory FL, there was a higher rate of fatal adverse reactions, primarily infections, including COVID-19, in patients older than 65 years of age compared to younger adult patients. No overall difference in efficacy was observed in patients with relapsed or refractory FL who were 65 years of age and older compared with younger patients.

Epcoritamab-bysp is a T-cell engaging bispecific antibody that binds to the CD3 receptor expressed on the surface of T-cells and CD20 expressed on the surface of lymphoma cells and healthy B-lineage cells. In vitro, epcoritamab-bysp activated T-cells, caused the release of proinflammatory cytokines, and induced lysis of B-cells. In nonclinical studies, the combination of epcoritamab-bysp and rituximab resulted in both T-cell mediated cytotoxicity and natural killer (NK) cell mediated antibody-dependent cellular cytotoxicity (ADCC).