Epcoritamab

12.1 Mechanism of Action 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).

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION For subcutaneous injection only. ( 2.2 ) Recommended Dosage: ( 2.2 ) DLBCL and High-grade B-cell Lymphoma Cycle Cycle = 28 days Day Dose of EPKINLY Cycle 1 1 Step-up dose 1 0.16 mg 8 Step-up dose 2 0.8 mg 15 First full dose 48 mg 22 48 mg Cycles 2 and 3 1, 8, 15 and 22 48 mg Cycles 4 to 9 1 and 15 48 mg Cycle 10 and beyond 1 48 mg EPKINLY as Monotherapy for FL Cycle Cycle = 28 days Day Dose of EPKINLY Cycle 1 1 Step-up dose 1 0.16 mg 8 Step-up dose 2 0.8 mg 15 Step-up dose 3 3 mg 22 First full dose 48 mg Cycles 2 and 3 1, 8, 15 and 22 48 mg Cycles 4 to 9 1 and 15 48 mg Cycle 10 and beyond 1 48 mg EPKINLY in Combination with Lenalidomide and Rituximab for FL Cycle Cycle = 28 days Day Dose of EPKINLY Cycle 1 1 Step-up dose 1 0.16 mg 8 Step-up dose 2 0.8 mg 15 Step-up dose 3 3 mg 22 First full dose 48 mg Cycles 2 and 3 1, 8, 15, and 22 48 mg Cycles 4 to 12 1 48 mg Monitor all patients for signs and symptoms of CRS and ICANS. ( 2.1 ) Patients with DLBCL or high-grade B-cell lymphoma should be hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg. ( 2.1 )For patients with FL, assess whether hospitalization or outpatient monitoring is appropriate after administration of the Cycle 1 Day 22 dosage of 48 mg. ( 2.1 ) Administer premedications, post-medications, and prophylaxis as recommended. ( 2.4 , 2.5 ) Dosages of EPKINLY 0.16 mg and 0.8 mg require dilution prior to administration. ( 2.7 , 2.8 ) See Full Prescribing Information for instructions on preparation and administration. ( 2.7 , 2.8 , 2.9 , 2.10 ) 2.1 Important Dosing Information Certain doses of EPKINLY require dilution prior to administration. There are 2 available methods to prepare diluted EPKINLY: Empty sterile vial method as described in subsection 2.7 [see Dosage and Administration (2.7) ] , or Sterile syringe method as described in subsection 2.8 [see Dosage and Administration (2.8) ] . Preparation of 3 mg and 48 mg EPKINLY doses does not require dilution. [see Dosage and Administration (2.9) ] . EPKINLY should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and ICANS [see Warnings and Precautions (5.1 , 5.2) ] . Administer EPKINLY to well-hydrated patients. Premedicate before each dose in Cycle 1 [see Dosage and Administration (2.4) ] . Administer EPKINLY subcutaneously according to the recommended step-up dosage schedule to reduce the incidence and severity of CRS [see Dosage and Administration (2.2) ] . Due to the risk of CRS and ICANS, monitor all patients for signs and symptoms [see Dosage and Administration (2.6) ] . For patients with DLBCL or high-grade B-cell lymphoma: Patients should be hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg [see Dosage and Administration (2.2) ]. For patients with FL: Assess whether hospitalization or outpatient monitoring is appropriate based on comorbidities or other situational factors for the Cycle 1 Day 22 dosage of 48 mg [see Dosage and Administration (2.2) ]. 2.2 Recommended Dosage EPKINLY is for subcutaneous injection only. The recommended DLBCL dosage for Cycle 1 consists of 2 step-up doses, and the recommended FL dosage (monotherapy or in combination with lenalidomide and rituximab) consists of 3 step-up doses. EPKINLY as Monotherapy: Administer EPKINLY in 28-day cycles until disease progression or unacceptable toxicity. Table 1: EPKINLY Dosage Schedule for Patients with DLBCL or High-grade B-cell Lymphoma Indication Cycle Cycle = 28 days. Day Dose of EPKINLY DLBCL or High-grade B-cell Lymphoma Cycle 1 1 Step-up dose 1 0.16 mg 8 Step-up dose 2 0.8 mg 15 First full dose 48 mg 22 48 mg Cycles 2 and 3 1, 8, 15 and 22 48 mg Cycles 4 to 9 1 and 15 48 mg Cycle 10 and beyond 1 48 mg Table 2: EPKINLY Dosage Schedule for Patients with FL when Given as Monotherapy Indication Cycle Cycle = 28 days. Day Dose of EPKINLY Follicular Lymphoma Cycle 1 1 Step-up dose 1 0.16 mg 8 Step-up dose 2 0.8 mg 15 Step-up dose 3 3 mg 22 First full dose 48 mg Cycles 2 and 3 1, 8, 15 and 22 48 mg Cycles 4 to 9 1 and 15 48 mg Cycle 10 and beyond 1 48 mg EPKINLY in Combination with Lenalidomide and Rituximab: Administer EPKINLY in 28-day cycles for a total of 12 cycles or until disease progression or unacceptable toxicity, whichever occurs first. Table 3: EPKINLY Dosage Schedule in Combination with Lenalidomide and Rituximab for Patients with FL Indication Cycle Cycle = 28 days. Day Dose of EPKINLY Follicular Lymphoma Cycle 1 1 Step-up dose 1 0.16 mg 8 Step-up dose 2 0.8 mg 15 Step-up dose 3 3 mg 22 First full dose 48 mg Cycles 2 and 3 1, 8, 15, and 22 48 mg Cycles 4 to 12 1 48 mg Administer EPKINLY in combination with lenalidomide 20 mg (Days 1 to 21 in Cycles 1 to 12) and rituximab 375 mg/m 2 (Cycles 1 to 5) [see Clinical Studies (14.2) ]. Refer to the lenalidomide prescribing information and rituximab prescribing information for the respective dosage recom

6 ADVERSE REACTIONS 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 rea

7 DRUG INTERACTIONS 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) ] .