Epkinly Drug Information

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 . 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

All Grades (%) Grade 3 or 4 (%) Immune system disorders Cytokine

release syndrome CRS was graded using ASTCT consensus criteria (Lee et al., 2019). 51

Only grade 3 adverse reactions occurred. General disorders and administration site conditions

Fatigue Fatigue includes asthenia, fatigue, lethargy. 29

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

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

Gastrointestinal disorders Abdominal pain Abdominal pain includes abdominal discomfort, abdominal pain, abdominal

pain lower, abdominal pain upper, abdominal tenderness. 23

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

Nervous system disorder Headache 13 0.6 Metabolism and nutrition disorders Decreased appetite

12

Cardiac disorders Cardiac arrhythmias Cardiac arrhythmias includes bradycardia, sinus bradycardia, sinus tachycardia

supraventricular extrasystoles, supraventricular tachycardia, tachycardia. 10

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

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

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). 56 N/A Aspartate aminotransferase increased 48

Alanine aminotransferase increased 45 5.3 Potassium decreased 34 5.3 Magnesium decreased 31

0 Creatinine increased 24

Potassium increased 21 1.3 Relapsed or Refractory Follicular Lymphoma (FL)

EPCORE FL-1 The safety of EPKINLY in combination with lenalidomide and rituximab was evaluated in EPCORE FL-1, an open-label, randomized, multicenter trial that included patients with relapsed or refractory FL after at least one line of systemic therapy . The study excluded patients with transformed lymphoma, absolute neutrophil count < 1.0 × 10 9 /L, platelet count < 70 × 10 9 /L (or < 50 × 10 9 /L if bone marrow infiltration by lymphoma or splenomegaly), known active infection, creatinine clearance < 50 mL/min, alanine or aspartate transaminase > 3 times the upper limit of normal, and clinically significant cardiovascular disease. Patients were randomized to receive EPKINLY in combination with lenalidomide and rituximab (N=243) or lenalidomide and rituximab alone (N=238). Patients received EPKINLY via subcutaneous injection in 28-day cycles for a total of 12 cycles or until disease progression or unacceptable toxicity, whichever occurred first. Of the 243 patients who received EPKINLY, 131 received the recommended 3 step-up dosage schedule.

The recommended EPKINLY dosage schedule was: Cycle 1: EPKINLY 0.16 mg on Day 1, 0.8 mg on Day 8, 3 mg on Day 15, and 48 mg on Day 22 Cycles 2-3: EPKINLY 48 mg on Days 1, 8, 15, and 22 Cycles 4-12: EPKINLY 48 mg on Day 1 In both treatment arms, lenalidomide was given orally at a dose of 20 mg once daily from Days 1 to 21 for 12 cycles. Rituximab was administered intravenously at a dose of 375 mg/m 2 on Days 1, 8, 15, and 22 of Cycle 1, followed by administration on Day 1 of Cycles 2 to 5. Safety results are based on all 243 patients who received EPKINLY, with the exception of data for CRS and ICANS which are based on patients who received EPKINLY at the recommended dosage schedule. The median duration of exposure in this arm was 10 cycles for EPKINLY and 9 cycles for lenalidomide.

Serious adverse reactions occurred in 51% of these patients, including serious infections in 28% of patients and serious CRS in 12% of patients. Fatal adverse reactions within 60 days of last treatment occurred in 0.8% of patients. Adverse reactions led to permanent discontinuation of EPKINLY in 6% of patients and dose interruption in 75% of patients, with infection as a leading cause.

Adverse reactions leading to interruption of EPKINLY in ≥ 5% of patients included respiratory tract infections, CRS, and rash. In the EPKINLY arm, adverse reactions led to lenalidomide dose interruption in 72%, dose reduction in 22%, and permanent discontinuation in 15%. The most common (≥ 20%) adverse reactions in the EPKINLY arm were 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%) were decreases in neutrophil count, lymphocyte count, and platelets.

Table 13 summarizes select adverse reactions in EPCORE FL-1. Table 13: Adverse Reactions (≥ 10% All Grade and ≥ 5% Higher) in Patients with Relapsed or Refractory FL Who Received EPKINLY in Combination with Lenalidomide and Rituximab in EPCORE FL-1 Adverse Reaction Adverse reactions were graded using CTCAE Version 5.0. CRS was graded using ASTCT consensus criteria (Lee et al., 2019). EPKINLY + Lenalidomide and Rituximab Lenalidomide and Rituximab All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) This table includes a combination of grouped and ungrouped terms. (N=131) (N=238) Immune system disorders Cytokine release syndrome 24 The frequency of CRS is based on 131 patients who received EPKINLY at the recommended dosage schedule . Grade 1 CRS: 19%; Grade 2 CRS: 5%. The frequency of CRS among the 243 patients who received either the 2-step up or 3-step up dosage schedule was the following: Any grade CRS 35%; Grade 1 CRS: 28%; Grade 2 CRS: 7%. 0 0.8 0 (N=243) (N=238) Skin and subcutaneous tissue disorders Rash Rash includes blister, dermatitis, erythema, rash, skin exfoliation, skin reaction, toxic skin eruption, urticaria and related terms. 46 11 Only Grade 3 adverse reactions occurred. 34 6 Infections and infestations Upper respiratory tract infections Upper respiratory tract infections include sinusitis, laryngitis, nasopharyngitis, pharyngitis, rhinitis, rhinovirus infection, upper respiratory tract infection, and related terms. 33 3.3 18

Pneumonia Pneumonia includes pneumonia

COVID-19 pneumonia, pneumonia fungal, Pneumocystis jirovecii pneumonia, pneumonia cytomegaloviral, and related terms. 24 16 8 Includes one case with a fatal outcome.

COVID-19

COVID-19 includes COVID-19, COVID-19 pneumonia, coronavirus infection, coronavirus pneumonia. 23 5 13

General disorders and administration site conditions Fatigue Fatigue includes asthenia, fatigue, lethargy

malaise. 31 4.9 24

Injection site reactions 27 0 0.4 0 Fever 23 0.4 11 1.3

Gastrointestinal disorders Constipation 26 0.8 21 0 Mucositis Mucositis includes gingival pain, glossitis, mouth ulceration, mucosal infection, mucosal inflammation, oral discomfort, oral mucosal exfoliation, oropharyngeal pain, stomatitis. 12 0 3.4 0 Nervous system disorders Neurological changes Neurological changes include brain fog, cognitive disorder, confusional state, disturbance in attention, dysphonia, epilepsy, essential tremor, gait disturbance, hypoacusis, lethargy, loss of consciousness, memory impairment, somnolence, syncope, tremor, vertigo, and ICANS. 15 1.2 8

Headache 11 0 3.8 0 Psychiatric disorders Insomnia 14 0 2.9 0

Other clinically relevant adverse reactions include: Gastrointestinal disorders: diarrhea (26%), nausea (16%), abdominal pain (11%), vomiting (4.1%) Musculoskeletal and connective tissue disorders: musculoskeletal pain (14%), arthralgia (8%) Nervous system disorders: peripheral neuropathy (12%), dizziness (7%), ICANS (0.8%) General disorders: edema (12%) Infections: cytomegalovirus infection (7%), herpesvirus infection (7%), sepsis (2.9%) Blood and lymphatic system disorders: febrile neutropenia (6%) Neoplasms: tumor flare (1.2%) Table 14 summarizes laboratory abnormalities in EPCORE FL-1. Grade 4 laboratory abnormalities in ≥ 2% of the EPKINLY arm included decreases in neutrophils (41%), lymphocytes (13%), and platelets decreased (4.1%). Table 14: Select Laboratory Abnormalities (≥ 30% All Grade and ≥ 10% Higher) That Worsened from Baseline in Patients with Relapsed or Refractory FL Who Received EPKINLY in Combination with Lenalidomide and Rituximab in EPCORE FL-1 Laboratory Abnormality EPKINLY + Lenalidomide and Rituximab The denominator used to calculate the rate varied from 240 to 242 in the EPKINLY arm, and 225 to 236 in the comparator arm, based on the number of patients with a baseline value and at least one post-treatment value. Lenalidomide and Rituximab All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Laboratory abnormalities were graded based on CTCAE Version

Hematology Neutrophils decreased 86 67 75 41 Lymphocytes decreased 86 62 56

15 Hemoglobin decreased 66 7 52

Platelets decreased 50 10 37 7 Chemistry Alanine aminotransferase increased 58 7

36

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). 49 N/A 28 N/A Sodium decreased 43 4.1 23

EPCORE

NHL-1 The safety of EPKINLY as monotherapy was evaluated in EPCORE NHL-1, a single-arm study of patients with relapsed or refractory FL after two or more lines of systemic therapy who received EPKINLY following a 2-step up dosage schedule (N=127) . A separate dose optimization cohort evaluated the recommended 3-step up dosage schedule for CRS mitigation (N=86), where EPKINLY was administered 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, 3 mg on Day 15, and 48 mg on Day 22 Cycle 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 With the exception of CRS, the safety results presented below and in Tables 15 and 16 represent data from patients who received the 2-step up dosage schedule. The data presented for CRS reflects the 86 patients who received the recommended 3-step up dosage schedule. The study excluded patients with CNS involvement of lymphoma, allogeneic HSCT or solid organ transplant, ongoing active infection, any patients with known impaired T-cell immunity, creatinine clearance < 45 ml/min, alanine aminotransferase > 3 times the upper limit of normal, and a cardiac ejection fraction < 45%. Recommended 3-step up Dosage Schedule Of the 86 patients with relapsed or refractory FL who received EPKINLY following the recommended 3-step up dosage schedule, the median age was 63 years (range: 33 to 90), 57% were male, and 100% had an ECOG performance status of 0 or 1. The median duration of exposure was 5 cycles (range: 1 to 12 cycles). CRS occurred in 49% of patients, with Grade 1 CRS occurring in 45% and Grade 2 in 9% of patients.

Serious adverse reactions due to CRS occurred in 28% of patients who received EPKINLY. Dose interruptions due to CRS occurred in 19% of patients who received EPKINLY. 2-step up Dosage Schedule Of the 127 patients with relapsed or refractory FL who received EPKINLY following a 2-step up dosage schedule, the median age was 65 years (range: 39 to 84), 62% were male, and 95% had an ECOG performance status of 0 or 1 . The median duration of exposure for patients receiving EPKINLY was 8 cycles (range: 1 to 33 cycles). Serious adverse reactions occurred in 66% of patients who received EPKINLY. Serious adverse reactions in ≥ 5% of patients included CRS, COVID-19, pneumonia, and second primary malignancies. Fatal adverse reactions occurred in 9% of patients who received EPKINLY, including COVID-19 (5%), pneumonitis (1.6%), cardiac failure (0.8%), pneumonia (0.8%), and sepsis (0.8%). Permanent discontinuation of EPKINLY due to an adverse reaction occurred in 19% of patients who received EPKINLY. Adverse reactions which resulted in permanent discontinuation of EPKINLY in ≥ 2% of patients included COVID-19, Hepatitis E, pneumonitis, and second primary malignancy. Dosage interruptions of EPKINLY due to an adverse reaction occurred in 59% of patients who received EPKINLY. Adverse reactions which required dosage interruption in ≥ 5% of patients included COVID-19, CRS, pneumonia, upper respiratory tract infection, and fatigue.

The most common (≥ 20%) adverse reactions were injection site reactions, CRS, COVID-19, fatigue, upper respiratory tract infection, musculoskeletal pain, rash, diarrhea, pyrexia, cough, and headache. The most common Grade 3 to 4 laboratory abnormalities (≥ 10%) were decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, and decreased hemoglobin. Table 15 summarizes the adverse reactions in EPCORE NHL-1. Table 15: Adverse Reactions (≥ 10%) in Patients with Relapsed or Refractory FL Who Received EPKINLY as Monotherapy in EPCORE NHL-1 Adverse Reaction Adverse reactions were graded based on CTCAE Version 5.0. EPKINLY All Grades (%) Grade 3 or 4 (%) (N=86) The frequency of CRS is based on 86 patients with FL who received the recommended 3-step up dosage schedule in EPCORE NHL-1 . Immune system disorders Cytokine release syndrome CRS was graded using ASTCT consensus criteria (Lee et al., 2019). The frequency of CRS based on the 127 patients with FL who received the 2-step up dosage schedule in EPCORE NHL-1 was the following: Any grade CRS 66%; Grade 1 CRS: 50%; Grade 2 CRS: 26%; Grade 3 CRS: 1.6%. 49 0 (N=127) General disorders and administration site conditions Injection site reactions Includes related grouped terms. 58 0 Fatigue 37 5 Only Grade 3 adverse reactions occurred.

Pyrexia 26 2 Edema 17 0 Infections and Infestations COVID-19 COVID-19 includes COVID-19, COVID-19 pneumonia, SARS-CoV-2 test positive. 40 19 Upper respiratory tract infection Upper respiratory tract infection includes preferred terms with upper respiratory infection and sinusitis, laryngitis viral, nasopharyngitis, oropharyngitis fungal, pharyngitis, rhinitis, rhinovirus infection, tonsillitis. 29 2 Pneumonia Pneumonia includes preferred terms with pneumonia, bronchopulmonary aspergillosis, infectious pleural effusion, infective exacerbation of bronchiectasis, Pneumocystis jirovecii pneumonia, pneumonia respiratory syncytial viral. 17 13 Urinary tract infection 13 5 Herpesvirus infection Herpesvirus infection includes herpes simplex, herpes simplex reactivation, herpes virus infection, herpes zoster, oral herpes, varicella zoster virus infection. 12

Musculoskeletal and connective tissue disorders Musculoskeletal pain 28 0.8 Arthralgia 14 0.8

Skin and subcutaneous disorders Rash 28 0 Gastrointestinal disorders Diarrhea 26

Nausea 17 0 Abdominal pain 17 0.8 Constipation 16 0 Mucositis Mucositis

includes aphthous ulcer, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal pain, stomatitis, tongue ulceration. 12 0 Respiratory disorders Cough 20 0 Dyspnea 17 0 Nervous system disorders Headache 20 0 Neurological changes Neurological changes includes amnesia, aphasia, balance disorder, brain fog, confusional state, dysphonia, encephalopathy, extrapyramidal disorder, hallucination, hypoacusis, memory impairment, mental status changes, tremor, vertigo. 13 0 Peripheral neuropathy and paresthesia Peripheral neuropathy and paresthesia includes bell's palsy, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, polyneuropathy. 13

Dizziness 11 0 Psychiatric disorders Insomnia 13 0 Renal and urinary disorders

Renal insufficiency Renal insufficiency includes acute kidney injury, blood creatinine increased, renal impairment. 10

Clinically relevant adverse reactions in < 10% of patients (N=127) who received

EPKINLY included vomiting, pruritus, hepatotoxicity, ICANS, lower respiratory tract infections, cardiac arrhythmias, respiratory tract infections, pneumonitis, second primary malignancy, vision changes, cellulitis, febrile neutropenia, cardiac failure, cytomegalovirus infection and sepsis. Table 16 summarizes laboratory abnormalities in EPCORE NHL-1. Table 16: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with Relapsed or Refractory FL Who Received EPKINLY in EPCORE NHL-1 Laboratory Abnormality Laboratory abnormalities were graded based on CTCAE Version

EPKINLY

The denominator used to calculate the rate varied from 123 to 127 based on the number of patients with a baseline value and at least one post-treatment value. (N=127) All Grades Grade 3 or 4 (%) Hematology Lymphocytes decreased 94 82 Hemoglobin decreased 59 10 White blood cells decreased 58 19 Neutrophils decreased 55 30 Platelets decreased 49 8 Chemistry Sodium decreased 51

ALT increased 47 8

AST increased 44 6 Creatinine increased 36

Magnesium decreased 20 0.8 6.2 Postmarketing Experience

The following adverse reaction has been identified during post-approval use of EPKINLY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders : Hemophagocytic Lymphohistiocytosis (HLH)

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 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 .

Pregnancy Risk Summary Based on the mechanism of action, EPKINLY may cause fetal harm when administered to a pregnant woman . 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.

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