Epcoritamab-bysp (Monograph)

Brand name: Epkinly
Drug class: Antineoplastic Agents

Introduction

Epcoritamab-bysp, a bispecific CD20-directed CD3 T-cell engager, is an antineoplastic agent.

Uses for Epcoritamab-bysp

Epcoritamab-bysp has the following uses:

Epcoritamab-bysp 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Epcoritamab-bysp Dosage and Administration

General

Epcoritamab-bysp is available in the following dosage form(s) and strength(s):

• Injection: 4 mg/0.8 mL in a single-dose vial. Dilute prior to use.

• Injection: 48 mg/0.8 mL in a single-dose vial; supplied as a ready-to-use solution that dose not need dilution prior to administration.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• For subcutaneous injection only.

• Recommended dosage schedule is as follows (see Table 1). Initiate therapy according to the step-up dosing schedule to reduce the incidence and severity of cytokine release syndrome (CRS). Administer the drug in 28-day cycles until disease progression or unacceptable toxicity occurs.

• Patients should be hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg.

• Administer premedications and prophylaxis as recommended.

• Administer to well-hydrated patients.

• Administer by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and immune effector cell-associated neurotoxicity syndrome (ICANS).

• Dosages of epcoritamab-bysp 0.16 mg and 0.8 mg require dilution prior to administration.

• See Full Prescribing Information for additional instructions on preparation and administration of the drug, and for dosage modifications for adverse reactions.

Cautions for Epcoritamab-bysp

Contraindications

• None.

Warnings/Precautions

Cytokine Release Syndrome

Epcoritamab can cause cytokine release syndrome (CRS), including serious or life-threatening reactions.

Cytokine release syndrome occurred in 51% of patients receiving epcoritamab-bysp at the recommended dose in the clinical trial, with Grade 1 CRS occurring in 37%, Grade 2 in 17%, and Grade 3 in 2.5% of patients. Recurrent CRS occurred in 16% of patients. Of all the CRS events, most (92%) occurred during Cycle 1. In Cycle 1, 9% of CRS events occurred after the 0.16 mg dose on Cycle 1 Day 1, 16% after the 0.8 mg dose on Cycle 1 Day 8, 61% after the 48 mg dose on Cycle 1 Day 15, and 6% after the 48 mg dose on Cycle 1 Day 22.

The median time to onset of CRS from the most recent administered epcoritamab-bysp dose across all doses was 24 hours (range: 0 to 10 days). The median time to onset after the first full 48 mg dose was 21 hours (range: 0 to 7 days). CRS resolved in 98% of patients and the median duration of CRS events was 2 days (range: 1 to 27 days).

In patients who experienced CRS, the signs and symptoms included pyrexia, hypotension, hypoxia, dyspnea, chills, and tachycardia. Concurrent neurological adverse reactions associated with CRS occurred in 2.5% of patients and included headache, confusional state, tremors, dizziness, and ataxia.

Initiate therapy according to the step-up dosing schedule. Administer pretreatment medications to reduce the risk of CRS and monitor patients for potential CRS following epcoritamab accordingly. Following administration of the first 48 mg dose, patients should be hospitalized for 24 hours. 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 epcoritamab based on the severity of CRS.

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.

Immune Effector Cell-associated Neurotoxicity Syndrome

Epcoritamab can cause life-threatening and fatal immune effector cell-associated neurotoxicity syndrome (ICANS).

ICANS occurred in 6% (10/157) of patients receiving epcoritamab-bysp at the recommended dose in the clinical trial, 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 epcoritamab-bysp 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 epcoritamab-bysp, 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. 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 epcoritamab. At the first signs or symptoms of ICANS, immediately evaluate patient and provide supportive therapy based on severity. Withhold or discontinue epcoritamab per recommendations and consider further management per current practice guidelines.

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.

Infections

Epcoritamab can cause serious and fatal infections.

In the clinical trial, serious infections, including opportunistic infections, were reported in 15% of patients treated with epcoritamab-bysp at the recommended dose with Grade 3 or 4 infections in 14% and fatal infections in 1.3%. The most common Grade 3 or greater infections were sepsis, COVID-19, urinary tract infection, pneumonia, and upper respiratory tract infection.

Monitor patients for signs and symptoms of infection prior to and during treatment with epcoritamab-bysp and treat appropriately. Avoid administration of epcoritamab in patients with active infections. Provide Pneumocystis jirovecii pneumonia (PJP) prophylaxis prior to initiating treatment with epcoritamab; consider initiating prophylaxis against herpes virus prior to starting the drug.

Withhold or consider permanent discontinuation of epcoritamab based on severity.

Cytopenias

Epcoritamab can cause serious or severe cytopenias, including neutropenia, anemia, and thrombocytopenia.

Among patients who received the recommended dosage of epcoritamab-bysp in the clinical trial, Grade 3 or 4 decreased neutrophils occurred in 32%, decreased hemoglobin in 12%, and decreased platelets in 12% of patients. Febrile neutropenia occurred in 2.5%.

Monitor complete blood counts throughout treatment. Based on the severity of cytopenias, temporarily withhold or permanently discontinue epcoritamab. Consider prophylactic granulocyte colony-stimulating factor administration as applicable.

Embryo-fetal Toxicity

Based on its mechanism of action, epcoritamab may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with epcoritamab and for 4 months after the last dose.

Specific Populations

Pregnancy

Based on the mechanism of action, epcoritamab may cause fetal harm when administered to a pregnant woman. There are no available data on the use of epcoritamab-bysp in pregnant women to evaluate for a drug-associated risk. No animal reproductive or developmental toxicity studies have been conducted with epcoritamab-bysp.

Epcoritamab 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 can cause B-cell lymphocytopenia in infants exposed to the drug in-utero. Human immunoglobulin G (IgG) is known to cross the placenta; therefore, epcoritamab 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.

Lactation

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 absorption leading to serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with the drug and for 4 months after the last dose.

Females and Males of Reproductive Potential

Epcoritamab may cause fetal harm when administered to a pregnant woman.

Verify pregnancy status in females of reproductive potential prior to initiating epcoritamab-bysp.

Advise females of reproductive potential to use effective contraception during treatment with epcoritamab-bysp and for 4 months after the last dose.

Pediatric Use

The safety and efficacy of epcoritamab-bysp in pediatric patients have not been established.

Geriatric Use

In patients with relapsed or refractory DLBCL who received epcoritamab-bysp in the clinical trial, 49% were ≥65 years of age, and 19% were ≥75 years of age. No clinically meaningful differences in safety or efficacy were observed between patients ≥65 years of age compared with younger adult patients.

Common Adverse Effects

The most common (≥20%) adverse reactions are cytokine release syndrome, fatigue, musculoskeletal pain, injection site reactions, pyrexia, abdominal pain, nausea, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥10%) are decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, decreased hemoglobin, and decreased platelets.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

For certain cytochrome P-450 (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 epcoritamab-bysp.

Epcoritamab 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 epcoritamab-bysp on Cycle 1 Day 1 and up to 14 days after the first 48 mg dose on Cycle 1 Day 15, and during and after CRS.

Actions

Mechanism of Action

Epcoritamab 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 activated T-cells, caused the release of proinflammatory cytokines, and induced lysis of B-cells.

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Medication Guide).

• Inform patients of the risk of cytokine release syndrome (CRS), and to immediately contact their healthcare provider should signs and symptoms associated with CRS (e.g., pyrexia, hypotension, hypoxia, chills, tachycardia, headache, and dyspnea) occur at any time. Advise patients that they should be hospitalized for 24 hours after administration of the Cycle 1 Day 15 dosage of 48 mg. Advise patients who experience symptoms that impair consciousness not to drive and refrain from operating heavy or potentially dangerous machinery until events resolve.

• Advise patients of the risk of immune effector cell-associated neurotoxicity syndrome (ICANS) and to immediately contact their healthcare provider if signs and symptoms associated with ICANS occur; manifestations may include confusional state, lethargy, tremor, dysgraphia, aphasia, and non-convulsive status epilepticus, and the onset of events may be delayed. Advise patients who experience symptoms of ICANS that impair consciousness to refrain from driving or operating heavy or potentially dangerous machinery until symptoms resolve

• Advise patients of the risk of serious infections, and to contact their healthcare professional if signs or symptoms of serious infection occur.

• Inform patients of the signs and symptoms associated with cytopenias, including neutropenia and febrile neutropenia, anemia, and thrombocytopenia.

• Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider if they are pregnant or become pregnant.

• Advise women not to breastfeed during treatment with epcoritamab-bysp and for 4 months after the last dose.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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