Epcoritamab

Epcoritamab is a humanised IgG1 bispecific antibody, produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology, that binds CD20 on B cells and CD3 on T cells at the same time. This brings the patient’s own T cells into contact with CD20-positive lymphoma cells and activates them to destroy those cells.

Mechanism of Action

• Two targets: one arm binds a specific extracellular epitope of CD20 on B cells (malignant cells and healthy B-lineage cells) and the other binds CD3 on T cells. Activity depends on both being engaged at once, which activates the T cell and leads to T-cell-mediated killing of the CD20-expressing cell.
• Silenced Fc region: the Fc region is silenced, which prevents target-independent immune effects such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP).
• With rituximab: in preclinical studies epcoritamab and rituximab did not interfere with each other and produced complementary NK-cell-mediated ADCC and T-cell-mediated cytotoxicity.
• B-cell depletion: in patients who had detectable circulating B cells at the start of treatment, epcoritamab caused rapid and sustained depletion of those cells.
• T cells and cytokines: circulating T cells fall transiently right after each dose in Cycle 1 and then expand in later cycles. Transient, modest rises in interferon-γ, TNF-α, IL-6, IL-2 and IL-10 occur mostly after the first full 48 mg dose and peak 1 to 4 days later. This cytokine release is the basis of cytokine release syndrome.

Pharmacokinetics

• Model: the pharmacokinetics are described by a two-compartment population model with first-order subcutaneous absorption and target-mediated drug elimination. Variability between patients is moderate to high.
• Absorption: after subcutaneous injection of the 48 mg dose, peak concentrations occur after about 3 to 4 days in large B-cell lymphoma. At the end of the weekly schedule the geometric mean peak concentration was 10.8 µg/mL and the AUC over 7 days 68.9 day·µg/mL; the trough at week 12 was 8.4 µg/mL. At steady state on the every-4-weeks schedule the peak was 4.76 µg/mL and the trough 1.2 µg/mL.
• Distribution: central volume of distribution 8.27 L; apparent steady-state volume of distribution 25.6 L.
• Metabolism: not studied directly. Like other protein medicines, epcoritamab is expected to be broken down into small peptides and amino acids by catabolic pathways.
• Elimination: expected to undergo saturable, target-mediated clearance; geometric mean clearance 0.441 L/day. The half-life depends on concentration and is about 22 days at the full 48 mg dose by the end of the third cycle.
• Special populations: exposure in follicular lymphoma is consistent with that in large B-cell lymphoma, and is similar with the 2-step and 3-step schedules apart from transiently lower trough concentrations on Cycle 1 Day 15 after the 3 mg dose of the 3-step schedule. No dose adjustment is needed for patients aged 65 and over, for mild to moderate renal impairment or for mild hepatic impairment.

Epcoritamab is used in adults, alone or (in follicular lymphoma) together with lenalidomide and rituximab.

• Diffuse large B-cell lymphoma (DLBCL): as monotherapy, for relapsed or refractory DLBCL after two or more lines of systemic therapy.
• Follicular lymphoma (FL), combination: together with lenalidomide and rituximab, for relapsed or refractory FL.
• Follicular lymphoma (FL), monotherapy: as monotherapy, for relapsed or refractory FL after two or more lines of systemic therapy.

• Hypersensitivity to epcoritamab or to any of the excipients.

In the main monotherapy study (382 patients with large B-cell lymphoma or follicular lymphoma after two or more lines of systemic therapy), the most common side effects (≥20%) were cytokine release syndrome (CRS), injection site reactions, fatigue, viral infection, neutropenia, musculoskeletal pain, pyrexia and diarrhoea. Serious reactions occurred in 50% of patients, and the most frequent was CRS (34%). Fatal reactions occurred in 3.7% (pneumonia 2.4%, viral infection 1.0%, ICANS 0.3%). Reactions led to treatment discontinuation in 6.8% of patients and to dose delays in 42%. With lenalidomide and rituximab (243 patients) the most common reactions (≥20%) were neutropenia, rash, upper respiratory tract infections, fatigue, diarrhoea, injection site reactions, anaemia, constipation, thrombocytopenia, CRS, hypogammaglobulinaemia, COVID-19, pyrexia and pneumonia; serious reactions occurred in 44%, epcoritamab was permanently stopped for a reaction in 6.6% and doses were delayed in 70%.

Very common (≥1/10): infections: viral infection (including COVID-19, herpes zoster and cytomegalovirus infection), pneumonia, upper respiratory tract infection; blood and lymphatic system: neutropenia, anaemia, thrombocytopenia, lymphopenia; immune system: cytokine release syndrome, hypogammaglobulinaemia; metabolism and nutrition: decreased appetite; nervous system: headache; gastrointestinal: diarrhoea, abdominal pain, nausea; skin: rash; musculoskeletal: musculoskeletal pain; general: injection site reactions, fatigue, pyrexia, oedema. Also very common with lenalidomide and rituximab: insomnia, neurological changes (such as tremor, memory impairment, balance disorder or confusion), constipation, low blood potassium, raised ALT and AST.

Common (≥1/100 to <1/10): infections: fungal infection, sepsis, cellulitis; neoplasms: tumour flare; blood: febrile neutropenia; metabolism: hypokalaemia, hypophosphataemia, hypomagnesaemia, tumour lysis syndrome; nervous system: immune effector cell-associated neurotoxicity syndrome (ICANS); cardiac: cardiac arrhythmias (including bradycardia and tachycardia); respiratory: pleural effusion; gastrointestinal: vomiting; skin: pruritus; investigations: raised ALT, AST, blood creatinine and alkaline phosphatase, low blood sodium. With lenalidomide and rituximab, cytomegalovirus infection, herpes virus infection and mucositis were also common.

Uncommon (≥1/1,000 to <1/100): haemophagocytic lymphohistiocytosis. With lenalidomide and rituximab, ICANS was also uncommon (0.8%).

Important serious reactions:

• Cytokine release syndrome: in monotherapy with the 2-step schedule, CRS of any grade occurred in 58% of patients (Grade 1 in 35%, Grade 2 in 21%, Grade 3 in 2.4%), most often after the first full dose (51%), with a median onset of about 19 hours after that dose; it resolved in 99% of patients, with a median duration of 2 days. With the 3-step schedule in follicular lymphoma it occurred in 49% (no Grade 3 or higher), and with lenalidomide and rituximab in 26% (no Grade 3 or higher). The commonest signs are pyrexia, hypotension and hypoxia.
• ICANS: occurred in 4.7% of monotherapy patients (Grade 1 in 3.1%, Grade 2 in 1.3%, one fatal case); the median time to first onset was 18 days after starting treatment, and 94% resolved with supportive care.
• Serious infections: 25% of patients with large B-cell lymphoma and 32% with follicular lymphoma on monotherapy, and 33% on the combination, mostly COVID-19 and pneumonia; fatal infections occurred in 4.2% and 3.7% of the two monotherapy groups.
• Neutropenia: 28% on monotherapy (23% Grade 3 or 4) and 74% on the combination (27% Grade 3, 42% Grade 4).
• Tumour lysis syndrome and tumour flare: tumour lysis syndrome occurred in 1.0% and tumour flare in 1.6% of monotherapy patients.

• No interaction studies have been performed.
• CYP450 substrates: the transient rise in proinflammatory cytokines after epcoritamab may suppress CYP450 enzyme activity. When starting epcoritamab in patients taking CYP450 substrates with a narrow therapeutic index, therapeutic monitoring should be considered.
• Lenalidomide and rituximab: see their SmPCs for premedication, dose modifications and interactions. In preclinical studies rituximab did not functionally interfere with epcoritamab.
• Antihypertensive medicines: during Cycle 1 they are held for 24 hours before each epcoritamab administration (see Administration and Dosage).

Epcoritamab must be given only under the supervision of a healthcare professional qualified in anti-cancer therapy. At least one dose of tocilizumab for use in CRS must be available before the Cycle 1 administration, and access to a further dose within 8 hours of the previous tocilizumab dose must be possible. Patients are monitored for signs and symptoms of CRS and ICANS after each administration and managed according to current practice guidelines.

Dose Schedule: Diffuse Large B-Cell Lymphoma (monotherapy)

A 2-step step-up schedule in 28-day cycles:

• Cycle 1 (weekly): Day 1, 0.16 mg (priming dose); Day 8, 0.8 mg (intermediate dose); Day 15, 48 mg (first full dose); Day 22, 48 mg.
• Cycles 2–3 (weekly): 48 mg on Days 1, 8, 15 and 22.
• Cycles 4–9 (every two weeks): 48 mg on Days 1 and 15.
• Cycle 10 onwards (every four weeks): 48 mg on Day 1.
• Treatment continues until disease progression or unacceptable toxicity.

Dose Schedule: Follicular Lymphoma (monotherapy)

A 3-step step-up schedule in 28-day cycles:

• Cycle 1 (weekly): Day 1, 0.16 mg (priming dose); Day 8, 0.8 mg (intermediate dose); Day 15, 3 mg (second intermediate dose); Day 22, 48 mg (first full dose).
• Cycles 2–3 (weekly): 48 mg on Days 1, 8, 15 and 22.
• Cycles 4–9 (every two weeks): 48 mg on Days 1 and 15.
• Cycle 10 onwards (every four weeks): 48 mg on Day 1.
• Treatment continues until disease progression or unacceptable toxicity.

Dose Schedule: Follicular Lymphoma with Lenalidomide and Rituximab

Epcoritamab is given for a total of 12 cycles of 28 days, or until disease progression or unacceptable toxicity, whichever occurs first:

• Cycle 1 (weekly): Day 1, 0.16 mg; Day 8, 0.8 mg; Day 15, 3 mg; Day 22, 48 mg (first full dose).
• Cycles 2–3 (weekly): 48 mg on Days 1, 8, 15 and 22.
• Cycles 4–12 (every four weeks): 48 mg on Day 1.
• Lenalidomide: 20 mg orally once daily on Days 1 to 21 of Cycles 1–12.
• Rituximab: 375 mg/m² intravenously weekly in Cycle 1 (Days 1, 8, 15 and 22) and every 4 weeks in Cycles 2–5 (Day 1).

Premedication, Hydration and Prophylaxis

• Cycle 1, all patients: a corticosteroid (dexamethasone 15 mg, the preferred choice, or prednisolone 100 mg, or an equivalent, orally or intravenously) 30 to 120 minutes before each weekly dose and on the three consecutive days after each weekly dose; plus diphenhydramine 50 mg (oral or intravenous) or an equivalent and paracetamol 650 to 1,000 mg orally, 30 to 120 minutes before each weekly dose.
• Cycle 2 onwards: patients who had Grade 2 or 3 CRS with the previous dose receive the corticosteroid again before the next dose and for three consecutive days after it, until a dose is given without any grade of CRS. Premedication used for the combination medicines may serve for epcoritamab if the doses are at least equivalent.
• Infection prophylaxis: prophylaxis against Pneumocystis jirovecii pneumonia and herpes virus infections is strongly recommended during treatment.
• Hydration in Cycle 1 (unless medically contraindicated): 2 to 3 L of fluid in the 24 hours before and in the 24 hours after each dose; antihypertensive medicines held for 24 hours before each dose; 500 mL of isotonic intravenous fluid on the day of each dose before the injection.
• Tumour lysis risk: patients at increased risk of clinical tumour lysis syndrome should receive hydration and a uric acid-lowering medicine.

Managing CRS and ICANS

CRS and ICANS are graded by the ASTCT consensus criteria. Other causes of fever, hypoxia, hypotension or neurological symptoms should be excluded first.

• CRS, Grade 1: supportive care (antipyretics, intravenous fluids); dexamethasone may be started; consider tocilizumab in older patients, with a high tumour burden, circulating tumour cells or fever that does not respond to antipyretics. Hold epcoritamab until the event resolves.
• CRS, Grade 2: supportive care; dexamethasone 10–20 mg a day should be considered and tocilizumab is recommended. Hold epcoritamab until resolution.
• CRS, Grade 3: dexamethasone (10–20 mg intravenously every 6 hours) and tocilizumab; if refractory, other immunosuppressants and methylprednisolone 1,000 mg a day. Hold epcoritamab until resolution; discontinue if Grade 3 CRS lasts longer than 72 hours or if there are more than two separate Grade 3 events.
• CRS, Grade 4: permanent discontinuation, with the same treatment as Grade 3.
• Tocilizumab dose: 8 mg/kg intravenously over 1 hour (not more than 800 mg per dose), repeated after at least 8 hours if needed, to a maximum of 2 doses in 24 hours.
• ICANS, Grade 1–2: dexamethasone (10 mg intravenously every 12 hours for Grade 1; 10–20 mg every 12 hours for Grade 2); consider a non-sedating anti-seizure medicine such as levetiracetam. Hold epcoritamab until resolution.
• ICANS, Grade 3–4: dexamethasone 10–20 mg intravenously every 6 hours, with methylprednisolone 1,000 mg a day if there is no response, and a non-sedating anti-seizure medicine. Permanently discontinue epcoritamab.
• ICANS with CRS: anti-cytokine therapy is not recommended for ICANS without CRS; with concurrent CRS, an alternative to tocilizumab (anakinra or siltuximab) is preferred where possible. With the combination, consider holding lenalidomide until the event resolves.

Dose Modifications for Other Adverse Reactions

• Infections (Grades 1–4): withhold epcoritamab in patients with an active infection until it resolves; consider permanent discontinuation for Grade 4.
• Neutropenia: withhold if the absolute neutrophil count is below 0.5 ×10⁹/L, until it is 0.5 ×10⁹/L or higher. Consider granulocyte colony-stimulating factor (G-CSF) for febrile neutropenia and recurring Grade 3 or higher neutropenia.
• Thrombocytopenia: withhold if platelets are below 50 ×10⁹/L, until they are 50 ×10⁹/L or higher.
• Other adverse reactions of Grade 3 or higher: withhold until the toxicity resolves to Grade 1 or baseline.

Missed or Delayed Doses

A re-priming cycle (identical to Cycle 1, with standard CRS prophylaxis) is required, after which treatment resumes on Day 1 of the next planned cycle:

• Diffuse large B-cell lymphoma: more than 8 days between the 0.16 mg and 0.8 mg doses, more than 14 days between the 0.8 mg dose and the first 48 mg dose, or more than 6 weeks between 48 mg doses.
• Follicular lymphoma: more than 8 days between the 0.16 mg and 0.8 mg doses, more than 8 days between the 0.8 mg and 3 mg doses, more than 14 days between the 3 mg dose and the first 48 mg dose, or more than 6 weeks between any two 48 mg doses.

Special Populations

• Elderly: no dose adjustment for patients aged 65 and over.
• Renal impairment: no adjustment for mild to moderate impairment. It has not been studied in severe impairment to end-stage renal disease, so no dose recommendation can be made.
• Hepatic impairment: no adjustment for mild impairment. It has not been studied in severe impairment and data are limited in moderate impairment, so no dose recommendation can be made for moderate to severe impairment.
• Children and adolescents: safety and efficacy under 18 years have not been established; no data are available.

Method of Administration

Subcutaneous injection only, preferably in the lower abdomen or the thigh. The injection site should be alternated between the left and right side, especially during the weekly schedule (Cycles 1–3). For instructions on dilution before administration, see section 6.6 of the SmPC.

Traceability

To improve the traceability of biological medicines, the name and batch number of the administered product must be recorded clearly.

Cytokine Release Syndrome

CRS can be life-threatening or fatal. Its commonest signs are fever, low blood pressure and low blood oxygen; chills, fast heart rate, headache and breathlessness also occur. Most events occur in Cycle 1 and are linked to the first full dose. Corticosteroid prophylaxis is given to lower the risk, patients are monitored after each administration, and at the first signs supportive care with tocilizumab and/or corticosteroids is started. Patients are told to contact their healthcare team and seek immediate medical attention if symptoms occur at any time. Management may require a delay or discontinuation of epcoritamab.

Haemophagocytic Lymphohistiocytosis

Haemophagocytic lymphohistiocytosis (HLH), including fatal cases, has been reported. It is a life-threatening syndrome with fever, skin rash, enlarged lymph nodes, enlarged liver or spleen and low blood counts. HLH should be considered when CRS looks atypical or lasts longer than expected. If it is suspected, epcoritamab is interrupted for diagnostic work-up and treatment; if it is confirmed, epcoritamab is discontinued.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

ICANS, including fatal events, has occurred. It may appear as aphasia, altered level of consciousness, impaired cognitive skills, motor weakness, seizures and cerebral oedema. Most cases occur in Cycle 1, but some begin later. Patients are monitored for signs and symptoms, treated with corticosteroids and non-sedating anti-seizure medicines as appropriate, and told that onset may be delayed and that they must seek immediate medical attention if symptoms appear.

Infections and Low Blood Counts

Epcoritamab increases the risk of serious and fatal infections. It should be avoided in patients with a clinically significant active systemic infection, and prophylactic antimicrobials should be given as appropriate (against Pneumocystis jirovecii and herpes viruses in particular). Neutropenia, thrombocytopenia and hypogammaglobulinaemia are common or very common, so blood counts need monitoring and doses are withheld as described above.

Tumour Lysis Syndrome and Tumour Flare

Tumour lysis syndrome and tumour flare have been reported. Patients at higher risk of clinical tumour lysis syndrome should receive hydration and a uric acid-lowering medicine.

Pregnancy, Breastfeeding and Fertility

• Pregnancy test and contraception: pregnancy status should be verified in women who can become pregnant before treatment starts. They should use effective contraception during treatment and for at least 4 months after the last dose.
• Pregnancy: based on its mechanism, epcoritamab may harm the foetus, including B-cell depletion and altered immune responses, because IgG1 antibodies cross the placenta. No data exist in pregnant women and animal reproduction studies have not been conducted. It is not recommended during pregnancy or in women of childbearing potential who are not using contraception.
• Breastfeeding: IgG is present in breast milk, so breastfeeding should be stopped during treatment and for at least 4 months after the last dose.
• Fertility: no fertility studies have been done and the effect on male and female fertility is unknown.

Excipients

Each vial contains 28.8 mg of sorbitol and 0.42 mg of polysorbate 80 (excipients with known effect); see the SmPC for the related precautions.

Effect on Driving

Epcoritamab has a major influence on the ability to drive and use machines. Because of the potential for ICANS, patients are at risk of altered consciousness and should take care when driving, cycling or using heavy or potentially dangerous machines, and avoid them if they have symptoms.

Store and transport refrigerated at 2–8 °C. Do not freeze. Keep the vial in the outer carton to protect it from light. This is a cold-chain product and must remain at 2–8 °C throughout storage and transport to the administering site. After dilution, the solution should be used immediately; if not, in-use stability has been shown for 24 hours at 2–8 °C, including up to 12 hours at room temperature (20–25 °C). Minimise exposure to daylight, allow the solution to reach room temperature before administration, and discard any unused solution beyond the allowed storage time.

Unopened vial: 2 years. Diluted or prepared epcoritamab: 24 hours at 2–8 °C, including up to 12 hours at room temperature (20–25 °C). From a microbiological point of view the product should be used immediately; otherwise in-use times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2–8 °C, unless dilution took place under controlled and validated aseptic conditions.

Prescription only (Rx), restricted medical prescription: treatment is given under the supervision of a healthcare professional qualified in anti-cancer therapy. Epcoritamab is a subcutaneous injection given by a healthcare professional, so it is supplied to the hospital or clinic that administers it, as a cold-chain product at 2–8 °C. The administering site must have tocilizumab available before the Cycle 1 administration.