4.1. Therapeutic indications

Tepkinly (epcoritamab), as monotherapy, is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy.

Tepkinly as monotherapy is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.

4.2. Posology and method of administration

Tepkinly must only be administered under the supervisions of a healthcare professional qualified in the use of anti-cancer therapies with access to appropriate medical support to manage severe reactions such as cytokine release syndrome (CRS) (see section 4.4).

Posology

Recommended pre-medication and dose schedule

Details on recommended premedication for cytokine release syndrome (CRS) are shown in Table 1.

Table 1 - Epcoritamab premedication and CRS prophylaxis

Cycle

Patient requiring premedication

Premedication

Corticosteroid prophylaxis

Cycle 1

All patients

30-120 minutes prior to each weekly administration of epcoritamab

• Dexamethasone (15 mg oral or intravenous) or Prednisolone (100 mg oral or IV) or equivalent

o Dexamethasone is the preferred corticosteroid for CRS prophylaxisb

• Diphenhydramine (50 mg oral or IV) or equivalent

• Paracetamol (1000 mg oral)

• Dexamethasone (15 mg oral or intravenous) or Prednisolone (100 mg oral or IV) or equivalent for three consecutive days following each weekly administration of epcoritamab in Cycle 1

Cycle 2 and beyond

Patients who experienced Grade 2 or 3a CRS with previous dose

30-120 minutes prior to next administration of epcoritamab after a grade 2 or 3a CRS event

• Dexamethasone (15 mg oral or intravenous) or Prednisolone (100 mg oral or IV) or equivalent

o Dexamethasone is the preferred corticosteroid for CRS prophylaxisb

• Dexamethasone (15 mg oral or intravenous) or

Prednisolone (100 mg oral or IV) or equivalent for three consecutive days following the next administration of epcoritamab until epcoritamab is given without subsequent CRS of any grade

a Patients will be permanently discontinued from epcoritamab after a Grade 4 CRS event.

b Based on the GCT3013-01 Optimisation study.

Administer Tepkinly according to the step-up dose schedule in 28-day cycles outlined in Table 2 for patients with diffuse large B-cell lymphoma and Table 3 for patients with follicular lymphoma.

Tepkinly is for subcutaneous (SC) injection only.

Table 2 - Tepkinly 2-step step-up dose schedule for patients with diffuse large B-cell lymphoma

Dosing schedule

Cycle of treatment

Days

Epcoritamab dose (mg)a

Weekly

Cycle 1

1

0.16 mg (Step-up dose 1)

8

0.8 mg (Step-up dose 2)

15

48 mg (First full dose)

22

48 mg

Weekly

Cycles 2 - 3

1, 8, 15, 22

48 mg

Every two weeks

Cycles 4 - 9

1, 15

48 mg

Every four weeks

Cycles 10 +

1

48 mg

a0.16 mg is a priming dose, 0.8 mg is an intermediate dose and 48 mg is a full dose.

Table 3 - Tepkinly 3-step step-up dose schedule for patients with follicular lymphoma

Dosing schedule

Cycle of treatment

Days

Epcoritamab dose (mg)a

Weekly

Cycle 1

1

0.16 mg (Step-up dose 1)

8

0.8 mg (Step-up dose 2)

15

3 mg (Step-up dose 3)

22

48 mg (First full dose)

Weekly

Cycles 2 - 3

1, 8, 15, 22

48 mg

Every two weeks

Cycles 4 - 9

1, 15

48 mg

Every four weeks

Cycles 10 +

1

48 mg

a0.16 mg is a priming dose, 0.8 mg is an intermediate dose, 3 mg is a second intermediate dose and 48 mg is a full dose.

Tepkinly should be administered until disease progression or unacceptable toxicity. Atypical responses (i.e. an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. It is recommended to continue treatment for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.

Tepkinly should be administered to well hydrated patients.

Prophylaxis against Pneumocystis jirovecii pneumonia (PCP) and herpes virus infections is strongly recommended especially during concurrent use of steroids.

It is strongly recommended that all patients adhere to the following fluid guidelines during Cycle 1, unless medically contraindicated:

• 2-3 L of fluid intake during the 24 hours prior to each epcoritamab administration

• Hold antihypertensive medications for 24 hours prior to each epcoritamab administration

• Administer 500 ml isotonic intravenous (IV) fluids on the day of epcoritamab prior to dose administration; AND

• 2-3 L of fluid intake during the 24 hours following each epcoritamab administration.

Patients at an increased risk for clinical tumour lysis syndrome (CTLS) are recommended to receive hydration and prophylactic treatment with a uric acid lowering agent.

Monitor patients for potential CRS and/or immune effector cell-associated neurotoxicity syndrome (ICANS) and managed per current practice guidelines following epcoritamab administration (see section 4.4).

Missed or delayed dose

Diffuse large B-cell lymphoma

A re-priming cycle (identical to Cycle 1 with standard CRS prophylaxis) is required:

• If there are more than 8 days between the priming dose (0.16 mg) and intermediate dose (0.8 mg), or

• If there are more than 14 days between the intermediate dose (0.8 mg) and first full dose (48 mg), or

• If there are more than 6 weeks between full doses (48 mg)

After the re-priming cycle, the patient should resume treatment with Day 1 of the next planned treatment cycle (subsequent to the cycle during which the dose was delayed).

Follicular lymphoma

A re-priming Cycle (identical to Cycle 1 with standard CRS prophylaxis) is required:

• If there are more than 8 days between the priming dose (0.16 mg) and intermediate dose (0.8 mg), or

• If there are more than 8 days between the intermediate dose (0.8 mg) and the second intermediate dose (3 mg), or

• If there are more than 14 days between the second intermediate dose (3 mg) and first full dose (48 mg), or

• If there are more than 6 weeks between any two full doses (48 mg)

After the re-priming cycle, the patient should resume treatment with Day 1 of the next planned treatment cycle (subsequent to the cycle during which the dose was delayed).

Dosage modifications and management of adverse reactions

Cytokine release syndrome (CRS)

Patients treated with epcoritamab may develop CRS.

Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to the recommendations in Table 4. Patients who experience CRS should be monitored more frequently during next scheduled epcoritamab administration.

Table 4 - CRS grading and management guidance

Grade1

Recommended therapy

Epcoritamab dose modification

Grade 1

• Fever (temperature ≥ 38°C) without hypotension or hypoxia

Provide supportive care such as antipyretics and intravenous hydration.

Anticytokine therapy:

Consider anti‑cytokine therapy in certain cases, e.g., advanced age, high tumour burden, circulating tumour cells, fever refractory to antipyretics. Tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg per dose). Repeat tocilizumab after at least 8 hours as needed. Maximum of 2 doses in a 24-hour period.

In case of concurrent ICANS choose alternative to tocilizumab. See Table 5.

Corticosteroids

In case of concurrent ICANS, initiation of corticosteroids is highly recommended. Consider dexamethasone 10-20 mg per day (or equivalent).

Hold epcoritamab until resolution of CRS event.

Grade 2a

• Fever (temperature ≥ 38°C)

AND/OR

• Hypotension not requiring vasopressors.

AND/OR

• Hypoxia requiring low-flow (≤6 l/minute) nasal cannula or blow-by

Provide supportive care such as antipyretics and intravenous hydration

Anticytokine therapy:

Tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg per dose). Repeat tocilizumab after at least 8 hours as needed. Maximum of 2 doses in a 24-hour period.

If CRS is refractory to initial anti‑cytokine therapy, initiate/increase dose of corticosteroid therapy and consider alternative anti‑cytokine therapy.

In case of concurrent ICANS choose alternative to tocilizumab. See Table 5.

Corticosteroids:

In case of concurrent ICANS, initiation of corticosteroids is highly recommended. Consider dexamethasone 10-20 mg per day (or equivalent).

Hold epcoritamab until resolution of CRS event.

Grade 3a

• Fever (temperature ≥ 38°C)

AND/OR

• Hypotension requiring 1 vasopressor with or without vasopressin.

AND/OR

• Hypoxia requiring high-flow (>6 l/minute) nasal cannula, facemask, non-rebreather mask, or venturi mask

Provide supportive care such as antipyretics and intravenous hydration

Anticytokine therapy

Tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg per dose). Repeat tocilizumab after at least 8 hours as needed. Maximum of 2 doses in a 24-hour period.

If CRS is refractory to initial anti‑cytokine therapy, initiate/increase dose of corticosteroid therapy and consider alternative anti‑cytokine therapy.

In case of concurrent ICANS choose alternative to tocilizumab. See Table 5.

Corticosteroids:

Dexamethasone (e.g., 10-20 mg IV every 6 hours). If no response, initiate methylprednisolone 1000 mg/day.

Hold epcoritamab until resolution of CRS event.

In the event of Grade 3 CRS lasting longer than 72 hours, epcoritamab should be discontinued

If more than 2 separate events of Grade 3 CRS, even if each event resolved to Grade 2 within 72 hours, epcoritamab should be discontinued.

Grade 4

• Fever (temperature ≥ 38°C)

AND/OR

Hypotension requiring ≥ 2 vasopressors (excluding vasopressin)

AND/OR

• Hypoxia requiring positive pressure ventilation (e.g., CPAP, BiPAP, intubation and mechanical ventilation)

Provide supportive care such as antipyretics and intravenous hydration

Anticytokine therapy

Tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg per dose). Repeat tocilizumab after at least 8 hours as needed. Maximum of 2 doses in a 24-hour

period.

If CRS is refractory to initial anti‑cytokine therapy, initiate/increase dose of corticosteroid therapy and consider alternative anti‑cytokine therapy.

In case of concurrent ICANS choose alternative to tocilizumab. See Table 5.

Corticosteroids

Dexamethasone (e.g., 10-20 mg IV every 6 hours). If no response, initiate methylprednisolone 1000 mg/day.

Permanently discontinue epcoritamab

1 CRS graded according to ASTCT (American Society for Transplant and Cellular Therapy) consensus criteria (Lee et al., 2019)

a If Grade 2 or 3 CRS occurs with the second full dose or beyond, administer CRS prophylaxis with each subsequent dose until epcoritamab dose is given without subsequent CRS (of any grade).

Immune effector cell associated neurotoxicity syndrome (ICANS)

Monitor patients for signs and symptoms of ICANS. Rule out other causes of neurologic symptoms. If ICANS is suspected, manage according to the recommendations in Table 5.

Table 5 - ICANS grading and management guidance

Gradea

Recommended therapy

Epcoritamab dose modification

Grade 1b

ICE score c 7-9 b or, depressed level of consciousnessb: awakens spontaneously.

Dexamethasone, 10 mg IV every 12 hours

Consider non-sedating anti-seizure medication (e.g., levetiracetam) until resolution of ICANS

No concurrent CRS:

• Anti-cytokine therapy not recommended

For ICANS with concurrent CRS:

• Treatment with dexamethasone

• Choose immunosuppressant alternativesd to tocilizumab, if possible

Hold epcoritamab until resolution of event.

Grade 2b

ICE scorec 3-6 or, depressed level of consciousnessb: awakens to voice.

Dexamethasone at 10-20 mg IV every 12 hours

Consider non-sedating anti-seizure medication (e.g., levetiracetam) until resolution of ICANS.

No concurrent CRS:

• Anti-cytokine therapy not recommended

For ICANS with concurrent CRS:

• Treatment with dexamethasone

• Choose immunosuppressant alternativesd to tocilizumab, if possible

Hold epcoritamab until resolution of event.

Grade 3b

ICE scorec 0-2 or, depressed level of consciousnessb: awakens only to tactile stimulus, or

seizuresb, either:

• any clinical seizure, focal or generalized that resolves rapidly,

or

• non-convulsive seizures on electroencephalogram (EEG) that resolve with intervention, or

raised intracranial pressure: focal/local oedemab on neuroimagingc.

Dexamethasone 10-20 mg IV every 6 hours.

• If no response, initiate methylprednisolone 1000 mg/day.

Consider non-sedating anti-seizure medication (e.g., levetiracetam) until resolution of ICANS.

No concurrent CRS:

• Anti-cytokine therapy not recommended

For ICANS with concurrent CRS:

• Treatment with dexamethasone

o If no response, initiate methylprednisolone 1000 mg/day

• Choose immunosuppressant alternativesd to tocilizumab, if possible

First episode: delay epcoritamab until full resolution of event.

Second episode: permanently discontinue epcoritamab.

Grade 4b ICE scorec, b 0

Or, depressed level of consciousnessb either:

• patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or

• stupor or coma, or

seizuresb, either:

• life-threatening prolonged seizure (>5 minutes), or

• repetitive clinical or electrical seizures without return to baseline in between,

motor findingsb:

• deep focal motor weakness such as hemiparesis or paraparesis, or

raised intracranial pressure / cerebral oedemab, with signs/symptoms such as:

• diffuse cerebral oedema on neuroimaging, or

• decerebrate or decorticate posturing,

or

• cranial nerve VI palsy, or

• papilloedema, or

• cushing's triad

Dexamethasone 10-20 mg IV every 6 hours.

• If no response, initiate methylprednisolone 1000 mg/day.

Consider non-sedating anti-seizure medication (e.g., levetiracetam) until resolution of ICANS.

No concurrent CRS:

• Anti-cytokine therapy not recommended

For ICANS with concurrent CRS:

• Treatment with dexamethasone

o If no response, initiate methylprednisolone 1000 mg/day

• Choose immunosuppressant alternativesd to tocilizumab, if possible

Permanently discontinue epcoritamab.

a ICANS graded according to ASTCT ICANS Consensus Grading (Lee et al., 2019)

bICANS grade is determined by the most severe event (ICE score, level of consciousness, seizures, motor findings, raised ICP/cerebral edema) not attributable to any other cause

c If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (name 3 objects, e.g., point to clock, pen, button = 3 points); Following Commands (e.g., “show me 2 fingers” or “close your eyes and stick out your tongue” = 1 point); Writing (ability to write a standard sentence = 1 point; and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points.

d Riegler L et al. (2019)

Table 6: Recommended Dosage Modifications for Other Adverse Reactions

Adverse Reaction1

Severity1

Action

Infections (see section 4.4)

Grades 1-4

Withhold epcoritamab in patients with active infection, until the infection resolves

Febrile neutropenia

Absolute neutrophil count less than 0.5 x 109/L

Withhold epcoritamab until absolute neutrophil count is 0.5 x 109/L or higher

Thrombocytopenia (see section 4.8)

Platelet count less than 50 x 109/L

Withhold epcoritamab until platelet count is 50 x 109/L or higher

Other Adverse Reactions (see section 4.8)

Grade 3 or higher

Withhold epcoritamab until the toxicity resolves to Grade 1 or baseline

1 Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.

Special populations

Renal impairment

No formal studies of Tepkinly in patients with renal impairment have been conducted. Based on population pharmacokinetic (PK) analyses, no dosage adjustment is necessary for patients with mild or moderate renal impairment. No data are available in patients with severe renal impairment (see section 5.2).

Hepatic impairment

No formal studies of Tepkinly in patients with hepatic impairment have been conducted. Based on population pharmacokinetic (PK) analyses, no dosage adjustment is necessary for patients with mild hepatic impairment. Data are limited in patients with moderate hepatic impairment and no data are available in patients with severe hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of Tepkinly in children aged less than 18 years of age have not yet been established. No data are available.

Elderly

No dose adjustment is necessary in patients ≥ 65 years.

Method of administration

Tepkinly should be administered by subcutaneous injection, preferably in the lower part of abdomen or the thigh. Change of injection site from left to right side or vice versa is recommended especially during the weekly administration schedule (i.e., Cycles 1-3).

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Cytokine release syndrome (CRS)

Cytokine release syndrome, which may be life-threatening or fatal, occurred in patients receiving epcoritamab (see section 4.8). The most common signs and symptoms of CRS include pyrexia, hypotension and hypoxia. Other signs and symptoms of CRS include chills, tachycardia, headache and dyspnoea.

Most CRS events occurred in Cycle 1 and were associated with the first full dose of epcoritamab. Administer prophylactic corticosteroids to mitigate the risk of CRS (see section 4.2).

Patients should be monitored for signs and symptoms of CRS following epcoritamab administration. At the first signs or symptoms of CRS, institute treatment of supportive care with tocilizumab and/or corticosteroids as appropriate (see section 4.2, Table 4).

Counsel patients on the signs and symptoms associated with CRS and instruct patients to contact their healthcare professional and seek immediate medical attention should signs or symptoms occur at any time. Management of CRS may require either temporary delay or discontinuation of epcoritamab based on the severity of CRS (see section 4.2).

Haemophagocytic lymphohistiocytosis (HLH)

Haemophagocytic lymphohistiocytosis (HLH), including fatal cases, have been reported in patients receiving epcoritamab. HLH is a life-threatening syndrome characterised by fever, skin rash, lymphadenopathy, hepato- and/or splenomegaly and cytopenias. HLH should be considered when the presentation of CRS is atypical or prolonged. Patients should be monitored for clinical signs and symptoms of HLH. For suspected HLH, epcoritamab must be interrupted for diagnostic workup and treatment for HLH initiated. If HLH is confirmed, administration of Tepkinly should be discontinued.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

ICANS, including fatal events, have occurred in patients receiving epcoritamab (see section 4.8). ICANS may manifest as aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, seizures, and cerebral oedema.

The majority of cases of ICANS occurred within the Cycle 1 of epcoritamab treatment, however some occurred with delayed onset.

Patients should be monitored for signs and symptoms of ICANS following epcoritamab administration. At the first signs or symptoms of ICANS institute treatment with corticosteroids and non-sedating-anti-seizure medications as appropriate (see section 4.2. Table 5).

Counsel patients on the signs and symptoms of ICANS and that the onset of events may be delayed. Instruct patients to contact their healthcare professional and seek immediate medical attention should signs or symptoms occur at any time. Delay or discontinue epcoritamab as recommended (see section 4.2).

Serious infections

Serious or fatal infections were observed in patients treated with epcoritamab in clinical studies (see section 4.8).

Epcoritamab must not be administered in patients with active infections. As appropriate, administer prophylactic antimicrobials prior to and during treatment with epcoritamab (see section 4.2). Caution should be exercised when considering the use of epcoritamab in patients with a history of recurring or chronic infections, with underlying conditions that may predispose to infections or who have had significant prior immunosuppressive treatment. Patients should be monitored for signs and symptoms of infection before and after epcoritamab, and treated appropriately. In the event of febrile neutropenia, patients should be evaluated for infection and managed with antibiotics, fluids and other supportive care, according to local guidelines.

Hypogammaglobulinaemia has also been reported in patients receiving epcoritamab (see section 4.8). Immunoglobulin (Ig) levels should be monitored prior to and during treatment. Patients should be treated according to local institutional guidelines, including infection precautions and antimicrobial prophylaxis.

Cases of progressive multifocal leukoencephalopathy (PML), including fatal cases, have been reported in patients treated with epcoritamab who have also received prior treatment with other immunosuppressive medications. If neurological symptoms suggestive of PML occur during epcoritamab therapy, treatment with epcoritamab should be discontinued and appropriate diagnostic measures initiated.

Tumour Lysis Syndrome (TLS)

TLS has been reported in patients receiving epcoritamab (see section 4.8). Patients at an increased risk for TLS are recommended to receive hydration and prophylactic treatment with a uric acid lowering agent. Patients should be monitored for signs or symptoms of TLS, especially patients with high tumour burden or rapidly proliferative tumours, and patients with reduced renal function. Patients should be monitored for blood chemistries and abnormalities should be managed promptly.

Tumour flare

Tumour flare has been reported in patients treated with epcoritamab (see section 4.8). Manifestations could include localised pain and swelling. Consistent with the mechanism of action of epcoritamab, tumour flare is likely due to the influx of T-cells into tumour sites following epcoritamab administration.

There are no specific risk factors for tumour flare that have been identified; however, there is a heightened risk of compromise and morbidity due to mass effect secondary to tumour flare in patients with bulky tumours located in close proximity to airways and/or a vital organ. Patients treated with epcoritamab should be monitored and evaluated for tumour flare at critical anatomical sites.

Patient card

The doctor must inform the patient of the risk of CRS and ICANS and any signs and symptoms of CRS and ICANS. Patients must be instructed to seek immediate medical attention if they experience signs and symptoms of CRS and/or ICANS. Patients should be provided with a patient card and instructed to carry the card at all times. This card describes symptoms of CRS and ICANS which, if experienced, should prompt the patient to seek immediate medical attention.

Immunisation

Live and/or live-attenuated vaccines should not be given during treatment with epcoritamab. Studies have not been conducted in patients who received live vaccines.

Excipients with known effect

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 'sodium‑free'.

This medicinal product contains 28.8 mg of sorbitol per vial.

This medicinal product contains 0.42 mg of polysorbate 80 per vial, equivalent to 0.4 mg/ml. Polysorbates may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. Transient elevation of certain proinflammatory cytokines by epcoritamab may suppress CYP450 enzyme activities. On initiation of epcoritamab therapy in patients being treated with CYP450 substrates with a narrow therapeutic index, therapeutic monitoring should be considered (see section 5.2).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in females

Women of childbearing potential should be advised to use effective contraception during treatment with epcoritamab and for at least 4 months after the last dose.

Pregnancy

Based on its mechanism of action, epcoritamab may cause foetal harm, including B-cell lymphocytopenia and alterations in normal immune responses, when administered to pregnant women. There are no data on the use of epcoritamab in pregnant women. Animal reproduction studies have not been conducted with epcoritamab. IgG1 antibodies, such as epcoritamab, can cross the placenta resulting in foetal exposure. Advise pregnant women of the potential risk to a foetus.

Epcoritamab is not recommended during pregnancy and in women of childbearing potential not using contraception.

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

Breast-feeding

It is not known whether epcoritamab is excreted in human milk or its effect on milk production. Since IgGs are known to be present in milk, neonatal exposure to epcoritamab may occur via lactational transfer. Breast‑feeding should be discontinued during treatment with epcoritamab and for at least 4 months after the last dose.

Fertility

No fertility studies have been conducted with epcoritamab (see section 5.3). The effect of epcoritamab on male and female fertility is unknown.

4.7. Effects on ability to drive and use machines

Epcoritamab has major influence on the ability to drive and use machines. Due to the potential for neurological events, such as ICANS, patients receiving epcoritamab are at risk of altered level of consciousness (see section 4.4). Patients who experience neurological signs and symptoms should be advised not to drive, cycle or use tools or potentially dangerous machines until symptoms resolve.

4.8. Undesirable effects

Summary of the safety profile

The safety of epcoritamab was evaluated in a non-randomised, single-arm GCT3013-01 study in 382 patients with relapsed or refractory large B-cell lymphoma (N=167), follicular lymphoma (N=129) and follicular lymphoma (3-step step-up dose schedule N=86) after two or more lines of systemic therapy and included all the patients who enrolled to the 48 mg dose and received at least one dose of epcoritamab. The following adverse reactions have been reported with epcoritamab during clinical studies and post marketing experience.

The median duration of exposure to epcoritamab was 4.9 months (range: <1 to 30 months).

The most common adverse reactions (≥20%) were CRS (56%), injection site reactions (40%), fatigue (32%), viral infection (28%), neutropenia (28%), muscoskeletal pain (27%), pyrexia (22%), and diarrhoea (21%). The most common Grade 3-4 adverse reactions (≥2%) were neutropenia (23%), viral infections (9.2%), lymphopenia (8.9%), anaemia (7.1%), pneumonia (5.8%), thrombocytopenia (5.5%), fatigue (2.9%), febrile neutropenia (2.4%), and sepsis (2.4%).

Serious adverse reactions occurred in 50% of patients. The most common serious adverse reaction (≥10%) was CRS (34%). Fourteen patients (3.7%) experienced a fatal adverse reaction (pneumonia in 9 (2.4%) patients, viral infection in 4 (1.0%) patients, and ICANS in 1 (0.3%) patient).

Adverse reactions that led to discontinuation occurred in 6.8% of patients. Discontinuation of epcoritamab due to pneumonia occurred in 14 (3.7%) patients, viral infection in 8 (2.1%) patients, fatigue in 2 (0.5%) patients and CRS, ICANS or diarrhoea occurred in 1 (0.3%) patient each.

Dose delays due to adverse reactions occurred in 42% of patients. Adverse reactions leading to dose delays (≥3% of patients) were viral infections (17%), CRS (11%), neutropenia (5.2%), pneumonia (4.7%), upper respiratory tract infection (4.2%), and pyrexia (3.7%).

Tabulated list of adverse reactions

Adverse reactions for epcoritamab from clinical studies (Table 7) are listed by MedDRA system organ class and are based on the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); and very rare (< 1/10 000).

Table 7 Adverse reactions reported in patients with relapsed or refractory LBCL or FL treated with epcoritamab

System organ class / preferred term or adverse reaction

All grades

Grade 3-4

Infections and infestations

Viral infectiona

Very common

Common

Pneumoniab

Very common

Common

Upper respiratory tract infectionc

Very common

Common

Fungal infectiond

Common

Sepsise

Common

Common

Cellulitis

Common

Common

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Tumour flare

Common

Blood and lymphatic system disorders

Neutropeniaf

Very common

Very common

Anaemiag

Very common

Common

Thrombocytopeniah

Very common

Common

Lymphopeniai

Very common

Common

Febrile neutropenia

Common

Common

Haemophagocytic lymphohistiocytosisj

Uncommon

Rare

Immune system disorders

Cytokine release syndromej

Very common

Common

Hypogammaglobulinaemia

Very common

Uncommon

Metabolism and nutrition disorders

Decreased appetite

Very common

Uncommon

Hypokalaemia

Common

Common

Hypophosphatemia

Common

Common

Hypomagnesaemia

Common

Uncommon

Tumour lysis syndromek

Common

Uncommon

Nervous system disorders

Headache

Very common

Uncommon

Immune effector cell-associated neurotoxicity syndromej

Common

Cardiac disorders

Cardiac arrhythmiasl

Common

Uncommon

Respiratory, thoracic and mediastinal disorders

Pleural effusion

Common

Common

Gastrointestinal disorders

Diarrhoea

Very common

Uncommon

Abdominal Painm

Very common

Common

Nausea

Very common

Uncommon

Vomiting

Common

Uncommon

Skin and subcutaneous tissue disorders

Rashn

Very common

Pruritus

Common

Musculoskeletal and connective tissue disorders

Musculoskeletal paino

Very common

Common

General disorders and administration site conditions

Injection site reactionsp

Very common

Fatigueq

Very common

Common

Pyrexiar

Very common

Common

Oedemas

Very common

Common

Investigations

Alanine aminotransferase increased

Common

Common

Aspartate aminotransferase increased

Common

Common

Blood creatinine increased

Common

Blood sodium decreasedt

Common

Uncommon

Alkaline phosphatase increased

Common

Adverse reactions were graded using NCI CTCAE version 5.0

a Viral infection includes COVID-19, cytomegalovirus chorioretinitis, cytomegalovirus colitis, cytomegalovirus infection, cytomegalovirus infection reactivation, gastroenteritis viral, herpes simplex, herpes simplex reactivation, herpes virus infection, herpes zoster, oral herpes, post-acute COVID-19 syndrome, and varicella zoster virus infection

b Pneumonia includes COVID-19 pneumonia and pneumonia

c Upper respiratory tract infection includes laryngitis, pharyngitis, respiratory syncytial virus infection, rhinitis, rhinovirus infection, and upper respiratory tract infection

d Fungal infection includes candida infection, oesophageal candidiasis, oral candidiasis and oropharyngeal candidiasis

e Sepsis includes bacteraemia, sepsis and septic shock

f Neutropenia includes neutropenia and neutrophil count decreased

g Anaemia includes anaemia and serum ferritin decreased

h Thrombocytopenia includes platelet count decreased and thrombocytopenia

i Lymphopenia includes lymphocyte count decreased and lymphopenia

j Events graded using American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria

k Clinical Tumour Lysis Syndrome was graded based on Cairo-Bishop

l Cardiac arrhythmias include bradycardia, sinus bradycardia, sinus tachycardia, supraventricular tachycardia, and tachycardia

m Abdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness

n Rash includes rash, rash erythematous, rash macular, rash maculo-papular, rash popular, rash prutitic, rash pustular and rash vesicular

o 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, and spinal pain

p Injection site reactions include injection site bruising, injection site erythema, injection site hypertrophy, injection site inflammation, injection site mass, injection site nodule, injection site oedma, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling, and injection site urticaria

q Fatigue includes asthenia, fatigue, and lethargy

r Pyrexia includes body temperature increased and pyrexia

s Oedema includes face oedema, generalized oedema, oedema, oedema peripheral, and peripheral swelling, swelling, and swelling face

t Blood sodium decreased includes blood sodium decreased and hyponatraemia

Description of selected adverse reactions

Cytokine release syndrome

2-step step-up dose schedule (large B-cell lymphoma and follicular lymphoma)

In study GCT3013-01, CRS of any grade occurred in 58% (171/296) of patients with large B-cell lymphoma and follicular lymphoma treated with epcoritamab at the 2-step step-up dose schedule. The incidence of Grade 1 was 35%, Grade 2 was 21%, and Grade 3 occurred in 2.4% of patients. Recurrent CRS occurred in 21% of patients with CRS. CRS of any grade occurred in 9.8% of patients after the priming dose (Cycle 1 Day 1); 13% after the intermediate dose (Cycle 1 Day 8); 51% after the first full dose (Cycle 1 Day 15); 6.5% after the second full dose (Cycle 1 Day 22); and 3.7% after the third full dose (Cycle 2 Day 1) or beyond. The median time to onset of CRS from the most recent administered epcoritamab dose was 2 days (range: 1 to 12 days). The median time to onset after the first full dose was 19.3 hours (range: <0.1 days to 7 days). CRS resolved in 99% of events, and the median duration of CRS events was 2 days (range 1 to 54 days).

Dose delays due to CRS occurred in 9.1% of patients. Treatment was discontinued in 0.3% of patients due to CRS.

Of the 171 patients that experienced CRS, the most common signs and symptoms of CRS included pyrexia (99%), hypotension (32%), and hypoxia (16%). Other signs and symptoms of CRS in ≥3% of patients included chills (11%), tachycardia (including sinus tachycardia (11%)), headache (8.2%), nausea (4.7%), and vomiting (4.1%). Tocilizumab was used to manage CRS events in 19% of patients and corticosteroids were used in 12% of patients. Out of the 67 events treated with tocilizumab, 84% responded within four (4) days of treatment.

Hospitalizations due to CRS occurred in 34% of patients and the median time to CRS resolution in those who were hospitalized was 1 day (range <1 to 26 days).

3-step step-up dose schedule follicular lymphoma

In study GCT3013-01, CRS of any grade occurred in 49% (42/86) of patients treated with epcoritamab at the recommended follicular lymphoma 3-step step-up dose schedule. The incidence of Grade 1 was 40% and Grade 2 was 9%. There were no Grade ≥3 CRS events reported. Recurrent CRS occurred in 23% of patients. Most CRS events occurred during Cycle 1, where 48% of patients experienced an event. In Cycle 1, CRS occurred in 12% of patients after the priming dose (Cycle 1 Day 1), 5.9% of patients after the intermediate dose (Cycle 1 Day 8), 15% of patients after the second intermediate dose (Cycle 1 Day 15), and 37% of patients after the first full dose (Cycle 1 Day 22). The median time to onset of CRS from the most recent administered epcoritamab dose was 59 hours (range: 1 to 8 days). The median time to onset after the first full dose was 61 hours (range: 1 to 8 days). CRS resolved in 100% of patients and the median duration of CRS events was 2 days (range 1 to 14 days).

Serious adverse reactions due to CRS occurred in 28% of patients who received epcoritamab.

Dose delays due to CRS occurred in 19% of patients who received epcoritamab.

Of the 42 patients that experienced CRS at the recommended dose, the most common (≥10%) signs and symptoms of CRS included pyrexia (100%) and hypotension (14%). In addition to corticosteroid use, tocilizumab was used to manage CRS event in 12% of patients.

Immune effector cell associated neurotoxicity syndrome

In study GCT3013-01, ICANS occurred in 4.7% (18/382) of patients treated with epcoritamab; 3.1% experienced Grade 1 and 1.3% experienced Grade 2. One patient (0.3%) experienced an ICANS event of Grade 5 (fatal). The median time to first ICANS onset from the start of epcoritamab treatment (Cycle 1 Day 1) was 18 days (range: 8 to 141 days). ICANS resolved in 94% (17/18) of patients with supportive care. The median time to resolution of ICANS was 2 days (range: 1 to 9 days).

Dose delays due to ICANS occurred in 1.0% of patients. Treatment was discontinued in 0.3% of patients due to ICANS.

Serious infections

Large B-cell lymphoma

In study GCT3013-01, serious infections of any grade occurred in 25% (41/167) of patients with large B-cell lymphoma treated with epcoritamab. The most frequent serious infections were COVID-19 (6.6%), COVID-19 pneumonia (4.2%), pneumonia (3.6%), sepsis (2.4%), cellulitis (1.8%), upper respiratory tract infection (1.8%), bacteraemia (1.2%), septic shock (1.2%), and progressive multifocal leukoencephalopathy (1.2%). The median time to onset of first serious infection was 56 days (range: 4 to 631 days), with median duration of 15 days (range: 4 to 125 days). Grade 5 events (fatal serious) of infections occurred in 7 (4.2%) patients.

Dose delays due to serious infections occurred in 15% of patients. Treatment was discontinued in 6.0% of patients due to serious infections (see Section 4.4).

Follicular lymphoma

In study GCT3013-01, serious infections of any grade occurred in 32% (68/215) of patients with follicular lymphoma treated with epcoritamab. The most frequent serious infections included COVID-19 (8.8%), COVID-19 pneumonia (5.6%), pneumonia (3.7%), urinary tract infection (1.9%), and Pneumocystis jirovecii pneumonia (1.4%). The median time to onset of first serious infection from the start of epcoritamab treatment (Cycle 1 Day 1) was 81 days (range: 1 to 636 days), with median duration of 18 days (range: 4 to 249 days). Grade 5 events of infection occurred in 8 (3.7%) patients, 6 (2.8%) of which were attributed to COVID-19 or COVID-19 pneumonia.

Immunogenicity

Epcoritamab has the potential to induce anti-product antibodies (ADA). The incidence of antibodies to epcoritamab was low and all the patients with LBCL who were ADA positive had low titres (≥1 in 0.6% (1/158)) and all the patients with FL who were ADA positive had titers <1. Due to the low number of patients with ADAs, a meaningful analysis of the impact of ADAs on safety is limited (see section 5.2).

Neutropenia

In study GCT3013-01, neutropenia of any grade occurred in 28% (105/382) of patients, including 23% Grade 3-4 events. The median time to onset of first neutropenia/neutrophil count decreased event was 65 days (range: 2 to 750 days), with median duration of 15 days (range: 2 to 415 days). Of the 105 patients who had neutropenia/neutrophil count decreased events, 61% received G-CSF to treat the events. Dose delays due to neutropenia occurred in 20 (5.2%) patients and there were no dose discontinuations due to neutropenia.

Tumour Lysis Syndrome

In study GCT3013-01, TLS occurred in 1.0% (4/382) of patients. Median time to onset was 18 days (range 8 to 33 days), and median duration was 3 days (range 2 to 4 days).

Tumour Flare

In study GCT3013-01, tumour flare occurred in 1.6% (6/382) of patients, all of which were grade 2. The median time to onset was 19.5 days (range 9 to 34 days), and median duration was 9 days (range 1 to 50 days).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme: Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In the event of overdose, monitor the patient for any signs or symptoms of adverse reactions and administer appropriate supportive treatment.