Tepkinly 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.

 

These indications are approved under accelerated approval based on response rate and durability of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Tepkinly must only be administered under the supervision of a healthcare professional qualified in the use of anti-cancer therapy. At least 1 dose of tocilizumab for use in the event of CRS should be available prior to epcoritamab administration for Cycle 1. Access to an additional dose of tocilizumab within 8 hours of use of the previous tocilizumab dose should be available.

 

Posology

 

Recommended pre-medication and dose schedule

 

Tepkinly should be administered according to the following step-up dose schedule in 28‑day cycles which is outlined in Table 1 for patients with diffuse large B-cell lymphoma and Table 2 for patients with follicular lymphoma.

 

 

Table 1 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 2 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.

 

Details on recommended pre-medication for cytokine release syndrome (CRS) are shown in Table 3.

 

Table 3 Epcoritamab pre-medication

 

Cycle	Patient requiring pre-medication	Pre-medication	Administration
Cycle 1	All patients	Dexamethasoneb (15 mg oral or intravenous) or Prednisolone (100 mg oral or intravenous) or equivalent	·        30-120 minutes prior to each weekly administration of epcoritamab  ·        And for three consecutive days following each weekly administration of epcoritamab in Cycle 1
		·        Diphenhydramine (50 mg oral or intravenous) or equivalent ·        Paracetamol (650 to 1 000 mg oral)	·        30-120 minutes prior to each weekly administration of epcoritamab
Cycle 2 and beyond	Patients who experienced Grade 2 or 3a CRS with previous dose	Dexamethasoneb (15 mg oral or intravenous) or Prednisolone (100 mg oral or intravenous) or equivalent	·        30-120 minutes prior to next administration of epcoritamab after a grade 2 or 3a CRS event ·        And for three consecutive days following the next administration of epcoritamab until epcoritamab is given without subsequent any grade of CRS
aPatients will be permanently discontinued from epcoritamab after a Grade 4 CRS event. bDexamethasone is the preferred corticosteroid for CRS prophylaxis based on the GCT3013-01 Optimisation study.

 

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

 

Tepkinly should be administered to adequately hydrated patients.

 

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.

 

Patients should be monitored for signs and symptoms of CRS and/or immune effector cell-associated neurotoxicity syndrome (ICANS) and managed per current practice guidelines following epcoritamab administration. Patients should be counselled on the signs and symptoms associated with CRS and ICANS and on seeking immediate medical attention should signs or symptoms occur at any time (see section 4.4).

 

Patients with DLBCL should be hospitalised for 24 hours after administration of the Cycle 1 Day 15 dose of 48 mg to monitor for signs and symptoms of CRS and/or ICANS.

 

Dose 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

 

Gradea	Recommended therapy	Epcoritamab dose modification
Grade 1 • Fever (temperature ≥ 38 °C)	Provide supportive care such as antipyretics and intravenous hydration   Dexamethasoneb may be initiated   In cases of advanced age, high tumour burden, circulating tumour cells, fever refractory to antipyretics ·        Anti‑cytokine therapy, tocilizumabd, should be considered For CRS with concurrent ICANS refer to Table 5	Hold epcoritamab until resolution of CRS event
Grade 2 • Fever (temperature ≥ 38 °C)   and   • Hypotension not requiring vasopressors   and/or   • Hypoxia requiring low-flow oxygene by nasal cannula or blow-by	Provide supportive care such as antipyretics and intravenous hydration   Dexamethasoneb should be considered   Anti‑cytokine therapy, tocilizumabd, is recommended   If CRS is refractory to dexamethasone and tocilizumab: ·        Alternative immunosuppressantsg and methylprednisolone 1 000 mg/day intravenously should be administered until clinical improvement For CRS with concurrent ICANS refer to Table 5	Hold epcoritamab until resolution of CRS event
Grade 3 • Fever (temperature ≥ 38 °C)   and   • Hypotension requiring a vasopressor with or without vasopressin   and/or   • Hypoxia requiring high-flow oxygenf by nasal cannula, facemask, non‑rebreather mask, or venturi mask	Provide supportive care such as antipyretics and intravenous hydration   Dexamethasonec should be administered   Anti‑cytokine therapy, tocilizumabd, is recommended   If CRS is refractory to dexamethasone and tocilizumab: ·        Alternative immunosuppressantsg and methylprednisolone 1 000 mg/day intravenously should be administered until clinical improvement   For CRS with concurrent ICANS refer to Table 5	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   • 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   Dexamethasonec should be administered   Anti‑cytokine therapy, tocilizumabd, is recommended   If CRS is refractory to dexamethasone and tocilizumab: ·       Alternative immunosuppressantsg and methylprednisolone 1 000 mg/day intravenously should be administered until clinical improvement   For CRS with concurrent ICANS refer to Table 5	Permanently discontinue epcoritamab
aCRS graded according to ASTCT consensus criteria bDexamethasone should be administered at 10-20 mg per day (or equivalent) cDexamethasone should be administered at 10-20 mg intravenously every 6 hours dTocilizumab 8 mg/kg intravenously 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 eLow-flow oxygen is defined as oxygen delivered at < 6 L/minute fHigh-flow oxygen is defined as oxygen delivered at ≥ 6 L/minute gRiegler L et al. (2019)

 

Immune effector cell-associated neurotoxicity syndrome (ICANS)

 

Patients should be monitored for signs and symptoms of ICANS. Other causes of neurologic symptoms should be ruled out. 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 scorec 7-9 b or, depressed level of consciousnessb: awakens spontaneously	Treatment with dexamethasoned   Consider non-sedating anti-seizure medicinal products (e.g., levetiracetam) until resolution of ICANS   No concurrent CRS: ·        Anti‑cytokine therapy not recommended   For ICANS with concurrent CRS: ·        Treatment with dexamethasoned ·        Choose immunosuppressant alternativese to tocilizumab, if possible	Hold epcoritamab until resolution of event
Grade 2b ICE scorec 3-6 or, depressed level of consciousnessb: awakens to voice	Treatment with dexamethasonef   Consider non-sedating anti-seizure medicinal products (e.g., levetiracetam) until resolution of ICANS   No concurrent CRS: ·        Anti‑cytokine therapy not recommended   For ICANS with concurrent CRS: ·        Treatment with dexamethasoned ·        Choose immunosuppressant alternativese 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 generalised that resolves rapidly, or ·        non-convulsive seizures on electroencephalogram (EEG) that resolve with intervention, or raised intracranial pressure: focal/local oedemab on neuroimagingc	Treatment with dexamethasoneg ·        If no response, initiate methylprednisolone 1 000 mg/day Consider non-sedating anti-seizure medicinal products (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 1 000 mg/day ·        Choose immunosuppressant alternativese to tocilizumab, if possible	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, or 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	Treatment with dexamethasoneg  ·        If no response, initiate methylprednisolone 1 000 mg/day   Consider non-sedating anti-seizure medicinal products (e.g., levetiracetam) until resolution of ICANS   No concurrent CRS: ·        Anti‑cytokine therapy not recommended   For ICANS with concurrent CRS: Treatment with dexamethasone If no response, initiate methylprednisolone 1 000 mg/day Choose immunosuppressant alternativese to tocilizumab, if possible	Permanently discontinue epcoritamab
aICANS graded according to ASTCT ICANS Consensus Grading bICANS grade is determined by the most severe event (ICE score, level of consciousness, seizures, motor findings, raised ICP/cerebral oedema) not attributable to any other cause cIf 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. dDexamethasone should be administered at 10 mg intravenously every 12 hours eRiegler L et al. (2019) fDexamethasone 10-20 mg intravenously every 12 hours gDexamethasone 10-20 mg intravenously every 6 hours

 

Table 6 Recommended dose 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 ·        For Grade 4, consider permanent discontinuation of epcoritamab
Neutropenia or febrile neutropenia (see section 4.8)	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
1Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.

 

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).

 

Special populations

 

Renal impairment

 

Dose adjustments are not considered necessary in patients with mild to moderate renal impairment. Epcoritamab has not been studied in patients with severe renal impairment to end stage renal disease.

No dose recommendations can be made for patients with severe renal impairment to end-stage renal disease (see section 5.2).

 

Hepatic impairment

 

Dose adjustments are not considered necessary in patients with mild hepatic impairment. Epcoritamab has not been studied in patients with severe hepatic impairment (defined as total bilirubin > 3 times ULN and any AST) and data are limited in patients with moderate hepatic impairment (defined as total bilirubin > 1.5 to 3 times ULN and any AST). No dose recommendations can be made for patients with moderate to severe hepatic impairment (see section 5.2).

 

Elderly

 

No dose adjustment is necessary in patients ≥ 65 years of age (see sections 5.1 and 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.

 

Method of administration

 

Tepkinly is for subcutaneous use. It should be administered by subcutaneous injection only, preferably in the lower part of the 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 dilution of the medicinal product before administration, see section 6.6.

 

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

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)

 

CRS, which may be life-threatening or fatal, occurred in patients receiving epcoritamab. The most common signs and symptoms of CRS include pyrexia, hypotension and hypoxia. Other signs and symptoms of CRS in more than two patients 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, treatment should be instituted of supportive care with tocilizumab and/or corticosteroids as appropriate (see section 4.2, Table 4). Patients should be counselled on the signs and symptoms associated with CRS and patients should be instructed 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).

 

Patients with DLBCL should be hospitalised for 24 hours after administration of the Cycle 1 Day 15 dose of 48 mg to monitor for signs and symptoms of CRS.

 

Immune effector cell-associated neurotoxicity syndrome (ICANS)

 

ICANS, including a fatal event, have occurred in patients receiving epcoritamab. 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 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, treatment with corticosteroids and non-sedating-anti-seizure medicinal products should be instituted as appropriate (see section 4.2, Table 5). Patients should be counselled on the signs and symptoms of ICANS and that the onset of events may be delayed. Patients should be instructed to contact their healthcare professional and seek immediate medical attention should signs or symptoms occur at any time. Epcoritamab should be delayed or discontinued as recommended (see section 4.2).

 

Patients with DLBCL should be hospitalised for 24 hours after administration of the Cycle 1 Day 15 dose of 48 mg to monitor for signs and symptoms of ICANS.

 

Serious infections

 

Treatment with epcoritamab may lead to an increased risk of infections. Serious or fatal infections were observed in patients treated with epcoritamab in clinical studies (see section 4.8).

 

Administration of epcoritamab should be avoided in patients with clinically significant active systemic infections.

As appropriate, prophylactic antimicrobials should be administered prior to and during treatment with epcoritamab (see section 4.2). Patients should be monitored for signs and symptoms of infection, before and after epcoritamab administration, 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.

 

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.

 

CD20-negative disease

 

There are limited data available on patients with CD20-negative DLBCL and patients with CD20-negative FL treated with  epcoritamab and it is possible that patients with CD20-negative DLBCL and patients with CD20-negative FL may have less benefit compared to patients with CD20-positive DLBCL and patients with CD20-positive FL, respectively. The potential risks and benefits associated with treatment of patients with CD20-negative DLBCL and FL with epcoritamab should be considered.

 

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 epcoritamab therapy. 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 21.9 mg of sorbitol per vial, which is equivalent to 27.33 mg/ml.

 

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

 

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.

 

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

 

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.

 

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.

Epcoritamab has minor influence on the ability to drive and use machines. Due to the potential for ICANS, patients should be advised to exercise caution while (or avoid if symptomatic) driving, cycling or using heavy or potentially dangerous machines.

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

 

The most common adverse reactions (≥ 20%) were CRS, injection site reactions, fatigue, viral infection, neutropenia, musculoskeletal pain, pyrexia, and diarrhoea.

 

Serious adverse reactions occurred in 50% of patients. The most frequent serious adverse reaction (≥ 10%) was cytokine release syndrome (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, in 1 (0.3%) patient each.

 

Dose delays due to adverse reactions occurred in 42% of patients. Adverse reactions leading to dose delays (≥ 3%) 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).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

 

Table 7 Adverse reactions reported in patients with relapsed or refractory LBCL or FL treated with epcoritamab in GCT3013-01 study

 

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
Neoplasm benign, malignant and unspecified (including 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
Immune system disorders
Cytokine release syndromej	Very common	Common
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

^aViral 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

^bPneumonia includes COVID-19 pneumonia and pneumonia

^cUpper respiratory tract infection includes laryngitis, pharyngitis, respiratory syncytial virus infection, rhinitis, rhinovirus infection, and upper respiratory tract infection

^dFungal infection includes candida infection, oesophageal candidiasis, oral candidiasis and oropharyngeal candidiasis

^eSepsis includes bacteraemia, sepsis, and septic shock

^fNeutropenia includes neutropenia and neutrophil count decreased

^gAnaemia includes anaemia and serum ferritin decreased

^hThrombocytopenia includes platelet count decreased and thrombocytopenia

ⁱLymphopenia 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

^lCardiac arrhythmias include bradycardia, sinus bradycardia, sinus tachycardia, supraventricular tachycardia, and tachycardia

^mAbdominal pain includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness

ⁿRash includes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, and rash vesicular

^oMusculoskeletal 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

^pInjection site reactions include injection site bruising, injection site erythema, injection site hypertrophy, injection site inflammation, injection site mass, injection site nodule, injection site oedema, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling, and injection site urticaria.

^qFatigue includes asthenia, fatigue, and lethargy

^rPyrexia includes body temperature increased and pyrexia

^sOedema includes face oedema, generalised oedema, oedema, oedema peripheral, peripheral swelling, swelling, and swelling face

^tBlood 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. 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 to 7 days). CRS resolved in 99% of patients, and the median duration of CRS events was 2 days (range 1 to 54 days).

 

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%). Transient elevated liver enzymes (ALT or AST > 3xULN) were concurrent with CRS in 4.1% of patients with CRS. See section 4.2 and 4.4 for monitoring and management guidance.

 

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%, 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). In the 18 patients with ICANS, the onset of ICANS was prior to CRS in 11% of patients, concurrent with CRS in 44%, following onset of CRS in 17%, and in the absence of CRS in 28%.

 

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 included COVID-19 (6.6%), COVID-19 pneumonia (4.2%), pneumonia (3.6%), sepsis (2.4%), upper respiratory tract infection (1.8%), bacteraemia (1.2%), and septic shock (1.2%). The median time to onset of first serious infection from the start of epcoritamab treatment (Cycle 1 Day 1) was 56 days (range: 4 to 631 days), with median duration of 15 days (range: 4 to 125 days). Grade 5 events of infections occurred in 7 (4.2%) patients.

 

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.

 

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.

 

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.

 

 

To reports any side effect(s):

Saudi Arabia:

· The National Pharmacovigilance Centre (NPC): - SFDA Call Center: 19999 - E-mail: npc.drug@sfda.gov.sa - Website: https://ade.sfda.gov.sa/

 

Other GCC States:

- Please contact the relevant competent authority.

 

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

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01FX27

 

Mechanism of action

 

Epcoritamab is a humanised IgG1-bispecific antibody that binds to a specific extracellular epitope of CD20 on B cells and to CD3 on T cells. The activity of epcoritamab is dependent upon simultaneous engagement of CD20-expressing cancer cells and CD3-expressing endogenous T cells by epcoritamab that induces specific T‑cell activation and T‑cell-mediated killing of CD20-expressing cells.

Epcoritamab Fc region is silenced to prevent target-independent immune effector mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cellular cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP).

 

Pharmacodynamic effects

 

Epcoritamab induced rapid and sustained depletion of circulating B‑cells (defined as CD19 B-cell counts  ≤10 cell/µl) in the subjects who have detectable B cells at treatment initiation. There were 21% subjects (n=33) with DLBCL and 50% subjects (n=56) with FL who had detectable circulating B-cells at treatment initiation. Transient reduction in circulating T cells was observed immediately after each dose in Cycle 1 and followed by T cell expansion in subsequent cycles.

 

In study GCT3013-01, following subcutaneous administration of epcoritamab at the recommended 2‑step step-up dose schedule in patients with LBCL, transient and modest elevations of circulating levels of selected cytokines (IFN-γ, TNFα, IL-6, IL-2, and IL-10) occurred mostly after the first full dose (48 mg), with peak levels between 1 to 4 days post dose. Cytokine levels returned to baseline prior to the next full dose, however elevations of cytokines could also be observed after Cycle 1.

In study GCT3013-01, following subcutaneous administration of epcoritamab at the recommended 3-step step-up dose schedule in patients with FL, median IL-6 levels associated with CRS risk remained consistently low after each dose in Cycle 1 and beyond, particularly after the first full dose, compared to patients who received the 2-step step-up dose.

 

Immunogenicity

 

Anti-drug antibodies (ADA) were commonly detected. The incidence of treatment-emergent ADAs with the 2-step step-up dose schedule (0.16/0.8/48 mg) in the combined population of DLBCL and FL was 3.4% (3.4 % positive, 93.9% negative and 2.7% indeterminate, N=261 evaluable patients) and 3.3% (3.3% positive, 95% negative and 1.7% indeterminate, N= 60 evaluable patients), in studies GCT3013‑01 and GCT3013-04, respectively.

The incidence of treatment-emergent ADAs with the 3-step step-up dose schedule (0.16/0.8/3/48 mg) in the FL optimisation cohort was 7% (7% positive, 91.5% negative and 1.4% indeterminate, N=71 evaluable patients) in study GCT3013-01. A subject is classified as indeterminate if the patient is confirmed ADA positive at baseline but there is no confirmed positive on-treatment record or if confirmed ADA positive on treatment record titre are equal or lower than baseline.

 

No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed, however, data are still limited. Neutralising antibodies were not evaluated.

 

Clinical efficacy and safety

 

Diffuse large B-cell lymphoma

Study GCT3013-01 was an open-label, multi-cohort, multicentre, single-arm study that evaluated epcoritamab as monotherapy in patients with relapsed or refractory large B-cell lymphoma (LBCL) after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL). The study includes a dose escalation part and an expansion part. The expansion part of the study included an aggressive non-Hodgkin lymphoma (aNHL) cohort, an indolent NHL (iNHL) cohort and a mantle-cell lymphoma (MCL) cohort. The pivotal aNHL cohort consisted of patients with LBCL (N=157), including patients with DLBCL (N=139, 12 patients of which had MYC, BCL2, and/or BCL6 rearrangements i.e., DH/TH), with high-grade B-cell lymphoma (HGBCL) (N=9), with follicular lymphoma grade 3B (FL) (N=5) and patients with primary mediastinal B-cell lymphoma (PMBCL) (N=4). In the DLBCL cohort, 29% (40/139) of patients had transformed DLBCL arising from indolent lymphoma. Patients included in the study were required to have documented CD20+ mature B-cell neoplasm according to WHO classification 2016 or WHO classification 2008 based on representative pathology report, failed prior autologous hematopoietic stem cell transplantation (HSCT) or were ineligible for autologous HSCT, patients who had lymphocyte counts < 5×10⁹/L, and patients with at least 1 prior anti-CD20 monoclonal antibody-containing therapy.

The study excluded patients with central nervous system (CNS) involvement of lymphoma, prior treatment with allogeneic HSCT or solid organ transplant, chronic ongoing infectious diseases, any patients with known impaired T‑cell immunity, a creatinine clearance of less than 45 ml/min, alanine aminotransferase > 3 times the upper limit of normal, cardiac ejection fraction less than 45%, and known clinically significant cardiovascular disease. Efficacy was evaluated in 139 patients with DLBCL who had received at least one dose of epcoritamab SC in cycles of 4 weeks, i.e., 28 days. Epcoritamab monotherapy was administered at the recommended 2-step step-up dose schedule as follows:

 

·        Cycle 1: epcoritamab 0.16 mg on Day 1, 0.8 mg on Day 8, 48 mg on Day 15 and Day 22

·        Cycles 2-3: epcoritamab 48 mg on Days 1, 8, 15, and 22

·        Cycles 4-9: epcoritamab 48 mg on Days 1 and 15

·        Cycles 10 and beyond: epcoritamab 48 mg on Day 1

 

Patients continued to receive epcoritamab until disease progression or unacceptable toxicity.

 

The demographics and baseline characteristics are shown in Table  8.

 

Table 8 Demographics and baseline characteristics of patients with DLBCL in GCT3013-01 study

 

Characteristics	(N=139)
Age
Median, years (min, max)	66 (22, 83)
< 65 years, n (%)	66 (47)
65 to < 75 years, n (%)	44 (32)
≥ 75 years, n (%)	29 (21)
Males, n (%)	85 (61)
Race, n (%)
White	84 (60)
Asian	27 (19)
Other	5 (4)
Not Reported	23 (17)
ECOG performance status; n (%)
0	67 (48)
1	67 (48)
2	5 (4)
Disease stagec at initial diagnosis, n (%)
III	16 (12)
IV	86 (62)
Number of prior lines of anti‑lymphoma therapy
Median (min, max)	3 (2, 11)
2, n (%)	41 (30)
3, n (%)	47 (34)
≥ 4, n (%)	51 (37)
DLBCL Disease history; n (%)
De Novo DLBCL	97 (70)
DLBCL transformed from indolent lymphoma	40 (29)
FISH Analysis Per Central labd, N=88
Double-hit/Triple-hit lymphoma, n (%)	12 (14)
Prior autologous HSCT	26 (19)
Prior therapy; n (%)
Prior CAR-T	53 (38)
Primary refractory diseasea	82 (59)
Refractory to ≥ 2 consecutive lines of prior anti‑lymphoma therapyb	104 (75)
Refractory to the last line of systemic antineoplastic therapyb	114 (82)
Refractory to prior anti-CD20 therapy	117 (84)
Refractory to CAR-T	39 (28)
aA patient is considered to be primary refractory if the patient is refractory to frontline anti‑lymphoma therapy. bA patient is considered to be refractory if the patient either experiences disease progression during therapy or disease progression within < 6 months after therapy completion. A patient is considered relapsed if the patient had recurred disease ≥ 6 months after therapy completion. cPer Ann Arbor Staging. dPost hoc central lab FISH analysis was performed on available diagnostic baseline tumour tissue sections from 88 DLBCL patients.

 

The primary efficacy endpoint was overall response rate (ORR) determined by Lugano criteria (2014) as assessed by Independent Review Committee (IRC). The median follow-up time was 15.7 months (range: 0.3 to 23.5 months). The median duration of exposure was 4.1 months (range: 0 to  23 months).

 

Table 9 Efficacy results in study GCT3013-01 in patients with DLBCL^a

 

Endpoint IRC assessment	Epcoritamab (N=139)
ORRb, n (%)	86 (62)
(95% CI)	(53.3, 70)
CRb, n (%)	54 (39)
(95% CI)	(30.7, 47.5)
PR, n (%)	32 (23)
(95% CI)	(16.3, 30.9)
DORb
Median (95% CI), months	15.5 (9.7, NR)
DOCRb
Median (95% CI), months	NR (12.0, NR)
TTR, median (range), months	1.4 (1, 8.4)
CI = confidence interval; CR = complete response; DOR = duration of response; DOCR = duration of complete response; IRC = independent review committee; ORR = overall response rate; PR = partial response; TTR = time to response aDetermined by Lugano criteria (2014) as assessed by independent review committee (IRC) bIncluded patients with initial PD by Lugano or IR by LYRIC who later obtained PR/CR.

 

The median time to CR was 2.6 months (range: 1.2 to 10.2 months).

 

Follicular lymphoma

 

Study GCT3013-01 was an open-label, multi-cohort, multicentre, single-arm trial that evaluated epcoritamab as monotherapy in patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. The study includes a dose escalation part, an expansion part and a 3‑step step-up dose optimisation part. The expansion part of the study included an aggressive non‑Hodgkin lymphoma (aNHL) cohort, an indolent NHL (iNHL) cohort and a mantle-cell lymphoma (MCL) cohort. The pivotal iNHL cohort, included patients with FL. Patients included in the study were required to have documented CD20+ mature B-cell neoplasm according to WHO classification 2016 or WHO classification 2008 based on representative pathology report with histologic confirmed FL 1-3A at initial diagnosis without clinical or pathological evidence of transformation. All patients had relapsed or refractory disease to the last prior line therapy and previously treated with at least 2 lines of systemic antineoplastic therapy, including at least 1 anti-CD20 monoclonal antibody-containing therapy and an alkylating agent or lenalidomide. The study excluded patients with CNS involvement of lymphoma, allogeneic HSCT or solid organ transplant, ongoing active infectious diseases, any patients with known impaired T-cell immunity, a creatinine clearance of less than 45 ml/min, alanine aminotransferase >3 times the upper limit of normal and cardiac ejection fraction less than 45%. Efficacy was evaluated in 128 patients who had received epcoritamab subcutaneously (SC) in cycles of 4 weeks, i.e., 28 days. Epcoritamab was administered as a monotherapy in a 2-step step-up dose schedule as follows:

 

·      Cycle 1: epcoritamab 0.16 mg on Day 1, 0.8 mg on Day 8, 48 mg on Day 15 and 48 mg on Day 22

·      Cycles 2-3: epcoritamab 48 mg on Days 1, 8, 15, and 22

·      Cycles 4-9: epcoritamab 48 mg on Days 1 and 15

·      Cycles 10 and beyond: epcoritamab 48 mg on Day 1

 

Patients continued to receive epcoritamab until disease progression or unacceptable toxicity.

 

The median number of cycles initiated was 8 and 60% received at least 6 cycles.

 

The demographics and baseline characteristics are shown in Table 10.

 

Table 10 Demographics and baseline characteristics of patients with FL in GCT3013-01 study

 

Characteristics	(N = 128)
Age
Median, years (min, max)	65 (39, 84)
< 65 years, n (%)	61 (48)
65 to < 75 years, n (%)	50 (39)
≥ 75 years, n (%)	17 (13)
Males, (%)	79 (62)
Race, n (%)
White	77 (60)
Asian	7 (6)
Other	2 (1.6)
Not Reported	42 (33)
ECOG performance status; n (%)
0	70 (55)
1	51 (40)
2	7 (6)
Number of prior lines of therapies, n (%)
Median (min, max)	3 (2, 9)
2	47 (37)
3	41 (32)
≥4	40 (31)
Ann Arbor Staging; (%)
Stage III/IV	109 (85)
FLIPI at baseline, n (%)
2	31 (24)
3- 5	78 (61)
Bulky Disease, n (%)	33 (26)
Prior Therapy; n (%)
Autologous stem cell transplant	24 (19)
Chimeric antigen receptor (CAR)-T cell therapy	6 (5)
Rituximab plus lenalidomide therapy	27 (21)
PI3K inhibitor	29 (23)
Progression of disease within 24 months of first systemic therapy	67 (52)
Refractory to:
≥ 2 consecutive lines of prior anti-lymphoma therapy	70 (55)
The last line of systemic antineoplastic therapy	88 (69)
Prior anti-CD20 monoclonal antibody therapy	101 (79)
Both anti-CD20 monoclonal antibody and alkylator therapy	90 (70)

 

Efficacy was established based on overall response rate (ORR) determined by Lugano criteria (2014) as assessed by Independent Review Committee (IRC). The median follow-up for DOR was 16.2 months. Efficacy results are summarised in Table 11.

 

Table 11 Efficacy Results in Study GCT3013-01 in FL Patients

 

Endpoint a   IRC assessment	Epcoritamab (N=128)
ORR b, n (%)	106 (83)
(95% CI)	(75.1, 88.9)
CRb, n (%)	81 (63)
(95% CI)	(54.3, 71.6)
PR b, n (%)	25 (20)
(95% CI)	(13.1, 27.5)
DORb
Median (95% CI), months	21.4 (13.7, NR)
DOCRb
Median (95% CI), months	NR (21.4, NR)
12-month estimate, % (95% CI)	78.6 (67.3, 86.4)
TTR, median (range), months	1.4 (1, 3)
CI = confidence interval; CR = complete response; DOR = duration of response; DOCR = duration of complete response; IRC = independent review committee; ORR = overall response rate; PFS = progression-free survival; TTR = time to response a determined by Lugano criteria (2014) as assessed by independent review committee (IRC) bIncluded patients with initial PD by Lugano or IR by LYRIC who later obtained PR/CR.

 

The median time to CR was 1.5 months (range: 1.2 to 11.1 months).

 

Paediatric population

 

The European Medicines Agency has deferred the obligation to submit the results of studies with epcoritamab in one or more subsets of the paediatric population in the treatment of mature B-cell malignancies, as per paediatric investigation plan (PIP) decision, for the granted indication (see section 4.2 for information on paediatric use).

 

 

The population pharmacokinetics following subcutaneous administration of epcoritamab was described by a two-compartment model with first order subcutaneous absorption and target-mediated drug elimination. The moderate to high pharmacokinetic variability for epcoritamab was observed and characterised by inter-individual variability (IIV) ranging from 25.7% to 137.5% coefficient of variation (CV) for epcoritamab PK parameters.

 

In patients with LBCL in study GCT3013-01, based on individually estimated exposures using population pharmacokinetic modelling, following the recommended 2-step step-up dose schedule SC dose of epcoritamab 48 mg, the geometric mean (% CV) C_max of epcoritamab is 10.8 mcg/ml (41.7%) and AUC_0-7d is 68.9 day*mcg/ml (45.1%) at the end of the weekly dosing schedule. The C_trough at Week 12 is 8.4 (53.3%) mcg/ml.The geometric mean (% CV) C_max of epcoritamab is 7.52 mcg/ml (41.1%) and AUC_0-14d is 82.6 day*mcg/ml (49.3%) at the end of q2w schedule. The C_trough for q2W schedule is 4.1 (73.9%) mcg/ml.The geometric mean (% CV) C_max of epcoritamab is 4.76 mcg/ml (51.6%) and AUC_0-28d is 74.3 day*mcg/ml (69.5%) at steady state during the q4w schedule. The C_trough for q4W schedule is 1.2 (130%) mcg/ml.

 

Exposure parameters of epcoritamab in patients with FL were consistent with the exposure parameters seen in the patients with LBCL. Epcoritamab exposures are similar between FL subjects who received the 3-step step-up dose schedule and 2-step step-up dose schedule except for transiently lower trough concentrations, as expected, at Cycle 1 Day 15 after the second intermediate dose (3 mg) with 3-step step-up dose schedule compared first full 48 mg dose with 2-step step-up dose schedule.

 

Absorption

The peak concentrations occurred around 3-4 days (T_max) in patients with LBCL receiving the 48 mg full dose.

 

Distribution

 

The geometric mean (% CV) central volume of distribution is 8.27 l (27.5%) and apparent steady-state volume of distribution is 25.6 l (81.8%) based on population PK modelling.

 

Biotransformation

 

The metabolic pathway of epcoritamab has not been directly studied. Like other protein therapeutics, epcoritamab is expected to be degraded into small peptides and amino acids via catabolic pathways.

 

Elimination

 

Epcoritamab is expected to undergo saturable target mediated clearance. The geometric mean (% CV) clearance (l/day) is 0.441 (27.8%). The half-life of epcoritamab is concentration dependent. The population PK model-derived geometric mean half-life of full dose epcoritamab (48 mg) ranged from 22 to 25 days based on frequency of dosing.

 

Special populations

 

No clinically important effects on the pharmacokinetics of epcoritamab (Cycle 1 AUC within approximately 36%) were observed based on age (20 to 89 years), sex, or race/ethnicity (white, Asian, and other), mild to moderate renal impairment creatinine clearance (CLcr ≥ 30 ml/min to CLcr < 90 ml/min), and mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 times ULN and any AST) after accounting for differences in bodyweight. No patients with severe to end-stage renal disease (CLcr < 30 ml/min) or severe hepatic impairment (total bilirubin > 3 times ULN and any AST) have been studied. There is very limited data in moderate hepatic impairment (total bilirubin > 1.5 to 3 times ULN and any AST, N=1). Therefore, the pharmacokinetics of epcoritamab is unknown in these populations.

 

Like other therapeutic proteins, body weight (39 to 172 kg) has a statistically significant effect on the pharmacokinetics of epcoritamab. Based on exposure-response analysis and clinical data, considering the exposures in patients at either low body weight (e.g., 46 kg) or high body weight (e.g., 105 kg) and across body weight categories (< 65 kg, 65-< 85, ≥ 85), the effect on exposures is not clinically relevant.

 

Paediatric population

 

The pharmacokinetics of epcoritamab in paediatric patients has not been established.

 

Animal pharmacology and/or toxicology

 

No reproductive or developmental toxicity studies in animals have been conducted with epcoritamab.

Effects generally consistent with the pharmacologic mechanism of action of epcoritamab were observed in cynomolgus monkeys. These findings included dose-related adverse clinical signs (including vomiting, decreased activity, and mortality at high doses) and cytokine release, reversible hematologic alterations, reversible B-cell depletion in peripheral blood, and reversible decreased lymphoid cellularity in secondary lymphoid tissues.

 

Mutagenicity

 

Mutagenicity studies have not been conducted with epcoritamab.

 

Carcinogenicity

 

Carcinogenicity studies have not been conducted with epcoritamab.

 

Impairment of fertility

 

Animal fertility studies have not been conducted with epcoritamab, however, epcoritamab did not cause toxicological changes in the reproductive organs of male or female cynomolgus monkeys at doses up to 1 mg/kg/week in intravenous general toxicity study of 5-week duration. The AUC exposures (time-averaged over 7 days) at the high dose in cynomolgus monkeys were similar to those in patients (AUC0-7d) receiving the recommended dose.

Sodium acetate trihydrate

Acetic acid

Sorbitol (E420)

Polysorbate 80

Water for injections

 

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products and/or diluents except those listed in section 6.6.

 

Unopened vial 2 years. Diluted or prepared epcoritamab Chemical and physical in-use stability has been demonstrated for 24 hours at 2 °C to 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. If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2 °C to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions. Minimise exposure to daylight. Allow epcoritamab solution to equilibrate to room temperature before administration. Discard unused epcoritamab solution beyond the allowable storage time.

Store and transport refrigerated (2 °C to 8 °C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

 

For storage conditions after dilution /first opening of the medicinal product, see section 6.3.

 

Type I glass vial with a bromobutyl rubber stopper coated with fluoropolymer at the contact site and aluminium seal with a plastic light blue flip off cap, containing 4 mg per 0.8 ml solution for injection.

 

Each carton contains one vial.

Epcoritamab must be prepared and administered by a healthcare provider as a subcutaneous injection.

Each vial of epcoritamab is intended for single use only.

 

Each vial contains an overfill that allows withdrawal of the labelled amount.

 

The administration of epcoritamab takes place over the course of 28-day cycles, following the dosing schedule in section 4.2.

 

Epcoritamab should be inspected visually for particulate matter and discolouration prior to administration. The solution for injection should be a colourless to slightly yellow solution. Do not use if the solution is discoloured, or cloudy, or if foreign particles are present.

 

Preparation of epcoritamab

Epcoritamab has to be prepared using aseptic technique. Filtration of the diluted solution is not required.

 

0.16 mg priming dose preparation instructions – 2 dilutions required

Use an appropriately sized, syringe, vial, and needle for each transfer step.

 

1)   Prepare epcoritamab vial a)      Retrieve one 4 mg/0.8 ml epcoritamab vial with the light blue cap from the refrigerator. b)     Allow the vial to come to room temperature for no more than 1 hour. c)      Gently swirl the epcoritamab vial. DO NOT vortex or vigorously shake the vial.

2)   Perform first dilution a)      Label an appropriately sized empty vial as “dilution A”. b)     Transfer 0.8 ml of epcoritamab into the dilution A vial. c)      Transfer 4.2 ml of sodium chloride 9 mg/ml (0.9%) sterile solution into the dilution A vial. The initial diluted solution contains 0.8 mg/ml of epcoritamab. d)     Gently swirl the dilution A vial for 30 – 45 seconds.

3)  Perform second dilution a)      Label an appropriately sized empty vial as “dilution B”. b)     Transfer 2 ml of solution from the dilution A vial into the dilution B vial. The dilution A vial is no longer needed and should be discarded. c)      Transfer 8 ml of sodium chloride 9 mg/ml (0.9%) sterile solution into the dilution B vial to make a final concentration of 0.16 mg/ml. d)     Gently swirl the dilution B vial for 30 – 45 seconds.

4)  Withdraw dose Withdraw 1 ml of the diluted epcoritamab from the dilution B vial into a syringe. The dilution B vial is no longer needed and should be discarded.

5)  Label syringe Label the syringe with the product name, dose strength (0.16 mg), date and the time of day. For storage of the diluted epcoritamab, see section 6.3.

6)    Discard the vial and any unused portion of epcoritamab in accordance with local requirements.

 

0.8 mg intermediate dose preparation instructions – 1 dilution required

Use an appropriately sized syringe, vial and needle for each transfer step.

 

1)   Prepare epcoritamab vial a)      Retrieve one 4 mg/0.8 ml epcoritamab vial with the light blue cap from the refrigerator. b)     Allow the vial to come to room temperature for no more than 1 hour. c)      Gently swirl the epcoritamab vial. DO NOT vortex or vigorously shake the vial.

2)   Perform dilution a)      Label an appropriately sized empty vial as “dilution A”. b)     Transfer 0.8 ml of epcoritamab into the dilution A vial. c)      Transfer 4.2 ml of sodium chloride 9 mg/ml (0.9%) sterile solution into the dilution A vial to make a final concentration of 0.8 mg/ml. d)     Gently swirl the dilution A vial for 30 – 45 seconds.

3)   Withdraw dose Withdraw 1 ml of the diluted epcoritamab from the dilution A vial into a syringe. The dilution A vial is no longer needed and should be discarded.

4)   Label syringe Label the syringe with the product name, dose strength (0.8 mg), date and the time of day. For storage of the diluted epcoritamab, see section 6.3.

5)    Discard the vial and any unused portion of epcoritamab in accordance with local requirements.

 

3 mg second intermediate dose preparation instructions- No dilution required

Epcoritamab 3 mg dose is required for FL patients only (see Section 4.2).

 

1) Prepare epcoritamab vial a) Retrieve one 4 mg/0.8 ml epcoritamab vial with the light blue cap from the refrigerator. b) Allow the vial to come to room temperature for no more than 1 hour. c) Gently swirl the epcoritamab vial. DO NOT vortex, or vigorously shake the vial.

2) Withdraw dose Withdraw 0.6 ml of epcoritamab into a syringe.

3) Label syringe Label the syringe with the product name, dose strength (3 mg), date and the time of day. For storage of the prepared epcoritamab, see section 6.3.

4) Discard the vial and any unused portion of epcoritamab in accordance with local requirements.

 

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.