Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The safety of epcoritamab was evaluated in a non-randomised, single-arm study in 167 patients with relapsed or refractory LBCL 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 3.7 months (range: 0 to 25 months).

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

Serious adverse reactions occurred in 52% of patients. The most frequent serious adverse reaction (≥ 10%) was cytokine release syndrome (31%). Seven patients (4.2%) experienced a fatal adverse reaction (pneumonia in 3 (1.8%) patients, viral infection in 3 (1.8%) patients, and ICANS in 1 (0.6%) patient).

Adverse reactions that led to discontinuation occurred in 6.6% of patients. Discontinuation of epcoritamab due to pneumonia occurred in 6 (3.6%) patients, viral infection in 3 (1.8%) patients, and CRS, ICANS, or fatigue in 1 (0.6%) patient each.

Dose delays due to adverse reactions occurred in 32% of patients. Adverse reactions leading to dose delays (≥ 3%) were viral infections (9.6%), CRS (7.2%), neutropenia (4.8%), pyrexia (3.0%), and thrombocytopenia (3.0%).


Tabulated list of adverse reactions
Adverse reactions for epcoritamab from clinical studies (Table 6) 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 6 Adverse reactions reported in patients with relapsed or refractory LBCL treated with epcoritamab in GCT3013-01 study
System organ class / preferred             All grades                       Grade 3-4 term or adverse reaction

Infections and infestations
Viral infectiona                   Very common                   Common Pneumoniab                         Very common                   Common Upper respiratory tract infectionc Common                        Common d
Fungal infections                  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 g
Anaemia                            Very common                   Very common Thrombocytopeniah                  Very common                   Common i
Lymphopenia                        Common                        Common Febrile neutropenia                Common                        Common Immune system disorders
Cytokine release syndromej         Very common                   Common Metabolism and nutrition disorders
Decreased appetite                 Very common                   Uncommon Hypophosphatemia                   Common                        Common Hypokalemia                        Common                        Uncommon Hypomagnesemia                     Common
Tumour lysis syndromek             Common                        Common Nervous system disorders
Headache                           Very common                   Uncommon Immune effector cell-associated Common neurotoxicity syndromej
Cardiac disorders
Cardiac arrhythmiasl               Very common                   Common 

Respiratory, thoracic and mediastinal disorders
Pleural effusion                      Common                               Common Gastrointestinal disorders
Abdominal painm                       Very common                          Common Nausea                                Very common                          Common Diarrhoea                             Very common
Vomiting                              Very common                          Uncommon Skin and subcutaneous tissue disorders
Rashn                                 Common
Pruritus                              Common
Musculoskeletal and connective tissue disorders
Musculoskeletal paino                 Very common                          Common General disorders and administration site conditions
Fatiguep                              Very common                          Common q
Injection site reactions              Very common
Pyrexiar                              Very common                          Uncommon s
Oedema                                Very common                          Common Investigations
Alanine aminotransferase              Common                               Uncommon increased
Aspartate aminotransferase            Common                               Common increased
Blood creatinine increased            Common t
Blood sodium decreased                Common                               Uncommon Alkaline phosphatase increased        Common
Adverse reactions were graded using NCI CTCAE version 5.0 a
Viral infection includes asymptomatic COVID-19, COVID-19, cytomegalovirus infection, cytomegalovirus infection reactivation, gastroenteritis viral, herpes simplex, herpes zoster, and oral herpes 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, and oral 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
CRS and ICANS adverse reactions were graded based on American Society for Transplantation and Cellular Therapy (ASTCT) criteria k
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 maculo-papular, and rash pustular 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
Fatigue includes asthenia, fatigue, and lethargy
q
Injection site reactions include injection site bruising, injection site erythema, injection site hypertrophy, injection site inflammation, injection site mass, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling, and injection site urticaria.
r
Pyrexia includes body temperature increased and pyrexia s
Oedema includes face oedema, generalised oedema, oedema, oedema peripheral, and peripheral swelling t
Blood sodium decreased includes blood sodium decreased and hyponatraemia 
Description of selected adverse reactions
Cytokine release syndrome

CRS of any grade occurred in 51% (85/167) of patients treated with epcoritamab. The incidence of Grade 1 was 31%, Grade 2 was 17%, and Grade 3 occurred in 3.0% of patients. Recurrent CRS occurred in 17% of patients. CRS of any grade occurred in 6.6% of patients after the priming dose (Cycle 1 Day 1); 13% after the intermediate dose (Cycle 1, Day 8); 44% after the first full dose (Cycle 1, Day 15), 4.6% after the second full dose (Cycle 1 Day 22) and 2.8% 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 11 days). The median time to onset after the first full dose was 20.2 hours (range: 0.2 to 7 days). CRS resolved in 100% of patients, and the median duration of CRS events was 2 days (range 0.1 to 27 days).

Of the 85 patients that experienced CRS, the most common signs and symptoms of CRS included pyrexia 99%, hypotension 31% and hypoxia 19%. Other signs and symptoms of CRS in greater than two patients included chills (11%), tachycardia (including sinus tachycardia (9%)), dyspnoea (3.5%), and headache (3.5%). Transient elevated liver enzymes (ALT or AST > 3xULN) were concurrent with CRS in 2.4% of patients with CRS. See section 4.2 and 4.4 for monitoring and management guidance.

Immune effector cell-associated neurotoxicity syndrome

ICANS occurred in 6.0% of patients treated with epcoritamab; 4.2% experienced Grade 1 and 1.2% experienced Grade 2. One patient (0.6%) 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 16.5 days (range: 8 to 141 days). ICANS resolved in 90% (9/10) of patients with supportive care. The median time to resolution of ICANS was 5 days (range: 1 to 9 days). In the 10 patients with ICANS, the onset of ICANS was prior to CRS in 20% of patients, concurrent with CRS in 40%, following onset of CRS in 10%, and in the absence of CRS in 30%.

Serious infections

Serious infections of any grade occurred in 25% of patients 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.

Neutropenia
Neutropenia of any grade occurred in 31% of patients, including 23% Grade 3-4 events. The median time to onset of first neutropenia/neutrophil count decreased event was 65 days (range: 1 to 750 days), with median duration of 15 days (range: 2 to 155 days). Of the 51 patients who had neutropenia/neutrophil count decreased events, 51% received G-CSF to treat the events.
Tumour lysis syndrome
TLS occurred in 1.8% of patients. There was one patient who experienced onset on Day 14 with resolution on Day 17. Two additional patients experienced onset on Day 8 and Day 33 and both events were ongoing at the time of death; the deaths were due to disease progression.

Tumour flare
Tumour flare occurred in 3.0% of patients, all of which were grade 2. The median time to onset was 17 days (range 9 to 34 days), and median duration was 15.5 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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form:
 https://sideeffects.health.gov.il