Glofitamab

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

The safety of immunisation with live vaccines during or following glofitamab therapy has not been studied. Immunisation with live vaccines is not recommended during glofitamab therapy.

The initial release of cytokines associated with the start of glofitamab treatment could suppress CYP450 enzymes and lead to fluctuations in concentrations of concomitantly administered drugs. On initiation of glofitamab therapy, patients being treated with CYP450 substrates with a narrow therapeutic index should be monitored as fluctuations in the concentration of concomitant drugs may lead to toxicity, loss of effect or adverse events. The highest drug-drug interaction risk is during the period of one week following each of the first 2 doses of glofitamab (i.e., Cycle 1 Day 8 and 15) in patients who are receiving concomitant CYP450 substrates with a narrow therapeutic index (e.g., warfarin, cyclosporine).

Glofitamab has not been studied in patients with severe renal impairment.

Glofitamab has not been studied in patients with moderate or severe hepatic impairment.

Caution should be exercised when considering the use of glofitamab in patients with a history of chronic or recurrent infection, those with underlying conditions that may predispose them to infections, or those who have had significant prior immunosuppressive treatment. Patients should be monitored before and during glofitamab treatment for the emergence of possible bacterial, fungal, and new or reactivated viral infections and treated appropriately.

There are no data on the use of glofitamab in pregnant women. No reproductive toxicity studies have been performed in animals.

Glofitamab is an immunoglobulin G (IgG). IgG is known to cross the placenta. Based on its mechanism of action, glofitamab is likely to cause foetal B-cell depletion when administered to a pregnant woman.

Glofitamab is not recommended during pregnancy and in women of childbearing potential not using contraception. Female patients receiving glofitamab should be advised of the potential harm to the foetus. Female patients should be advised to contact the treating physician, should pregnancy occur.

It is not known whether glofitamab is excreted in human milk. No studies have been conducted to assess the impact of glofitamab on milk production or its presence in breast milk. Human IgG is known to be present in human milk. The potential for absorption of glofitamab and the potential for adverse reactions in the breast-feeding child is unknown. Women should be advised to discontinue breast-feeding during treatment with glofitamab and for 2 months after the final dose of glofitamab.

Women of childbearing potential/Contraception

Female patients of childbearing potential must use highly effective contraceptive methods during treatment with glofitamab and for at least 2 months following the last dose of glofitamab.

Fertility

No human data on fertility are available. No fertility assessments in animals have been performed to evaluate the effect of glofitamab on fertility.

Glofitamab has major influence on the ability to drive and use machines.

Due to the potential for ICANS, patients receiving glofitamab are at risk of depressed level of consciousness. Patients should be instructed to avoid driving or operating machines for 48 hours after each of the first two doses during the step-up dosing and in the event of new onset of any symptoms of ICANS (confusion, disorientation, depressed level of consciousness) and/or CRS (pyrexia, tachycardia, hypotension, chills, hypoxia) until symptoms resolve.

Summary of the safety profile

Glofitamab monotherapy

The most common adverse reactions (≥20%) were cytokine release syndrome, neutropenia, anaemia, thrombocytopenia, and rash.

The most common serious adverse reactions reported in ≥2% of patients were cytokine release syndrome (22.1%), sepsis (4.1%), COVID-19 (3.4%), tumour flare (3.4%), COVID-19 pneumonia (2.8%), febrile neutropenia (2.1%), neutropenia (2.1%), and pleural effusion (2.1%).

Permanent discontinuation of glofitamab due to an adverse reaction occurred in 5.5% of patients. The most common adverse reactions leading to permanent discontinuation of glofitamab were COVID-19 (1.4%) and neutropenia (1.4%).

Glofitamab in combination with gemcitabine and oxaliplatin

The most common adverse reactions (≥20%) were thrombocytopenia, cytokine release syndrome, neutropenia, anaemia, nausea, peripheral neuropathy, diarrhoea, aspartate aminotransferase increased, alanine aminotransferase increased, rash, lymphopenia, pyrexia, and vomiting.

The most common serious adverse reactions reported in ≥2% of patients were cytokine release syndrome (20.3%), pyrexia (6.4%), pneumonia (5.8%), COVID-19 (5.8%), thrombocytopenia (4.7%), respiratory tract infection (3.5%), sepsis (2.3%), febrile neutropenia (2.3%), and diarrhoea (2.3%).

Permanent discontinuation of glofitamab due to an adverse reaction occurred in 20.9% of patients. The most common adverse reactions leading to permanent discontinuation of glofitamab were COVID-19 (11.6%), sepsis (1.2%), and pneumonitis (1.2%).

Tabulated list of adverse reactions

Adverse reactions occurring in relapsed or refractory DLBCL patients treated with glofitamab monotherapy (n=145) in study NP30179 are listed in Table 1. Patients received a median of 5 cycles of glofitamab treatment (range: 1 to 13 cycles).

Adverse reactions occurring in relapsed or refractory DLBCL patients treated with glofitamab in combination with gemcitabine and oxaliplatin (n=172) in study GO41944 (STARGLO) are listed in Table 2. Patients received a median of 11 cycles of glofitamab treatment (range: 1 to 13 cycles).

The adverse reactions are listed by MedDRA system organ class and categories of frequency. The following categories of frequency have been used: 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), very rare (<1/10 000). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 1. Adverse reactions reported in patients with relapsed or refractory DLBCL treated with glofitamab monotherapy:

^* Grade 5 reactions reported. See Description of selected adverse reactions.
^** No Grade 3-4 events were reported.
¹ Includes COVID-19, COVID-19 pneumonia, herpes zoster, influenza, and ophthalmic herpes zoster.
² Includes vascular device infection, bacterial infection, Campylobacter infection, biliary tract infection bacterial, urinary tract infection bacterial, Clostridium difficile infection, Escherichia infection, and peritonitis.
³ Includes upper respiratory tract infection, sinusitis, nasopharyngitis, chronic sinusitis, and rhinitis.
⁴ Includes sepsis and septic shock.
⁵ Includes lower respiratory tract infection and bronchitis.
⁶ Includes urinary tract infection and Escherichia urinary tract infection.
⁷ Includes oesophageal candidiasis and oral candidiasis.
⁸ Includes febrile neutropenia and neutropenic infection.
⁹ Based on ASTCT consensus grading (Lee 2019).
¹⁰ ICANS based on Lee 2019 and includes somnolence, cognitive disorder, confusional state, delirium, and disorientation.
¹¹ Myelitis occurred concurrently with CRS.
¹² Includes gastrointestinal haemorrhage, large intestinal haemorrhage, and gastric haemorrhage.
¹³ Includes rash, rash pruritic, rash maculo-papular, dermatitis, dermatitis acneiform, dermatitis exfoliative, erythema, palmar erythema, pruritis, and rash erythematous.

Table 2. Adverse reactions reported in patients with relapsed or refractory DLBCL treated with glofitamab in combination with gemcitabine and oxaliplatin:

^* Grade 5 reactions reported. See Description of selected adverse reactions.
^** No Grade 3-4 events were reported.
¹ Includes COVID-19, COVID-19 pneumonia, and SARS-CoV-2 test positive.
² Includes upper respiratory tract infection, lower respiratory tract infection, respiratory tract infection, and respiratory tract infection bacterial.
³ Includes pneumonia, pneumonia bacterial, and pneumonia pneumococcal.
⁴ New onset or reactivation. Includes cytomegalovirus infection, cytomegalovirus test positive, cytomegalovirus infection reactivation and cytomegalovirus viraemia.
⁵ New onset or reactivation. Includes herpes zoster and herpes virus infection.
⁶ Includes urinary tract infection and urosepsis.
⁷ Includes sepsis, streptococcal sepsis, septic shock, and enterococcal sepsis.
⁸ Includes oral candidiasis and candida infection.
⁹ Includes tumour flare and tumour pain.
¹⁰ Based on ASTCT consensus grading (Lee 2019).
¹¹ Includes neuropathy peripheral, peripheral sensory neuropathy, dysaesthesia, paraesthesia, hypoaesthesia, peripheral motor neuropathy, and polyneuropathy.
¹² Includes confusional state, delirium, and ICANS.
¹³ Includes abdominal pain, abdominal discomfort, abdominal pain upper, abdominal pain lower, and gastrointestinal pain.
¹⁴ Includes colitis, colitis ischaemic, and enterocolitis.
¹⁵ Includes pancreatitis and pancreatitis acute.
¹⁶ Includes rash, rash pruritic, rash maculo-papular, erythema, pruritus, rash erythematous, urticaria, and erythema multiforme.
¹⁷ Includes arthralgia, musculoskeletal pain, back pain, bone pain, myalgia, neck pain, pain in extremity, musculoskeletal chest pain, and non-cardiac chest pain.
¹⁸ Includes blood bilirubin increased and hyperbilirubinaemia.

Description of selected adverse reactions

The descriptions below reflect information for significant adverse reactions for glofitamab monotherapy and/or combination therapy. Details for the significant adverse reactions for glofitamab when given in combination are presented separately if clinically relevant differences were noted in comparison to glofitamab monotherapy.

Cytokine release syndrome

Glofitamab monotherapy

Any grade CRS (by ASTCT criteria) occurred in 67.6% of patients who received glofitamab monotherapy, with Grade 1 CRS reported in 50.3% of patients, Grade 2 CRS in 13.1% of patients, Grade 3 CRS in 2.8% of patients and Grade 4 CRS in 1.4% of patients. CRS occurred more than once in 32.4% (47/145) of patients; 36/47 patients experienced multiple Grade 1 CRS events only. There were no fatal cases of CRS. CRS resolved in all patients except one. One patient discontinued treatment due to CRS.

In patients with CRS, the most common manifestations of CRS included pyrexia (99.0%), tachycardia (25.5%), hypotension (23.5%), chills (14.3%) and hypoxia (12.2%). Grade 3 or higher events associated with CRS included hypotension (3.1%), hypoxia (3.1%), pyrexia (2.0%) and tachycardia (2.0%).

CRS of any grade occurred in 54.5% of patients following the first 2.5 mg dose of glofitamab at Cycle 1 Day 8 with median time to onset (from start of infusion) of 12.6 hours (range: 5.2 to 50.8 hours) and median duration of 31.8 hours (range: 0.5 to 316.7 hours); in 33.3% of patients following the 10 mg dose at Cycle 1 Day 15 with median time to onset of 26.8 hours (range: 6.7 to 125.0 hours) and median duration of 16.5 hours (range: 0.3 to 109.2 hours); and in 26.8% of patients following the 30 mg dose at Cycle 2 with median time to onset of 28.2 hours (range: 15.0 to 44.2 hours) and median duration of 18.9 hours (range: 1.0 to 180.5 hours). CRS was reported in 0.9% of patients at Cycle 3 and in 2% of patients beyond Cycle 3.

Grade ≥ 2 CRS occurred in 12.4% of patients following the first glofitamab dose (2.5 mg) with median time to onset of 9.7 hours (range: 5.2 to 19.1 hours) and median duration of 50.4 hours (range: 6.5 to 316.7 hours). Following glofitamab 10 mg dose at Cycle 1 Day 15, the incidence of Grade ≥2 CRS decreased to 5.2% of patients with median time to onset of 26.2 hours (range: 6.7 to 144.2 hours) and median duration of 30.9 hours (range: 3.7 to 227.2 hours). Grade ≥2 CRS following glofitamab 30 mg dose at Cycle 2 Day 1 occurred in one patient (0.8%) with time to onset of 15.0 hours and duration of 44.8 hours. No Grade ≥2 CRS was reported beyond Cycle 2.

In 145 patients, 7 patients (4.8%) experienced elevated liver function tests (AST and ALT >3 × ULN and/or total bilirubin >2 × ULN) reported concurrently with CRS (n=6) or with disease progression (n=1).

Among the 25 patients who experienced Grade ≥2 CRS after glofitamab, 22 (88.0%) received tocilizumab, 15 (60.0%) received corticosteroids and 14 (56.0%) received both tocilizumab and corticosteroids. Ten patients (40.0%) received oxygen. All 6 patients (24.0%) with Grade 3 or 4 CRS received a single vasopressor.

Hospitalisations due to patients experiencing CRS following glofitamab administration occurred in 22.1% of patients and the reported median duration of hospitalisation was 4 days (range: 2 to 15 days).

Glofitamab in combination with gemcitabine and oxaliplatin

Any grade CRS (by ASTCT criteria) occurred in 44.2% of patients who received glofitamab with gemcitabine and oxaliplatin, with Grade 1 CRS reported in 31.4% of patients, Grade 2 CRS in 10.5% of patients, and Grade 3 CRS in 2.3% of patients. CRS occurred more than once in 21.5% (37/172) of patients; 30/37 patients experienced multiple Grade 1 CRS events only. There were no Grade 4 or fatal cases of CRS. CRS resolved in all patients except one. One patient discontinued treatment due to CRS.

In patients with CRS, the most common manifestations of CRS included pyrexia (98.7%), hypotension (22.4%), chills (17.1%) and hypoxia (14.5%). Grade 3 or higher events associated with CRS included hypotension (6.6%), hypoxia (5.3%), pyrexia (3.9%), chills (1.3%) and diarrhoea (1.3%).

CRS of any grade occurred in 34.9% of patients following the first 2.5 mg dose of glofitamab at Cycle 1 Day 8 with median time to onset (from start of infusion) of 12.6 hours (range: 4.4 to 54.7 hours) and median duration of 19.8 hours (range: 2.0 to 168.0 hours); in 14.4% of patients following the 10 mg dose at Cycle 1 Day 15 with median time to onset of 22.8 hours (range: 7.4 to 81.2 hours) and median duration of 10.6 hours (range: 1.0 to 248.5 hours); and in 9.3% of patients following the 30 mg dose at Cycle 2 with median time to onset of 23.5 hours (range: 14.7 to 33.4 hours) and median duration of 18.4 hours (range: 8.3 to 137.0 hours). CRS was reported in 6.7% of patients at Cycle 3 and in 11.0% of patients beyond Cycle 3.

Grade ≥2 CRS occurred in 10.5% of patients following the first glofitamab dose (2.5 mg) with median time to onset of 12.0 hours (range: 4.4 to 30.5 hours) and median duration of 42.3 hours (range: 3.5 to 143.7 hours). The majority (14/18) of patients who experienced Grade ≥2 CRS had onset of CRS within 8 hours of the start of the first glofitamab dose (2.5 mg). Following glofitamab 10 mg dose at Cycle 1 Day 15, the incidence of Grade ≥2 CRS decreased to 1.8% of patients with median time to onset of 22.3 hours (range: 7.4 to 22.8 hours) and median duration of 37.0 hours (range: 34.8 to 248.5 hours). There were no Grade ≥2 CRS events following glofitamab 30 mg dose at Cycle 2 Day 1. Three patients (2.0%) had Grade ≥2 CRS beyond Cycle 2 (all Grade 2 events).

Of the 172 patients, 2 patients (1.2%) experienced elevated liver function tests (AST and ALT >3 × ULN) reported concurrently with CRS.

Out of the 76 patients with any grade CRS, 28 patients (36.8%) were treated with tocilizumab, 39 patients (51.3%) were treated with corticosteroids, and 18 patients (23.7%) received both tocilizumab and corticosteroids.

Among the 22 patients who experienced Grade ≥2 CRS after glofitamab, 16 (72.7%) received tocilizumab, 15 (68.2%) received corticosteroids, and 12 (54.5%) received both tocilizumab and corticosteroids. Eleven patients (50.0%) received oxygen. All 4 patients (18.2%) with Grade 3 CRS received a single vasopressor.

Hospitalisations due to patients experiencing CRS following glofitamab administration occurred in 19.8% of patients and the reported median duration of hospitalisation was 5 days (range: 2 to 85 days).

Immune effector cell-associated neurotoxicity syndrome

ICANS, including Grade 3 and higher, was reported in clinical trials and with post-marketing experience. The most frequent clinical manifestations of ICANS were confusion, depressed level of consciousness, disorientation, seizure, aphasia, and dysgraphia. Based on the available data, the onset of neurologic toxicity was concurrent with CRS in the majority of cases.

The observed time to onset of the majority of ICANS was 1-7 days with median of 2 days after the most recent dose. Only few events were reported to have occurred more than one month after the initiation of glofitamab.

Serious infections

Serious infections were reported in 15.9% of patients who received glofitamab monotherapy. The most frequent serious infections reported in ≥2% of patients were sepsis (4.1%), COVID-19 (3.4%), and COVID-19 pneumonia (2.8%). Infection-related deaths were reported in 4.8% of patients (due to sepsis, COVID-19 pneumonia and COVID-19). Four patients (2.8%) experienced serious infections concurrently with Grade 3 or 4 neutropenia.

Serious infections were reported in 22.7% of patients who received glofitamab with gemcitabine and oxaliplatin. The most frequent serious infections reported in ≥2% of patients were pneumonia (5.8%), COVID-19 (4.7%), and lower respiratory tract infection (2.9%). Infection-related deaths were reported in 3.5% of patients (due to COVID-19, pneumonia, respiratory tract infection, and septic shock). One patient (0.6%) experienced a serious infection (pneumonia) concurrently with Grade 3 neutropenia.

Pneumonitis

Pneumonitis events (excluding pneumonia of infectious aetiology) were reported in 2 patients (1.2%) who received glofitamab with gemcitabine and oxaliplatin, both of which were fatal events. The median time to onset of pneumonitis from the first glofitamab dose was 168 days (range: 102 to 255 days).

Colitis

Colitis events (excluding infectious aetiology) were reported in 4/172 patients (2.3%) who received glofitamab with gemcitabine and oxaliplatin. Two patients (1.2%) had Grade 3 events. The median time to onset of colitis from the first glofitamab dose was 154 days (range: 115 to 187 days).

Opportunistic infections

Cytomegalovirus (CMV) events were reported in 10 patients (5.8%) who received glofitamab with gemcitabine and oxaliplatin, with 1 patient (0.6%) experiencing Grade 3 CMV viraemia. Oral candidiasis was reported in 3 patients (1.7%) all of which were Grade 1-2 events. Pneumocystis jirovecii pneumonia (Grade 3) was reported in 1 patient (0.6%), the same patient with Grade 3 CMV viraemia. Borellia meningitis (Grade 2) was reported in 1 patient (0.6%).

Neutropenia

Neutropenia (including neutrophil count decreased) was reported in 40.0% of patients and severe neutropenia (Grade 3 or 4) was reported in 29.0% of patients who received glofitamab monotherapy. The median time to onset of the first neutropenia event was 29 days (range: 1 to 203 days). Prolonged neutropenia (lasting longer than 30 days) occurred in 11.7% of patients. The majority of patients with neutropenia (79.3%) were treated with G-CSF. Febrile neutropenia was reported in 3.4% of patients.

Tumour flare

Tumour flare was reported in 11.7% of patients who received glofitamab monotherapy, including Grade 2 tumour flare in 4.8% of patients and Grade 3 tumour flare in 2.8% of patients. Tumour flare was reported involving lymph nodes in the head and neck presenting with pain and involving lymph nodes in the thorax with symptoms of breathlessness due to development of pleural effusion. Most tumour flare events (16/17) occurred during Cycle 1, and no tumour flare events were reported beyond Cycle 2. The median time to onset of tumour flare of any grade was 2 days (range: 1 to 16 days), and the median duration was 3.5 days (range: 1 to 35 days).

Among the 11 patients who experienced Grade ≥2 tumour flare, 2 patients (18.2%) received analgesics, 6 patients (54.5%) received corticosteroids and analgesics including morphine derivatives, 1 patient (9.1%) received corticosteroids and anti-emetics, and 2 patients (18.2%) did not require treatment. All tumour flare events resolved except in one patient with a Grade ≥2 event. No patients discontinued treatment due to tumour flare.

Tumour lysis syndrome

TLS was reported in 2 patients (1.4%) who received glofitamab monotherapy and was Grade 3 in severity in both cases. The median time to onset of TLS onset was 2 days, and the median duration was 4 days (range: 3 to 5 days).